bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ligand-induced shifts in conformational ensembles that predict transcriptional activation
Authors: Khan Sabab Hasan , Braet Sean M , Koehler Stephen John , Elacqua Elizabeth , Anand Ganesh S , Okafor C. Denise 
Published: May 2022

AbstractNuclear receptors function as ligand-regulated transcription factors whose ability to regulate diverse physiological processes is closely linked with conformational changes induced upon ligand binding. Understanding how conformational populations of nuclear receptors are shifted by various ligands could illuminate strategies for the design of synthetic modulators to regulate specific transcriptional programs. Here, we investigate ligand-induced conformational changes using a reconstructed, ancestral nuclear receptor. By making substitutions at a key position, we engineer receptor variants with altered ligand specificities. We use atomistic molecular dynamics (MD) simulations with enhanced sampling to generate ensembles of wildtype and engineered receptors in combination with multiple ligands, followed by conformational analysis and prediction of ligand activity. We combine cellular and biophysical experiments to allow correlation of MD-based predictions with functional ligand profiles, as well as elucidation of mechanisms underlying altered transcription in receptor variants. We determine that conformational ensembles accurately predict ligand responses based on observed population shifts, even within engineered receptors that were constitutively active or transcriptionally unresponsive in experiments. These studies provide a platform which will allow structural characterization of physiologically-relevant conformational ensembles, as well as provide the ability to design and predict transcriptional responses in novel ligands.
Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in a mice acute-on-chronic liver failure model
Authors: Chen Feng , Che Zhaodi , Liu Yingxia , Luo Pingping , Xiao Lu , Song Yali , Wang Cunchuan , Dong Zhiyong , Li Mianhuan , Tipoe George L. , Wu Dongqing , Yang Min , Lv Yi , Wang Fei , Wang Hua , Xiao Jia 
Published: May 2022

ABSTRACTBoosting stem cell resilience against an extrinsically harsh recipient environment is critical to therapeutic efficiency of stem cell-based transplantation innovations in liver disease contexts. We aimed to establish the efficacy of a transient plasmid-based preconditioning strategy to boost mesenchymal stromal cells (MSCs) capacity for anti-inflammation/antioxidant defense and paracrine actions on recipient hepatocytes. In MSCs, the master antioxidant regulator Nrf2 was found to bind directly to the antioxidant response element in the DKK1 promoter region. Activation of Nrf2 and DKK1 enhanced the anti-stress capacities of MSCs in vitro. In an acute-on-chronic liver failure (ACLF) murine model, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection markedly improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy and promoted recipient liver regeneration because of a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Moreover, specific ablation of DKK1 receptor CKAP4 but not LRP6 in recipient hepatocytes nullified therapeutic benefits from MSC transplantation. In long-term observations, tumorigenicity was undetected in mice following transplantation of such transiently preconditioned MCSs. In conclusion, co-stimulation of Nrf2/DKK1 signaling decisively and safely improves the efficacy of human MSC-based therapies in mouse ACLF models through apparently CKAP4-dependent paracrine mechanisms.
Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-oxidation: A Molecular Dynamic Simulation Study
Authors: Maghsoodi Fahimeh , Martin Tye D. , Chi Eva Y. 
Published: May 2022

AbstractSelective photosensitized oxidation of amyloid protein aggregates is being investigated as a possible therapeutic strategy for treating Alzheimer’s disease (AD). Photo-oxidation has been shown to lead to the degradation of amyloid-β (Aβ) aggregates, ameliorate aggregate toxicity and reduce aggregate levels in the brains of AD animal models. To shed light on the mechanism by which photo-oxidation induces fibril destabilization, we carried out an all-atom molecular dynamics (MD) simulation to examine the effect of methionine (Met35) oxidation on the conformation and stability of a highly β-sheet-rich Aβ9-40protofibril composed of 12 monomers. Analyses of up to 1 μs MD simulations showed that the oxidation of the Met35 residues reduced the overall conformational stability of the protofibril. Specifically, Met35 oxidation that resulted in the addition of hydrophilic oxygens disrupted the hydrophobic interface that stabilizes the stacking of the two hexamers that composed the protofibril. The oxidized protofibril is more solvent exposed, less compact, and exhibits more backbone flexibility. However, it retained the underlying U-shaped architecture of each peptide. Although some loss of β-sheets occurred, a significant portion (~76%) remained. twisting of the peptides along the protofibril axis was observed, and the hexamers remained. Our simulation results are thus consistent with our experimental observation that photo-oxidation of Aβ40 fibrils results in the dis-agglomeration and fragmentation of Aβ fibrils, but did not cause complete disruption of the fibrillar morphology or β-sheet structures. The partial destabilization of Aβ aggregates supports the further development of photosensitized platforms for the selective targeting and clearance of Aβ aggregates as a therapeutic strategy for treating AD.
scReadSim: a single-cell RNA-seq and ATAC-seq read simulator
Authors: Yan Guanao , Song Dongyuan , Li Jingyi Jessica 
Published: May 2022

AbstractBenchmarking single-cell RNA-seq (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) computational tools demands simulators to generate realistic sequencing reads. However, none of the few read simulators aim to mimic real data. To fill this gap, we introduce scReadSim, a single-cell RNA-seq and ATAC-seq read simulator that allows user-specified ground truths and generates synthetic sequencing reads (in FASTQ and BAM formats) by mimicking real data. At both read-sequence and read-count levels, scReadSim mimics real scRNA-seq and scATAC-seq data. Moreover, scReadSim provides ground truths, including unique molecular identifier counts for scRNA-seq and open chromatin regions for scATAC-seq. In particular, scReadSim allows users to design cell-type-specific ground-truth open chromatin regions for scATAC-seq data generation. In benchmark applications of scReadSim, we show that cell-ranger is a preferred scRNA-seq UMI deduplication tool, and HMMRATAC and MACS3 achieve top performance in scATAC-seq peak calling.
Pattern of frustration formation in the functional brain network
Authors: Saberi Majid , Khosrowabadi Reza , Khatibi Ali , Misic Bratislav , Jafari Gholamreza 
Published: May 2022

AbstractThe brain is a frustrated system that contains conflictual link arrangements named frustration. The frustration as a source of disorder prevents the system from settling into low energy states and provides flexibility for brain network organization. In this research, we tried to identify the pattern of frustration formation in the brain at the levels of region, connection, canonical network, and hemisphere. We found that frustration formation has not a uniform pattern. Some subcortical elements have an active role in frustration formation, despite many low contributed cortical elements. Frustrating connections are mostly between-network types and triadic frustrations are mainly formed between three regions from three distinct canonical networks. Although there were no significant differences between brain hemispheres. We also did not find any robust differences between the frustration formation patterns of various lifespan stages. Our results may be interesting for those who study the organization of brain links and promising for those who want to manipulate brain networks.
Suction feeding of West African lungfish (Protopterus annectens): An XROMM analysis of jaw mechanics, cranial kinesis, and hyoid mobility
Authors: Gartner Samantha M. , Whitlow Katrina R. , Laurence-Chasen J.D. , Kaczmarek Elska B. , Granatosky Michael C. , Ross Callum F. , Westneat Mark W. 
Published: May 2022

AbstractSuction feeding in fishes is characterized by rapid cranial movements, but extant lungfishes (Sarcopterygii: Dipnoi) exhibit a reduced number and mobility of cranial bones relative to actinopterygian fishes. Despite fusion of cranial elements, lungfishes are proficient at suction feeding, though the impacts of novel cranial morphology and reduced cranial kinesis on feeding remain poorly understood. We used X-ray Reconstruction of Moving Morphology (XROMM) to study the kinematics of seven mobile skeletal elements (neurocranium, upper jaw, lower jaw, tongue, ceratohyal, clavicle, and cranial rib) and two muscles (costoclavicular portion of the hypaxialis and rectus cervicis) during the feeding strikes of West African lungfish (Protopterus annectens). We found that feeding byP. annectenson non-evasive prey is relatively slow, with a mean time to peak gape of 273 ms. Lower jaw depression and clavicular rotation were hingelike, with one degree of freedom, but the ceratohyals rotated in a complex motion involving depression and long-axis rotation. We quantified the relative contributions to oral cavity volume change (RCVC) and found that oral cavity expansion is created primarily by ceratohyal and clavicle motion.P. annectenssuction feeds relatively slowly but successfully through muscle shortening of hypaxial and rectus cervicis muscles contributing to hyoid mobility.Summary StatementThree-dimensional hyoid movements and clavicle retraction generate suction during the relatively slow, but successful, feeding strikes of the West African lungfish (Protopterus annectens).
Multi-synaptic boutons are a feature of CA1 hippocampal connections that may underlie network synchrony
Authors: Rigby Mark , Grillo Federico , Compans Benjamin , Neves Guilherme , Gallinaro Julia , Nashashibi Sophie , Vizcay-Barrena Gema , Levet Florian , Sibarita Jean-Baptiste , Kirkland Angus , Fleck Roland A. , Clopath Claudia , Burrone Juan 
Published: May 2022

AbstractExcitatory synapses are typically described as single synaptic boutons (SSBs), where one presynaptic bouton contacts a single postsynaptic spine. Using serial section block face scanning electron microscopy, we found that this textbook definition of the synapse does not fully apply to the CA1 region of the hippocampus. Roughly half of all excitatory synapses in the stratum oriens involved multi-synaptic boutons (MSBs), where a single presynaptic bouton containing multiple active zones contacted many postsynaptic spines (from 2 to 7) on the basal dendrites of different cells. The fraction of MSBs increased during development (from P21 to P100) and decreased with distance from the soma. Curiously, synaptic properties such as active zone (AZ) or postsynaptic density (PSD) size exhibited less within-MSB variation when compared to neighbouring SSBs, features that were confirmed by super-resolution light microscopy. Computer simulations suggest that these properties favour synchronous activity in CA1 networks.
The effect of paracrine factors released by irradiated peripheral blood mononuclear cells on neutrophil extracellular trap formation
Authors: Klas Katharina , Ondracek Anna S , Hofbauer Thomas M , Mangold Andreas , Pfisterer Karin , Laggner Maria , Copic Dragan , Direder Martin , Bormann Daniel , Ankersmit Hendrik Jan , Mildner Michael 
Published: May 2022

AbstractNeutrophil extracellular trap (NET)-formation represents an important defence mechanism for rapid clearance of infections. However, exaggerated NET formation has been shown to negatively affect tissue-regeneration after injury. As our previous studies revealed strong tissue-protective and regenerative properties of the secretome of stressed peripheral blood mononuclear cells (PBMCsec), we here investigated the influence of PBMCsec on the formation of NETs. The effect of PBMCsec on NET formation was assessed ex vivo in ionomycin stimulated neutrophils derived from healthy donors using flow cytometry, image stream analysis and quantification of released extracellular DNA. Molecular mechanisms involved in NET formation that were potentially impaired by PBMCsec treatment, including protein kinase C activity, reactive oxygen species production and peptidyl arginine deiminase 4 activity were analysed. Our results showed that PBMCsec significantly inhibited NET formation. Investigation of the different biological substance classes found in PBMCsec revealed only partial reduction of NET formation, suggesting a synergistic effect. Mechanistically, PBMCsec treatment did not interfere with calcium signalling and PKC-activation, but exerted anti-oxidant activity, as evidenced by reduced levels of reactive oxygen species and upregulation of heme oxygenase 1, hypoxia inducible-factor 1 as well as heat shock protein 27 in PBMCsec-treated neutrophils. In addition, PBMCsec strongly inhibited the activation of peptidyl arginine deiminase 4 (PAD4), ultimately leading to the inhibition of NET formation. As therapeutics antagonizing excessive NET formation are currently not available, our study provides a promising novel treatment option for a variety of conditions resulting from exaggerated NET formation.
Investigating the differential structural organization and gene expression regulatory networks of lamin A Ig fold domain mutants of muscular dystrophy
Authors: Dutta Subarna , Kumar Vikas , Barua Arnab , Vasudevan Madavan 
Published: May 2022

AbstractIn metazoan cells, lamins form a proteinaceous meshwork as a major structural component of the nucleus and also play a role in regulating essential cellular processes. Lamins, along with their interactors, act as determinants for chromatin organization throughout the nucleus. The major dominant missense mutations responsible for autosomal dominant forms of muscular dystrophies reside in the Ig fold domain of lamin A. However, how lamin A contributes to the distribution of heterochromatin and balances euchromatin, and how it relocates epigenetic marks to shape chromatin states, remains poorly defined, making it difficult to draw conclusions about the prognosis of lamin A-mediated muscular dystrophies.In the first part of this report, we identified the in-vitro organization of full-length lamin A proteins due to two well-documented Ig LMNA mutations, R453W and W514R, through biophysical and electron microscopy observations. We further demonstrated that both lamin A/C mutant cells predominantly expressed nucleoplasmic aggregates with reduced amounts at the nuclear envelope. Labeling specific markers of epigenetics, such as H3K9me3, H3K27me3, H3K36me3, and HP1α, allowed correlation of lamin A mutations with epigenetic mechanisms. Immunofluorescence and biochemical analyses indicated transcriptional upregulation. In addition to manipulating epigenetic mechanisms, our proteomic studies traced diverse expressions of transcription regulators, RNA synthesis and processing proteins, protein translation components, and posttranslational modifications. These data suggest severe perturbations in targeting other proteins to the nucleus.Our study also predicts specific structural configurations of lamin A determined by its interacting partners’ patterns.SignificanceThis study investigates the effects of two severe mutations in the LMNA gene associated with muscular dystrophies:R453WandW514R.This research aims to provide new insights into the structural environment of full-length lamin A protein due to single-point mutations.Our study employs proteomics to map expression levels of regulators involved in epigenetic states, RNA synthesis and processing, and protein synthesis and processing.It assesses potential effects on binding affinity and transcription, as well as alterations in heterochromatin protein distribution and RNA polymerase II functionality due to mutations affecting lamin A.A systematic investigation of lamin A interactors is conducted to explore their associations with other proteins.Graphical AbstractFigure:Schematic diagram representing the results. Mutations in lamin A protein evicts the nucleosome from nuclear periphery and consequently promotes aberrant gene expression.
Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model
Authors: Sun Junjie , Qiu Jiaying , Yang Qiongxia , Ju Qianqian , Qu Ruobing , Wang Xu , Wu Liucheng , Xing Lingyan 
Published: May 2022

AbstractAlthough spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival of motor neuron (SMN) proteins, there is growing evidence that non-neuronal cells play important roles in SMA pathogenesis. However, transcriptome alterations occurring at the single-cell level in SMA spinal cord remain unknown, preventing us from fully comprehending the role of specific cells. Here, we performed single-cell RNA sequencing of the spinal cord of a severe SMA mouse model, and identified ten cell types as well as their differentially expressed genes. Using CellChat, we found that cellular communication between different cell types in the spinal cord of SMA mice was significantly reduced. A dimensionality reduction analysis revealed 29 cell subtypes and their differentially expressed gene. A subpopulation of vascular fibroblasts showed the most significant change in the SMA spinal cord at the single-cell level. This subpopulation was drastically reduced, possibly causing vascular defects and resulting in widespread protein synthesis and energy metabolism reductions in SMA mice. This study reveals for the first time a single-cell atlas of the spinal cord of mice with severe SMA, and sheds new light on the pathogenesis of SMA.
Fixational eye movements enable robust edge detection
Authors: Schmittwilken Lynn , Maertens Marianne 
Published: May 2022

AbstractHuman vision relies on mechanisms that respond to luminance edges in space and time. Most edge models use orientation-selective mechanisms on multiple spatial scales and operate on static inputs assuming that edge processing occurs within a single fixational instance. Recent studies, however, demonstrate functionally relevant temporal modulations of the sensory input due to fixational eye movements. Here we propose a spatiotemporal model of human edge detection which combines elements of spatial and active vision. The model augments a spatial vision model by temporal filtering and shifts the input images over time mimicking an active sampling scheme via fixational eye movements. The first model test was White’s illusion, a lightness effect that has been shown to depend on edges. The model reproduced the spatial-frequency-specific interference with the edges by superimposing narrowband noise (1-5 cpd), similar to the psychophysical interference observed in White’s effect. Second, we compare the model’s edge detection performance in natural images in the presence and absence of Gaussian white noise with human-labeled contours for the same (noise-free) images. Notably, the model detects edges robustly against noise in both test cases without relying on orientation-selective processes. Eliminating model components, we demonstrate the relevance of multiscale spatiotemporal filtering and scale-specific normalization for edge detection. The proposed model facilitates efficient edge detection in (artificial) vision systems and challenges the notion that orientation-selective mechanisms are required for edge detection.
Development of comprehensive carbon footprint and environmental impact indicators for building transportation assessment
Authors: Abdullah Kamil , Usman Abdullahi Mohammed 
Published: May 2022

PurposeThe purpose of the study is to consolidate a set of indicators for assessing design and construction phase strategies for reducing operational greenhouse gas (GHG) emission. They will also estimate the quantity of operational GHG emission and its associated reduction over assessment period.Design/methodology/approachFive steps framework adopted include defining the purpose of the indicators and selection of candidate indicators. Others are defining the criteria for indicator selection, selecting and defining the proposed indicators. Relevancy, measurability, prevalence, preference, feasibility and adaptability of the indicator were the criteria used for selecting the indicators.FindingsThe study consolidated public transport accessibility, sustainable parking space, green vehicle priority, proximity to amenities and alternative modes as indicators for design and construction phase strategies. Transportation accounting and carbon footprint (CFP) and their associated reduction are indicators for operational GHG emission while plan and policy is an indicator for policymakers and stakeholders.Practical implicationsThe study shows that providing correct indicators for assessing direct and indirect GHG emission with easy to obtain data is essential for assessment of built environment. Stakeholder can use the indicators in developing new rating systems and researchers as an additional knowledge. Policy makers and stakeholders can use the study in monitoring and rewarding the sustainability and activities of building related industries and organisations.Originality/valueThe study was conducted at the Center for Energy and Industrial Environmental Studies (CEIES) Universiti Tun Hussein Onn Malaysia and utilises existing rating systems and tools, Intergovernmental Panel on Climate Change (IPCC) and GHG protocol reports and guides and several other standards, which are open for research.
Investigating the net benefits of contactless technologies in quick-service restaurants: the moderating roles of social interaction anxiety and language proficiency
Authors: Lee Kyung Young , Han Sumin , Shin Soo Il , Yang Sung-Byung 
Published: May 2022

PurposeThis study aims to apply the information system success model (ISSM) to examine the relationships among actual use, use continuance intention, user satisfaction and net benefits in the context of quick-service restaurant (QSR) patrons using two contactless technologies (CT): self-service kiosks (SSK) and mobile applications (MA) for food ordering. The study also investigates the moderating roles of social interaction anxiety (SIA) and language proficiency (LP) in the abovementioned relationships.Design/methodology/approachSurvey data from 421 QSR patrons with experience using McDonald's SSK and MA were collected and analyzed through a seemingly unrelated regressions (SUR) technique.FindingsResearch findings reveal positive associations among actual use, use continuance intention and satisfaction with CT (i.e. SSK and MA). The actual use and satisfaction with CT are positively associated with individual benefits, leading to improved patron satisfaction with QSR. Findings also reveal that, in the case of MA, SIA positively moderates relationships between actual use/satisfaction and individual benefits and between satisfaction and organizational benefit, while LP shows negative moderating effects on those relationships.Originality/valueThis study is one of the first attempts to present empirical evidence of constructs in the ISSM (actual use, use continuance intention, satisfaction and individual/organizational benefits) in the context of QSR patrons using SSK and MA. It also shows that using MA can address some patrons' psychological problems interacting with others in their food-ordering processes.