bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating Electronic Structure Variations in Nucleic Acid-Protein Complexes Involved in Transcription Regulation Using a Tight-Binding Approach
Authors: Du Likai , Liu Chengbu 
Published: April 2024

AbstractTranscription factor (TF) are proteins that regulates the transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence. Nucleic acid-protein interactions are crucial in regulating transcription in biological systems. This work presents a quick and convenient method for constructing tight-binding models and offers physical insights into the electronic structure properties of transcription factor complexes and DNA motifs. The tight binding Hamiltonian parameters are generated using the random forest regression algorithm, which reproduces the givenab-initiolevel calculations with reasonable accuracy. We present a library of residue-level parameters derived from extensive electronic structure calculations over various possible combinations of nucleobases and amino acid side chains from high-quality DNA-protein complex structures. As an example, our approach can reasonably generate the subtle electronic structure details for the orthologous transcription factors human AP-1 and Epstein-Barr virus Zta within a few seconds on a laptop. This method potentially enhances our understanding of the electronic structure variations of gene-protein interaction complexes, even those involving dozens of proteins and genes. We hope this study offers a powerful tool for analyzing transcription regulation mechanisms at an electronic structural level.Topic of ContentTranscription factors that bind to DNA modulate gene expression, with the stability and reactivity of their interactions elucidated by eigenvalues derived from the tight-binding model. Visualization of these interactions reveals the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO), the gap between which determines the reactivity and stability of the molecular complex. This approach advances our understanding of gene regulation by revealing the dynamics of charge transfer and electronic states within transcription factor-DNA complexes.
High-efficiency PET Degradation with a Duo-enzyme System Immobilized on Magnetic Nanoparticles
Authors: Kotnis Siddhi , Gulati Siddhant , Sun Qing 
Published: April 2024

AbstractThe widespread consumption of PET worldwide has necessitated the search for environment-friendly methods for PET degradation and recycling. Among these methods, biodegradation stands out as a promising approach for recycling PET. The discovery of duo enzyme system PETase and MHETase in 2016, along with their engineered variants, has demonstrated significant potential in breaking down PET. Previous studies have also demonstrated that the activity of the enzyme PETase increases when it is immobilized on nanoparticles. To achieve highly efficient and complete PET depolymerization, we immobilized both FAST PETase and MHETase at a specific ratio on magnetic nanoparticles. This immobilization resulted in a 2.5-fold increase in product release compared with free enzymes. Additionally, we achieved reusability and enhanced stability of the enzyme bioconjugates.
Quantifying the evolutionary paths to endomembranes
Authors: Schavemaker Paul E. , Lynch Michael 
Published: April 2024

AbstractEukaryotes exhibit a complex and dynamic internal meshwork of membranes—theendomembrane system—used to insert membrane proteins, ingest food, and digest cells and macromolecules. Verbal models explaining the origin of endomembranes abound, but explicit quantitative considerations of fitness are lacking. A wealth of quantitative data on vesicle sizes, local protein abundances, protein residence times at functional loci, nutrient transporter rates, membrane protein insertion rates, etc., have been made available in the past couple of decades. Drawing on these data allows for the derivation of two biologically-grounded analytical models of endomembrane evolution that quantify organismal fitness: 1) vesicle-based uptake of nutrient molecules—pinocytosis, and 2) vesicle-based insertion of membrane proteins—proto-endoplasmic reticulum. Surprisingly, pinocytosis doesn’t provide a net fitness gain under biologically sensible parameter ranges. Explaining why it is primarily used for protein, and not small molecule, uptake in contemporary organisms. The proto-endoplasmic reticulum does provide net fitness gains, making it the more likely candidate for initiating the origin of the endomembrane system. With modifications, the approach developed here can be used to understand the present-day endomembrane system and to further flesh out the cell-level fitness landscape of endomembranes and illuminate the origin of the eukaryotic cell.
Tumoroid-on-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening
Authors: Seyfoori Amir , Liu Kaiwen , Caruncho Hector , Walter Patrick , Akbari Mohsen 
Published: April 2024

AbstractEmploying three-dimensional (3D)in vitromodels, including tumor organoids and spheroids, stands pivotal in enhancing cancer therapy. These models bridge the gap between 2D cell cultures and complex in vivo environments, effectively mimicking the intricate cellular interplay and microenvironmental factors found in solid tumors. Consequently, they offer versatile tools for comprehensive studies into cancer progression, drug responses, and tailored therapies. In this study, we present a novel open-surface microfluidic-integrated platform called the Tumoroid-on-a-Plate (ToP) device, designed for generating intricate predictive 3D solid tumor models. By incorporating a tumor mass, stromal cells, and extracellular matrix components, we successfully replicate the complexity of glioblastoma (GBM) and pancreatic adenocarcinoma (PDAC) within our system. Using our advanced ToP model, we were able to successfully screen the effect of various GBM extracellular matrix compositions, such as Collagen and Reelin, on the invasiveness of the GBM cells with the ToP model. The ToP in vitro model also allowed for the screening of chemotherapeutic drugs such as temozolomide and iron-chelators in a single and binary treatment setting on the complex ECM-embedded tumoroids. This helped to investigate the toxic effect of different therapeutics on the viability and apoptosis of our in vitro GBM and PDAC cancer models. Additionally, by co-culturing human-derived fibroblast cells with PDAC tumoroids, the pro-invasive impact of the stromal component of the tumor microenvironment on growth behaviour and drug response of the tumoroids was revealed. This study underscores the transformative role of predictive 3D models in deciphering cancer intricacies and highlights the promise of ToP in advancing therapeutic understanding.
Receptor activity modifying protein modulation of parathyroid hormone-1 receptor function and signalling
Authors: Avgoustou Paris , Jailani Ameera B. A. , Desai Aditya J. , Roberts Dave J. , Lilley Ewan R. , Stothard Grant W. , Skerry Timothy M. , Richards Gareth O. 
Published: April 2024

AbstractReceptor activity-modifying proteins (RAMPs) are known to modulate the pharmacology and function of several G protein-coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R). However, the precise effects of different RAMPs on PTH1R signalling and trafficking remain poorly understood. Here we investigated the impact of RAMP2 and RAMP3 on PTH1R function using a range of PTHand PTH-related protein (PTHrP)-derived ligands.FRET imaging revealed that PTH1R preferentially interacts with RAMP2 and, to a lesser extent, RAMP3, but not RAMP1. Interestingly, RAMP3 co-expression resulted in reduced cell surface expression of PTH1R, suggesting a potential role in receptor trafficking or internalization. The presence of RAMP2 significantly enhanced PTH1R-mediated cAMP accumulation, β-arrestin recruitment, and calcium signalling in response to PTH (1–34), PTHrP (1-34), PTH (1-84), and the PTH (1-17) analogue ZP2307. In contrast, RAMP3 co-expression attenuated or completely abolished those responses.We found that full-length PTHrP analogues, PTHrP (1-108) and PTHrP (1-141), exhibited lower potency and efficacy than PTHrP (1-34) in activating PTH1R. RAMP2 significantly increased potency and/or efficacy when compared to PTH1R alone cells, while RAMP3 significantly reduced these responses. Antibody-capture scintillation proximity assays demonstrated that RAMP2 differentially modulates G protein activation by PTH1R in a ligand-dependent manner, with PTH (1-34) and PTHrP (1-34) inducing distinct patterns of G protein subtype activation.These findings highlight the complex role of RAMPs in regulating PTH1R signalling and trafficking, revealing differential effects of RAMP2 and RAMP3 on receptor function. The data suggest that targeting the PTH1R/RAMP2 complex may be a promising strategy for developing novel bone anabolic therapies by leveraging biased agonism and functional selectivity. Further research using physiologically relevant models is needed to elucidate the therapeutic potential of this approach.
Wampee chromosome-level reference genome elucidates fruit sugar-acid metabolism
Authors: Chen Huiqiong , Wang Jingxuan , Wang Xiangfeng , Peng Cheng , Chang Xiaoxiao , Chen Zhe , Yang Bowen , Wang Xinrui , Qiu Jishui , Guo Li , Lu Yusheng 
Published: April 2024

AbstractWampee (Clausena lansium) is an economically significant subtropical fruit tree widely cultivated in Southern China. High-quality genomic resources are unavailable, but they are essential for functional genomics and germplasm enhancement of wampee. Here, we provide a chromosome-level genome sequence for the wampee cultivar JinFeng and a population genomic analysis of 266 accessions. The 297.1 Mb wampee genome, containing nine chromosomes with a scaffold N50 of 29.2 Mb and encoding 23,468 protein-coding genes, showed a significant improvement over the previous version. We dissected the wampee population structure and genetic differentiation in China using population genomic analysis, which detected 110 and 671 genes under a selective sweep associated with sour and sweet wampee evolution in domesticated clones, respectively. Homozygous non-synonymous single nucleotide polymorphisms are likely associated with fruit flavor differentiation. A genome-wide association study identified 220 remarkable marker-trait associations for total acid content, harboring 289 genes encoding transcription factors, transporters, and enzymes involved in sugar and acid metabolism, which are potentially useful for sour and sweet taste development in wampee fruit. Furthermore, the ethylene response factor family geneClERF061and the SWEET family geneClSWEET7were identified. Linkage assessment between the relative expression levels ofClERF061orClSWEET7and the total acid/total sugar contents implied their potential involvement in sugar-acid metabolism in wampee fruits. High-quality genome resources are valuable for expediting wampee research and genome-assisted breeding.
Protein-ligand binding affinity prediction: Is 3D binding pose needed?
Authors: Wu Ming-Hsiu , Xie Ziqian , Zhi Degui 
Published: April 2024

AbstractAccurate protein-ligand binding affinity prediction is crucial in drug discovery. Existing methods are predominately docking-free, without explicitly considering atom-level interaction between proteins and ligands in scenarios where crystallized protein-ligand binding conformations are unavailable. Now, with breakthroughs in deep learning AI-based protein folding and binding conformation prediction, can we improve binding affinity prediction? This study introduces a framework, Folding-Docking-Affinity (FDA), which folds proteins, determines protein-ligand binding conformations, and predicts binding affinities from three-dimensional protein-ligand binding structures. Our experiments demonstrate the feasibility of our FDA framework and its superiority over state-of-the-art docking-free models, showcasing the potential of explicit modeling of three-dimensional binding conformations for enhancing binding affinity prediction accuracy.
Massively parallel jumping assay decodesAluretrotransposition activity
Authors: Matharu Navneet , Zhao Jingjing , Sohota Ajuni , Deng Linbei , Hung Yan , Li Zizheng , Sims Jasmine , Rattanasopha Sawitree , Meyer Josh , Carbone Lucia , Kircher Martin , Ahituv Nadav 
Published: April 2024

AbstractThe human genome contains millions of retrotransposons, several of which could become active due to somatic mutations having phenotypic consequences, including disease. However, it is not thoroughly understood how nucleotide changes in retrotransposons affect their jumping activity. Here, we developed a novel massively parallel jumping assay (MPJA) that can test the jumping potential of thousands of transposonsen masse. We generated nucleotide variant library of selected fourAluretrotransposons containing 165,087 different haplotypes and tested them for their jumping ability using MPJA. We found 66,821 unique jumping haplotypes, allowing us to pinpoint domains and variants vital for transposition. Mapping these variants to theAlu-RNA secondary structure revealed stem-loop features that contribute to jumping potential. Combined, our work provides a novel high-throughput assay that assesses the ability of retrotransposons to jump and identifies nucleotide changes that have the potential to reactivate them in the human genome.
A systematic bi-genomic split-GFP assay illuminates the mitochondrial matrix proteome and protein targeting routes
Authors: Bykov Yury S. , Zuttion Solène , Senger Bruno , Klein Ofir , Asraf Yeynit , Meyer Hadar , Becker Hubert D. , Kucharczyk Róża , Schuldiner Maya 
Published: April 2024

AbstractThe majority of mitochondrial proteins are encoded in the nuclear genome and often lack clear targeting signals. Therefore, what constitutes the entire mitochondrial proteome is still unclear. We here build on our previously developed bi-genomic (BiG) split-GFP assay (Bader et al. 2020) to solidify the list of matrix and inner membrane mitochondrial proteins. The assay relies on one fragment (GFP1-10) encoded in the mitochondrial DNA enabling specific visualization of only the proteins tagged with a smaller fragment, GFP11, and localized to the mitochondrial matrix or the inner membrane. We used the SWAp-Tag (SWAT) strategy to tag every protein with GFP11and mated them with the BiG GFP strain. Imaging the collection in six different conditions allowed us to visualize almost 400 mitochondrial proteins, 50 of which were never visualized in mitochondria before, and many are poorly studied dually localized proteins. We also show how this data can be applied to study mitochondrial inner membrane protein topology and sorting. This work brings us closer to finalizing the mitochondrial proteome and the freely distributed library of GFP11-tagged strains will be a useful resource to study protein localization, biogenesis and interactions.
Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4′-CN-4-Aza-7,9-DideazaadenosineC-Nucleoside with Broad-Spectrum Potency Against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys
Authors: Siegel Dustin S. , Hui Hon C. , Pitts Jared , Vermillion Meghan S. , Ishida Kazuya , Rautiola Davin , Keeney Michael , Irshad Hammad , Zhang Lijun , Chun Kwon , Chin Gregory , Goyal Bindu , Doerffler Edward , Yang Hai , Clarke Michael O. , Palmiotti Chris , Vijjapurapu Arya , Riola Nicholas C. , Stray Kirsten , Murakami Eisuke , Ma Bin , Wang Ting , Zhao Xiaofeng , Xu Yili , Lee Gary , Marchand Bruno , Seung Minji , Nayak Arabinda , Tomkinson Adrian , Kadrichu Nani , Ellis Scott , Barauskas Ona , Feng Joy Y. , Perry Jason K. , Perron Michel , Bilello John P. , Kuehl Philip J. , Subramanian Raju , Cihlar Tomas , Mackman Richard L. 
Published: April 2024

AbstractAcute respiratory viral infections (ARVI), such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1) a novel phosphoramidate prodrug of a 4′-CN-4-aza-7,9-dideazaadenosineC-nucleoside GS-646089 (2) with broad antiviral activity against RSV EC50= 3-46 nM, human metapneumovirus (hMPV) EC50= 210 ± 50 nM, human rhinovirus (RV) EC50= 54-61 nM, and enterovirus (EV) EC50= 83-90 nM. Prodrug optimization for cellular potency and lung cell metabolism identified the 5’-methyl((S)-hydroxy(phenoxy)phosphoryl)-L-alaninate in combination with 2’,3’-diisobutyrate promoieties as optimal for high intracellular triphosphate formation in vitro and in vivo.1demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together these finding support additional evaluation of1and its analogs as a potential therapeutic for pneumo- and picornaviruses.
RESIST ACINETO test for the rapid detection of NDM and OXA acquired carbapenemases directly from blood culture inAcinetobacterspecies
Authors: Potron Anaïs , Daniel Marion , Bay Mila , Choulet Pauline , Garrigos Thomas , Sababadichetty Loïk , Belmonte Olivier , Fournier Damien , Jeannot Katy , Miltgen Guillaume 
Published: April 2024

AbstractThe immunochromatographic assay RESIST ACINETO (Coris BioConcept) was evaluated on a collection of 121Acinetobacterspp. clinical isolates, including 104 carbapenemase producers. The strains producing carbapenemases OXA-23, -40, -58, or/and NDM were accurately detected from bacterial cultures and directly from blood cultures, with the exception of an OXA-23/NDM-1-positiveA. radioresistensisolate (only detected through standard culture). The performance of the RESIST ACINETO test was excellent (sensitivity 99%, specificity 100%) on this collection of isolates.
A variant prioritization tool leveraging multiple instance learning for rare Mendelian disease genomic testing
Authors: Kim Ho Heon , Baek Ju Yeop , Han Heonjong , Jeong Won Chan , Kim Dong-Wook , Kwon Kisang , Song Yongjun , Lee Hane , Seo Go Hun , Lee Jungsul , Lee Kyoungyeul 
Published: April 2024

AbstractBackgroundGenomic testing such as exome sequencing and genome sequencing is being widely utilized for diagnosing rare Mendelian disorders. Because of a large number of variants identified by these tests, interpreting the final list of variants and identifying the disease-causing variant even after filtering out likely benign variants could be labor-intensive and time-consuming. It becomes even more burdensome when various variant types such as structural variants need to be considered simultaneously with small variants. One way to accelerate the interpretation process is to have all variants accurately prioritized so that the most likely diagnostic variant(s) are clearly distinguished from the rest.MethodsTo comprehensively predict the genomic test results, we developed a deep learning based variant prioritization system that leverages multiple instance learning and feeds multiple variant types for variant prioritization. We additionally adopted learning to rank (LTR) for optimal prioritization. We retrospectively developed and validated the model with 5-fold cross-validation in 23,115 patients with suspected rare diseases who underwent whole exome sequencing. Furthermore, we conducted the ablation test to confirm the effectiveness of LTR and the importance of permutational features for model interpretation. We also compared the prioritization performance to publicly available variant prioritization tools.ResultsThe model showed an average AUROC of 0.92 for the genomic test results. Further, the model had a hit rate of 96.8% at 5 when prioritizing single nucleotide variants (SNVs)/small insertions and deletions (INDELs) and copy number variants (CNVs) together, and a hit rate of 95.0% at 5 when prioritizing CNVs alone. Our model outperformed publicly available variant prioritization tools for SNV/INDEL only. In addition, the ablation test showed that the model using LTR significantly outperformed the baseline model that does not use LTR in variant prioritization (p=0.007).ConclusionA deep learning model leveraging multiple instance learning precisely predicted genetic testing conclusion while prioritizing multiple types of variants. This model is expected to accelerate the variant interpretation process in finding the disease-causing variants more quickly for rare genetic diseases.
Comparative Analysis of COVID-19 Serological testing methods to Polymerase Chain Reaction: A systematic review and meta-analysis
Authors: Chisompola David , Maleti Alex , Tembo Kingsley , Banda Tioni , Chishinji George , Phiri Richard 
Published: April 2024

AbstractBackgroundAccurate and reliable diagnosis of COVID-19 is essential for effective disease management and public health interventions. SARS-CoV-2 antibody/antigen tests play a crucial role in identifying covid-19 infections and assessing immunity in populations. This systematic review aimed to evaluate the sensitivity, specificity, and accuracy of SARS-CoV-2 antibody tests in diagnosing COVID-19.MethodA comprehensive systematic review of the literature was conducted using prominent scientific databases, including PubMed, Google Scholar, Cochrane, and Scopus to search studies published from January 2020 to May 2023. The review followed the PRISMA-DTA framework to ensure transparency and rigor in the selection and evaluation of studies. The QUADAS-2 tool was utilized to assess study quality and risk of bias. This review was registered on PROSPERO (registration number CRD 42023445695).ResultsThe pooled sensitivity of SARS-CoV-2 antibody/antigen tests was found to be 73% (95% CI: 60–86), with individual studies reporting a wide range from 30% to 100%. The pooled specificity was 98% (95% CI: 97–100), with values ranging from 85.9% to 100%. The pooled accuracy was 88%, showing variation from 50% to 100% across different studies.ConclusionThis review highlights the moderate to high sensitivity and specificity of SARS-CoV-2 antibody/antigen tests for COVID-19 diagnosis. The substantial variability in test performance necessitates the standardization of testing protocols and further research to improve accuracy and reliability. These findings offer valuable insights for clinical decision-making and the formulation of effective public health strategies related to COVID-19 diagnosis.
The Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis cohort population structure and disease etiology
Authors: Pagalilauan Alison M. , Everest Elif , Rachimi Suzanna , Reich Daniel , Waldman Alex D. , Sadovnick A. Dessa , Vilariño-Guell Carles , Lenardo Michael J. 
Published: April 2024

AbstractBackgroundPrevious genetic and epidemiological studies have examined subpopulations from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) patient cohort, but an encompassing analysis of the study population has not yet been carried out.ObjectiveThis study examines patterns of multiple sclerosis (MS) prevalence in 13,663 cohort members, including 4,821 patients with MS or suspected MS and 8,842 family members.MethodsWe grouped participants into epidemiologic subgroups based on age of MS onset, clinical stage at diagnosis, symptom type at disease onset, sex, proband status, disability as measured by the EDSS, and ancestry based on reported ethnicity.ResultsWe observed a 2.7:1 MS prevalence ratio of women to men, though disease severity was greater for male patients. Variation in the age of disease onset between patients was only slightly associated with sex and strongly associated with disease type. Specific types of clinical symptoms at disease onset were associated with the prognosis. Regional residence did not correlate with disease onset, type, or severity.ConclusionPopulation trends, as presented here, are not explained by environmental factors alone, highlighting the need for a comprehensive genetic analysis to understand disease variance across families.