bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chimeric chikungunya virus-like particles with surface exposed SARS-CoV-2 RBD elicits potent immunogenic responses in mice
Authors: Singh Vedita Anand , Nehul Sanket , Kumar Chandra Shekhar , Banerjee Manidipa , Kumar Pravindra , Sharma Gaurav , Tomar Shailly 
Published: February 2023

AbstractThe SARS-CoV-2 pandemic has reinforced efforts for developing effective vaccination strategy for existing and emerging viruses. Currently there are various vaccine technology available for treating viral diseases, however it is imperative to develop and investigate second-generation vaccines such as chimeric virus-like particles (chi-VLPs) vaccine for increased immunogenicity, ease of production and scalability to supplement the worldwide vaccine supply. Intriguingly, chi-VLPs expresses more than one antigenic epitope on its surface, hence it is expected to be a more effective vaccine candidate. Hereby, this study reports, a novel bivalent vaccine design of chimeric alphavirus coronavirus virus-like particles (ChAC-VLPs), displaying fusion glycoproteins of CHIKV and receptor binding domain (RBD) of SARS-CoV-2 on its surface. Uniqueness and versatility of ChAC-VLPs has been demonstrated via a various techniques including Western blot, Immunofluorescence, cryoEM, and dynamic light scattering (DLS). The multimeric epitope display of immunogenic antigens, i.e CHIKV envelop glycoprotein and SARS-CoV-2 RBD was validated by cell-based assays. ChAC-VLP immunized mice has shown substantial neutralization titres for CHIKV (PRNT50 of 1:25) from the serum collected after 2ndbooster doses. Similarly, serum antibodies were detected for SARS-CoV2 RBD as observed by antigen specific ELISA and validated using surface plasmon resonance (SPR). SPR binding response was detected to be >200 RU for anti-RBD antibody in post-immunized mice sera. In conclusion, present study proposes ChAC-VLPs as a potential hybrid vaccine candidate for CHIKV and SARS-CoV-2 infection and contributes valuable insights in chi-VLPs domain.
The development and usability testing of two arts-based knowledge translation tools for pediatric anaphylaxis
Authors: Scott Shannon D. , Hartling Lisa 
Published: February 2023

AbstractAnaphylaxis, or anaphylactic reactions, are a severe allergic reaction with a rapid onset and can be fatal. Children are disproportionately at risk for hospitalization and emergency department visits due to anaphylaxis. A previously conducted mixed studies systematic review and qualitative descriptive study found that parents lacked confidence in recognizing and treating an anaphylactic reaction in their child, and were unsure of when to bring their child to the emergency department. This demonstrates that more effective knowledge translation (KT) tools are needed to satisfy parent information needs.The purpose of this research was to work with parents to develop and test the usability of an animated video and an interactive infographic about anaphylactic reactions in children. These tools merge the best available research evidence with narratives of parent experiences to respond to their information needs. Prototypes were evaluated by parents (video n=31; infographic n=30) through usability testing in an urban emergency department waiting room in Alberta. Parents viewed the tools on an iPad and answered questions via an electronic survey. The usability survey consisted of 9, 5-point Likert items, which assessed: 1) usefulness, 2) aesthetics, 3) length, 4) relevance, and 5) future use. Parents were also asked to provide their positive and negative opinions of the tool via two free text boxes. Overall, results were positive and the tools were highly rated across most usability items. Mean scores across usability items were 4.26 to 4.71 for the video and 3.83 to 4.43 for the infographic. The scores from the usability testing suggest arts-based digital tools are useful in sharing complex health information with parents about managing an anaphylactic reaction in their child and provide meaningful guidance on how to improve KT tools to better reflect the needs of parents.
A global test of hybrid ancestry from genome-scale data
Authors: Haque Md Rejuan , Kubatko Laura 
Published: February 2023

AbstractMethods based on the multi-species coalescence have been widely used in phylogenetic tree estimation using genome-scale DNA sequence data to understand the underlying evolutionary relationship between the sampled species. Evolutionary processes such as hybridization, which creates new species through interbreeding between two different species, necessitate inferring a species network instead of a species tree. A species tree is strictly bifurcating and thus fails to incorporate hybridization events which require an internal node of degree three. Hence, it is crucial to decide whether a tree or network analysis should be performed given a DNA sequence data set, a decision that is based on the presence of hybrid species in the sampled species. Although many methods have been proposed for hybridization detection, it is rare to find a technique that does so globally while considering a data generation mechanism that allows both hybridization and incomplete lineage sorting. In this paper, we consider hybridization and coalescence in a unified framework and propose a new test that can detect whether there are any hybrid species in a given set of species. We propose that based on this global test of hybridization, one can decide whether a tree or network analysis is appropriate for a given data set.
Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity ofSORL1variants in Alzheimer’s disease
Authors: Andersen Olav M. , Monti Giulia , Jensen Anne Mette G. , de Waal Matthijs , Hulsman Marc , Olsen Johan G. , Holstege Henne 
Published: February 2023

ABSTRACTSORL1encodes the retromer-associated receptor SORLA that functions in endosomal recycling. Rare variants inSORL1have been associated with Alzheimer’s disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified inSORL1, are pathogenic. Here we address this question by relying on SORLA’s distinct molecular architecture. First, we completed a structure-guided sequence alignment for all the protein domains. Next, we identified proteins that contain domains homologous to those of SORLA, which include pathogenic variants for monogenic diseases. We identified the analogous domain positions of these variants in the SORLA protein sequence and showed that variants in these positions similarly impairSORL1, and lead to AD. Together, our findings represent a comprehensive compendium on SORLA protein variation and functional effects, which allowed us to prioritizeSORL1genetic variants into high or moderate priority mutations. We envision that this compendium will be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Utimately, this compendium will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies forSORL1variant-carrying patients.
A generic binding pocket for small moleculeIKsactivators at the extracellular inter-subunit interface of KCNQ1 and KCNE1 channel complexes
Authors: Chan Magnus , Sahakyan Harutyun , Eldstrom Jodene , Sastre Daniel , Wang Yundi , Dou Ying , Pourrier Marc , Vardanyan Vitya , Fedida David 
Published: February 2023

AbstractThe cardiacIKsion channel comprises KCNQ1, calmodulin, and KCNE1 in a dodecameric complex which provides a repolarizing current reserve at higher heart rates and protects from arrhythmia syndromes that cause fainting and sudden death. Pharmacological activators ofIKsare therefore of interest both scientifically and therapeutically for treatment ofIKsloss-of-function disorders. One group of chemical activators are only active in the presence of the accessory KCNE1 subunit and here we investigate this phenomenon using molecular modeling techniques and mutagenesis scanning in mammalian cells. A generalized activator binding pocket is formed extracellularly by KCNE1, the domain-swapped S1 helices of one KCNQ1 subunit and the pore/turret region made up of two other KCNQ1 subunits. A few residues, including K41, A44 and Y46 in KCNE1, W323 in the KCNQ1 pore, and Y148 in the KCNQ1 S1 domain, appear critical for the binding of structurally diverse molecules, but in addition, molecular modeling studies suggest that induced fit by structurally different molecules underlies the generalized nature of the binding pocket. Activation ofIKsis enhanced by stabilization of the KCNQ1-S1/KCNE1/pore complex, which ultimately slows deactivation of the current, and promotes outward current summation at higher pulse rates. Our results provide a mechanistic explanation of enhancedIKscurrents by these activator compounds and provide a map for future design of more potent therapeutically useful molecules.
Jet injection potentiates naked mRNA SARS-CoV-2 vaccine in mice and non-human primates by adding physical stress to the skin
Authors: Abbasi Saed , Matsui-Masai Miki , Yasui Fumihiko , Hayashi Akimasa , Tockary Theofilus A. , Akinaga Shiro , Kohara Michinori , Kataoka Kazunori , Uchida Satoshi 
Published: February 2023

AbstractNaked mRNA-based vaccines may reduce the reactogenicity associated with delivery carriers, but their effectiveness has been suboptimal against infectious diseases. Herein, we aimed to enhance their efficacy by using a pyro-drive liquid jet injector that precisely controls pressure to widely disperse mRNA solution in the skin. The jet injection boosted naked mRNA delivery efficiency in the mouse skin. Mechanistic analyses indicate that dendritic cells, upon uptake of antigen mRNA in the skin, migrate to the draining lymph nodes for antigen presentation. Additionally, the jet injector activated innate immune responses in the skin, presumably by inducing physical stress, thus serving as a physical adjuvant. From a safety perspective, our approach, utilizing naked mRNA, restricted mRNA distribution solely to the injection site, preventing systemic pro-inflammatory reactions following vaccination. Ultimately, the jet injection of naked mRNA encoding SARS-CoV-2 spike protein elicited robust humoral and cellular immunity, providing protection against SARS-CoV-2 infection in mice. Furthermore, our approach induced plasma activity of neutralizing SARS-CoV-2 in non-human primates, comparable to that observed in mice, with no detectable systemic reactogenicity.
Modelling Speed-Accuracy Tradeoffs in the Stopping Rule for Confidence Judgments
Authors: Herregods Stef , Denmat Pierre Le , Vermeylen Luc , Desender Kobe 
Published: February 2023

AbstractMaking a decision and reporting confidence in the accuracy of that decision are thought to be driven by the same mechanism: the accumulation of evidence. Previous research has shown that choices and reaction times are well accounted for by a computational model assuming noisy accumulation of evidence until crossing a decision boundary (e.g., the drift diffusion model). Decision confidence can be derived from the amount of evidence following post-decision evidence accumulation. Currently, the stopping rule for post-decision evidence accumulation is underspecified. In the current work, we quantitatively and qualitatively compare the ability of four prominent models of confidence couched within evidence accumulation to account for this stopping rule. In two experiments, participants were instructed to make fast or accurate decisions, and to give fast or carefully considered confidence judgments. We then compared the different models in their ability to capture the speed-accuracy effects on confidence. Both qualitatively and quantitatively, the data were best accounted for by our newly proposed Flexible Collapsing Boundaries model, in which post-decision accumulation terminates once it reaches one of two opposing slowly collapsing confidence boundaries. Inspection of the parameters of this model revealed that instructing participants to make fast versus accurate decisions influenced the height of the decision boundaries, while instructing participants to make fast versus careful confidence judgments influenced height of the confidence boundaries. Our data show that the stopping rule for confidence judgments can be well described as an accumulation-to-bound process, and that the height of these confidence boundaries are under strategic control.
Mitochondrial translocation of TFEB regulates complex I and inflammation
Authors: Calabrese Chiara , Nolte Hendrik , Pitman Melissa R , Ganesan Raja , Lampe Philipp , Laboy Raymond , Ripa Roberto , Fischer Julia , Chipurupalli Sandhya , Gutierrez Saray , Polara Ruhi , Thomas Daniel , Pitson Stuart M , Antebi Adam , Robinson Nirmal 
Published: February 2023

AbstractTFEB is a master regulator of autophagy, lysosome biogenesis and mitochondrial metabolism that works, and immunity, primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomic analysis revealed extensive TFEB co-precipitation with several mitochondrial proteins, whose interactions are disrupted upon infection withS.Typhimurium. Localization of TFEB in the mitochondrial matrix was confirmed by high resolution confocal microscopy and biochemistry with translocation dependent on a conserved N-terminal TOMM20-binding motif enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.
Autophagy in maternal tissues contributes toArabidopsis thalianaseed development
Authors: Erlichman Ori , Weiss Shahar , Abu-Arkia Maria , Khaner Moria Ankary , Soroka Yoram , Jasinska Weronika , Rosental Leah , Brotman Yariv , Avin-Wittenberg Tamar 
Published: February 2023

AbstractSeeds are an essential food source, providing nutrients for germination and early seedling growth. Degradation events in the seed and the mother plant accompany seed development. One degradation mechanism is autophagy, facilitating cellular component breakdown in the lytic organelle. Autophagy influences various aspects of plant physiology, specifically nutrient availability and remobilization, suggesting its involvement in source-sink interactions. During seed development, autophagy was shown to affect nutrient remobilization from mother plants and function in the embryo. Yet, these studies examined autophagy-knockout (atgmutant) plants, making it impossible to distinguish between the contribution of autophagy in the source (i.e., the mother plant) and the sink tissue (i.e., the embryo).To address this, we employed a novel approach to differentiate between autophagy in source and sink tissues. We investigated how autophagy in the maternal tissue affects seed development by performing reciprocal crosses between WT andatgmutantArabidopsis thalianaplants. Although F1 seedlings possessed a functional autophagy mechanism, etiolated F1 plants from maternalatgmutants displayed reduced growth. This was attributed to altered protein but not lipid accumulation in the seeds, suggesting autophagy differentially regulates carbon and nitrogen remobilization. Surprisingly, F1 seeds of maternalatgmutants exhibited faster germination, resulting from different seed coat development.Our study emphasizes the significance of examining autophagy in a tissue-specific manner, revealing valuable insights into the interplay between different tissues during seed development. It sheds light on the tissue-specific functions of autophagy, offering potential for new research into the underlying mechanisms governing seed development and crop yield.
Directing Protein Design Choices by Per-Residue Energy Breakdown Analysis with an Interactive Web Application
Authors: Engelberger Felipe , Zakary Jonathan D. , Künze Georg 
Published: February 2023

AbstractRecent developments in machine learning have greatly facilitated the design of proteins with improved properties. However, accurately assessing the contributions of an individual or multiple amino acid mutations to overall protein stability to select the most promising mutants remains a challenge. Knowing the specific types of amino acid interactions that improve energetic stability is crucial for finding favorable combinations of mutations and deciding which mutants to test experimentally. In this work, we present an interactive workflow for assessing the energetic contributions of single and multi-mutant designs of proteins. Theenergy breakdown guided protein design (ENDURE) workflow includes several key algorithms, including per-residue energy analysis and the sum of interaction energies calculations, which are performed using the Rosetta energy function, as well as a residue depth analysis, which enables tracking the energetic contributions of mutations occurring in different spatial layers of the protein structure. ENDURE is available as a web application that integrates easy-to-read summary reports and interactive visualizations of the automated energy calculations and helps users selecting protein mutants for further experimental characterization. We demonstrate the effectiveness of the tool in identifying the mutations in a designed polyethylene terephthalate (PET)-degrading enzyme that add up to an improved thermodynamic stability. We expect that ENDURE can be a valuable resource for researchers and practitioners working in the field of protein design and optimization. ENDURE is freely available for academic use at:http://endure.kuenzelab.org.
Controlled protein activities with viral proteases, antiviral peptides, and antiviral drugs
Authors: Tague Elliot P. , McMahan Jeffrey B. , Tague Nathan , Dunlop Mary J. , Ngo John T. 
Published: February 2023

AbstractChemical control of protein activity is a powerful tool for scientific study, synthetic biology, and cell therapy; however, for broad use, effective chemical inducer systems must minimally crosstalk with endogenous processes and exhibit desirable drug delivery properties. Accordingly, the drug-controllable proteolytic activity of hepatitis Ccis-protease NS3 and its associated antiviral drugs have been used to regulate protein activity and gene modulation. These tools advantageously exploit non-eukaryotic/prokaryotic proteins and clinically approved inhibitors. Here we expand the toolkit by utilizing catalytically inactive NS3 protease as a high affinity binder to genetically encoded, antiviral peptides. Through our approach, we create NS3-peptide complexes that can be displaced by FDA-approved drugs to modulate transcription, cell signaling, split-protein complementation. With our developed system, we discover a new mechanism to allosterically regulate Cre recombinase. Allosteric Cre regulation with NS3 ligands enables orthogonal recombination tools in eukaryotic cells and functions in divergent organisms to control prokaryotic recombinase activity.
FREEDA: an automated computational pipeline guides experimental testing of protein innovation by detecting positive selection
Authors: Dudka Damian , Akins R. Brian , Lampson Michael A. 
Published: February 2023

AbstractCell biologists typically focus on conserved regions of a protein, overlooking innovations that can shape its function over evolutionary time. Computational analyses can reveal potential innovations by detecting statistical signatures of positive selection that leads to rapid accumulation of beneficial mutations. However, these approaches are not easily accessible to non-specialists, limiting their use in cell biology. Here, we present an automated computational pipeline FREEDA (Finder of Rapidly Evolving Exons in De novo Assemblies) that provides a simple graphical user interface requiring only a gene name, integrates widely used molecular evolution tools to detect positive selection, and maps results onto protein structures predicted by AlphaFold. Applying FREEDA to >100 mouse centromere proteins, we find evidence of positive selection in intrinsically disordered regions of ancient domains, suggesting innovation of essential functions. As a proof-of-principle experiment, we show innovation in centromere binding of CENP-O. Overall, we provide an accessible computational tool to guide cell biology research and apply it to experimentally demonstrate functional innovation.
Neutralizing antibody levels and epidemiological information of patients with breakthrough COVID-19 infection in Toyama, Japan
Authors: Tani Hideki , Inasaki Noriko , Shimada Takahisa , Saga Yumiko , Kaya Hiroyasu , Maruyama Yumiko , Matano Sadaya , Itoh Hiroyuki , Kashii Tatsuhiko , Yamazaki Emiko , Yazawa Shunsuke , Itamochi Masae , Oishi Kazunori 
Published: February 2023

AbstractBreakthrough infection (BI) after coronavirus disease 2019 (COVID-19) vaccination has exploded owing to the emergence of various SARS-CoV-2 variants and has become a major problem at present. In this study, we analyzed the epidemiological information and possession status of neutralizing antibodies in patients with BI using SARS-CoV-2 pseudotyped viruses (SARS-CoV-2pv). Analysis of 44 specimens diagnosed with COVID-19 after two or more vaccinations showed high inhibition of infection by 90% or more against the Wuhan strain and the Alpha and Delta variants of pseudotyped viruses in 40 specimens. In contrast, almost no neutralizing activity was observed against the Omicron BA.1 variant. Many cases without neutralizing activity or BI were immunosuppressed individuals. The results of this study show that BI occurs even when there are sufficient neutralizing antibodies in the blood due to exposure to close contacts at the time of infection. Thus, even after vaccination, sufficient precautions must be taken to prevent infection.
A socio-technical system perspective to exploring the negative effects of social media on work performance
Authors: Cao Xiongfei , Xu Caixiang , Ali Ahsan 
Published: February 2023

PurposeThis research aims to explore the potential negative effects of social media on employees' work performance in a stressful working environment.Design/methodology/approachThis study model was tested using a sample of 398 social media users from China.FindingsStructural equation modeling analysis provide support for most of the hypothesized relationships as results reveal that social stressors and technical stressors are related to exhaustion and anxiety of employees using social media. Furthermore, results reveal that exhaustion and anxiety exhibit a negative influence on employees' work performance.Originality/valueThis study extends the authors’ understanding of how social stressors and technical stressors are related to work performance. The integration of the transactional theory of stress and coping with socio-technical systems offers a holistic view to explain the phenomenon of stress in the social media context.