bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of the Usability of SARS-CoV-2 Self Tests in a Peer-Assisted Model among Factory Workers in Bengaluru, India
Authors: Pydi Meghana Ratna , Stankard Petra , Parikh Neha , Ranawat Purnima , Kaur Ravneet , Shankar AG , Chaudhuri Angela , Shilton Sonjelle , Srinivasan Aditi , Chowdhury Joyita , Reipold Elena Ivanova 
Published: November 2023

AbstractIn order to mitigate the inequities in health outcomes and healthcare access for vulnerable populations during the COVID-19 pandemic, the government of India introduced antigen-based SARS-CoV-2 self-testing kits for self-administered use. In this study, we aimed to determine the usability of these nasal-sampling-based self-tests in a peer-assisted model among factory workers in Bengaluru. The mixed-method cross-sectional study was conducted with 106 factory workers, spanning two sites from February to March 2022 in Bengaluru, India. Panbio™ COVID-19 Antigen Self-Test kit and the mobile application NAVICA for self-reporting results were used. A peer assistant distributed test kits, guided participants on conducting tests and using the app, and offered demonstrations with their own kit, ensuring no contact with the participants’ kits. Findings were encapsulated by an observer, who used standardized product-specific usability checklists and pictures of contrived results to assess the usability of the kit and mobile application, result interpretation, and the efficiency of peer instruction/demonstration. Additionally, a post-test survey and focus group discussions with selected participants and peer assistants were conducted to understand user perceptions of the facilitators and barriers to usability. Study findings show that the overall usability score of the test kit with peer assistance was 75.9%, rising to 80.7% for critical steps and 33.8% for all critical steps in uploading results through NAVICA. Additionally, it was seen that peer assistants provided accurate instructions and support for 93.4% of the tests. Among the critical steps in test kit use, maximum errors were made in sample collection and using the correct amount of buffer solution. Concordance between the participant and observer/NAVICA was 97.9%. 62.0% and 56.6% of the participants reported confidence in a) performing and interpreting the test and b) capturing and uploading their results using the mobile application with the assistance of a peer, respectively. Less than half the participants reported confidence in performing these steps independently. The study indicates that the COVID-19 nasal self-testing kit has good usability in factories’ peer-assisted workplace testing model. Such models can empower vulnerable worker groups to access early detection and self-care tools equitably.
Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA Damage Response inhibitors
Authors: Papp Orsolya , Jordán Viktória , Hetey Szabolcs , Balázs Róbert , Bartha Árpád , Ordasi Nóra N. , Kamp Sebestyén , Farkas Bálint , Mettetal Jay , Dry Jonathan R. , Young Duncan , Sidders Ben , Bulusu Krishna C. , Veres Daniel V. 
Published: November 2023

AbstractCombination therapy is well established as a key intervention strategy for cancer treatment, with the potential to overcome monotherapy resistance and deliver a more durable efficacy. However, given the scale of unexplored potential target space and the resulting combinatorial explosion, identifying efficacious drug combinations is a critical unmet need that is still evolving. In this paper, we demonstrate a network biology-driven, simulation-based solution, the Simulated Cell. Integration of omics data with a curated signaling network enables the accurate and interpretable prediction of 66,348 combination-cell line pairs obtained from a large-scale combinatorial drug sensitivity screen of 684 combinations across 97 cancer cell lines (BAC= 0.62, AUC=0.7). We highlight drug combination pairs that interact with DNA Damage Response pathways and are predicted to be synergistic, and deep network insight to identify biomarkers driving combination synergy. We demonstrate that the cancer cell ‘avatars’ capture the biological complexity of theirin vitrocounterparts, enabling the identification of pathway-level mechanisms of combination benefit to guide clinical translatability.
Genome-Scale Modeling ofRothia mucilaginosaReveals Insights into Metabolic Capabilities and Therapeutic Strategies for Cystic Fibrosis
Authors: Leonidou Nantia , Ostyn Lisa , Coenye Tom , Crabbé Aurélie , Dräger Andreas 
Published: November 2023

ABSTRACTBackgroundCystic fibrosis (CF) is an inherited genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in the production of sticky and thick mucosal fluids. This leads to an environment that facilitates the colonization of various microorganisms, some of which can cause acute and chronic lung infections, while others may have a positive influence on the disease process.Rothia mucilaginosa, an oral commensal, is relatively abundant in the lungs of CF patients. Recent studies have unveiled the anti-inflammatory properties ofR. mucilaginosausingin vitrothree-dimensional (3-D) lung epithelial cell cultures andin vivomouse models relevant to chronic lung diseases. Apart from a potentially beneficial anti-inflammatory role in chronic lung diseases,R. mucilaginosahas been associated with severe infections. This dual nature highlights the bacterium’s complexity and diverse impact on health and disease. However, its metabolic capabilities and genotype-phenotype relationships remain largely unknown.ResultsTo gain insights into the cellular metabolism and genetic content ofR. mucilaginosa, we developed the first manually curated genome-scale metabolic model,iRM23NL. Through growth kinetic experiments and high-throughput phenotypic microarray testings, we defined its complete catabolic phenome. Subsequently, we assessed the model’s effectiveness in accurately predicting growth behaviors and utilizing multiple substrates. We used constraint-based modeling techniques to formulate novel hypotheses that could expedite the development of antimicrobial strategies. More specifically, we detected putative essential genes and assessed their effect on metabolism under varying nutritional conditions. These predictions could offer novel potential antimicrobial targets without laborious large-scale screening of knock-outs and mutant transposon libraries.ConclusionOverall,iRM23NL demonstrates a solid capability to predict cellular phenotypes and holds immense potential as a valuable resource for accurate predictions in advancing antimicrobial therapies. Moreover, it can guide metabolic engineering to tailorR. mucilaginosa’s metabolism for desired performance.
Chikungunya-virus-specific CD4+T cells are associated with chronic chikungunya viral arthritic disease in humans
Authors: Chang James , Agarwal Rimjhim , Côrtes Fernanda H , Ha Calvin , Villalpando John , Castillo Izabella N. , Gálvez Rosa Isela , Grifoni Alba , Sette Alessandro , Romero-Vivas Claudia M , Heise Mark T , Premkumar Lakshmanane , Falconar Andrew K , Weiskopf Daniela 
Published: November 2023

SUMMARYChikungunya virus (CHIKV) is a mosquito-borne re-emerging viral infection that can cause chronic chikungunya viral arthritic disease (CHIKVD), which is characterized by incapacitating arthralgia and inflammation that can last for months to years following infection. Despite CHIKV outbreaks occurring worldwide and several vaccines currently in development, immune responses to CHIKV in humans remains largely understudied, and targets of T cell response are currently unknown. In this study, we tested peripheral blood mononuclear cells (PBMCs) collected from patients diagnosed with CHIKV infection during the 2014-2015 outbreak in Colombia against pools of overlapping peptides sequentially spanning each CHIKV protein. Using high-resolution flow cytometry, we detected robust CHIKV-specific CD4+, but not CD8+T cell responses, in these patients. Patients still experiencing disease symptoms six years after infection displayed significantly stronger CHIKV- specific CD4+T cell responses against nsP1, nsP2 and E2 proteins, compared to patients that resolved the infection. CHIKV-specific CD4+ T cells in symptomatic patients displayed a significantly lower Th1 CD4+helper T cell responses and were enriched within the Th17 CD4+helper subset, identifying tumor necrosis factor-alpha (TNFα) as the predominantly produced cytokine. In conclusion, this study comprehensively characterizes the T cell response against CHIKV in humans during the chronic phase and provides insights into the role of T cells and possible treatment of CHIKVD.
Interspecific transfer of genetic information through polyploid bridges
Authors: Kauai Felipe , Bafort Quinten , Mortier Frederik , Van Montagu Marc , Bonte Dries , Van de Peer Yves 
Published: November 2023

AbstractMany organisms have more than two sets of chromosomes, due to whole genome duplication (WGD), and are thus polyploid. Despite usually being an ephemeral state in the history of life, polyploidy is widely recognized as an important source of genetic novelty over macroevolutionary scales. More recently, polyploidy has also been shown to facilitate interspecific gene flow, circumventing reproductive barriers between their diploid ancestors. Yet, the implications of WGD-linked introgression on community-level evolutionary dynamics remain unknown. Here, we develop a model of cytotype dynamics within mixed-ploidy populations to demonstrate that polyploidy can in fact serve as a bridge for gene flow between diploid lineages, where introgression is fully or partially hampered by the species barrier. Polyploid bridges emerge in the presence of triploid organisms, which despite critically low levels of viability, can still allow the transfer of alleles between diploid states of independently evolving mixed-ploidy species. Notably, while marked genetic divergence prevents WGD-mediated interspecific gene flow, we show that increased recombination rates can offset these evolutionary constraints, which allows a more efficient sorting of alleles at higher-ploidy levels before introgression into diploid gene pools. Additionally, we derive an analytical approximation for the rate of gene flow at the tetraploid level necessary to supersede introgression between diploids with non-zero introgression rates, which is especially relevant for plant species complexes, where interspecific gene flow is ubiquitous. Altogether, our results illustrate the potential impact of polyploid bridges on evolutionary change within and between mixed-ploidy populations.
Plant-pollinator interactions in apple orchards from a production and conservation perspective
Authors: Mupepele Anne-Christine , von Königslöw Vivien , Bleile Anna-Maria , Fornoff Felix , Fründ Jochen , Klein Alexandra-Maria 
Published: November 2023

AbstractIn an agricultural landscape, production and conservation ideally go hand in hand. In a win-win scenario, conservation measures provide support for biodiversity and crop production, mediated by pollination for example. Hedges and flower strips are conservation measures that support pollinating insects, such as wild bees and hoverflies. They can be beneficial for crop pollination, but also harmful by dragging away pollinators from crops if flowering simultaneously. Here, we studied plant-pollinator interactions from two different perspectives. First we look at the apple-flower/production perspective investigating whether plant-pollinator networks in apple orchards differ with adjacent flower strips and hedges compared to isolated orchards. With help of the Bayes factor, we investigated similarity and conclude that there are no differences between pollination networks with or without adjacent flower strips and hedges. Second, we look at the pollinator/conservation perspective and analyse the impact of hedges and flower strips on pollinators and their interactions with plants before and after the apple bloom in April. We show that apple pollinators use more flower resources in flower strips and hedges across the whole season compared to isolated orchards. In orchards with flower strips and hedges interactions are more constant over time. We conclude that flower strips and hedges are beneficial for conservation of apple pollinators without being harmful for apple flower pollination being crucial for production.
DNA-binding factor footprints and enhancer RNAs identify functional non-coding genetic variants
Authors: Biddie Simon C , Weykopf Giovanna , Hird Elizabeth F. , Friman Elias T. , Bickmore Wendy A 
Published: November 2023

AbstractGenome-wide association studies (GWAS) have revealed a multitude of candidate genetic variants affecting the risk of developing complex traits and diseases. However, these highlighted regions are typically in the non-coding genome, and uncovering the functional causative single nucleotide variants (SNVs) is challenging. Prioritisation of variants is commonly based on functional genomic annotation with markers of active regulatory elements, but current approaches still poorly predict functional variants. To address this, we systematically analyse six markers of active regulatory elements for their ability to identify functional variants. We benchmark against molecular quantitative trait loci (molQTL) from assays of regulatory element activity that identify allelic effects on DNA-binding factor occupancy, reporter assay expression, and chromatin accessibility. We identify the combination of DNase footprints and divergent enhancer RNA as markers for functional variants. This signature provides high precision, trading-off low recall, thus substantially reducing candidate variant sets to prioritise variants for functional validation. We present this as a framework called FINDER – Functional SNV IdeNtification using DNase footprints and Enhancer RNA, and demonstrate its utility to prioritise variants using leukocyte count trait and analyse variants in linkage disequilibrium with a lead variant to predict a functional variant in asthma. Our findings have implications for prioritising variants from GWAS, in development of predictive scoring algorithms, and for functionally informed fine mapping approaches.
Substrate accessibility regulation of human TopIIa decatenation by cohesin
Authors: Cutts Erin E. , Saravanan Sanjana , Fisher Gemma L. M. , Rueda David S. , Aragon Luis 
Published: November 2023

AbstractHuman topoisomerase II alpha (TOP2α) is the main mitotic decatenase1–3resolving intertwines between sister chromatids that form during DNA replication4. Here, we employ quadruple-trap optical tweezers to generate braids between a pair of λ-DNA molecules to study, at the single-molecule level and in real-time, how TOP2α untangles these DNAs. We find that TOP2α rapidly resolves single and multiple braids and is inhibited by chemotherapy agent, etoposide. TOP2α is sensitive to DNA conformation, exhibiting a chiral preference for the removal of braids with right-handed crossings and is inhibited when DNAs are held at forces over 20pN. We show that TOP2α must load at the cross between the two DNAs to resolve braids efficiently. TOP2α pre-loaded onto individual DNAs is unable to resolve newly formed braids in the presence of ATP, suggesting that the geometry of pre-bound enzyme is incompatible with the capture of the second DNA. Finally, we show that cohesin binds to braids, preventing TOP2α from resolving them. Our study unveils novel insights into the regulation of TOP2α’s decatenation, underscoring the importance of substrate accessibility and the role of cohesin in modulating TOP2α activity.
Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes
Authors: Wang Yihan , Armendariz Daniel , Wang Lei , Zhao Huan , Xie Shiqi , Hon Gary C. 
Published: November 2023

ABSTRACTGenetic studies have associated thousands of enhancers with breast cancer. However, the vast majority have not been functionally characterized. Thus, it remains unclear how variant-associated enhancers contribute to cancer. Here, we perform single-cell CRISPRi screens of 3,512 regulatory elements associated with breast cancer to measure the impact of these regions on transcriptional phenotypes. Analysis of >500,000 single-cell transcriptomes in two breast cancer cell lines shows that perturbation of variant-associated enhancers disrupts breast cancer gene programs. We observe variant-associated enhancers that directly or indirectly regulate the expression of cancer genes. We also find one-to-multiple and multiple-to-one network motifs where enhancers indirectly regulate cancer genes. Notably, multiple variant-associated enhancers indirectly regulate TP53. Comparative studies illustrate sub-type specific functions between enhancers in ER+ and ER- cells. Finally, we developed the pySpade package to facilitate analysis of single-cell enhancer screens. Overall, we demonstrate that enhancers form regulatory networks that link cancer genes in the genome, providing a more comprehensive understanding of the contribution of enhancers to breast cancer development.
Highly parallelized construction of DNA from low-cost oligonucleotide mixtures using Data-optimized Assembly Design and Golden Gate
Authors: Lund Sean , Potapov Vladimir , Johnson Sean R. , Buss Jackson , Tanner Nathan A. 
Published: November 2023

AbstractCommercially synthesized genes are typically made using variations of homology-based cloning techniques, including polymerase cycling assembly from chemically synthesized microarray-derived oligonucleotides. Here we apply Data-optimized Assembly Design to the synthesis of hundreds of codon-optimized genes in both constitutive and inducible vectors using Golden Gate Assembly. Starting from oligonucleotide pools, we synthesize genes in three simple steps: 1) Amplification of parts belonging to individual assemblies in parallel from a single pool; 2) Golden Gate Assembly of parts for each construct; and 3) Transformation. We construct genes from receiving DNA to sequence confirmed isolates in as little as 4 days. By leveraging the ligation fidelity afforded by T4 DNA ligase, we expect to be able to construct a larger breadth of sequences not currently supported by homology-based methods which require stability of extensive single-stranded DNA overhangs.
Decoding the chemical language ofSuillusfungi: genome mining and untargeted metabolomics uncover terpene chemical diversity
Authors: Mudbhari Sameer , Lofgren Lotus , Appidi Manasa R. , Vilgalys Rytas , Hettich Robert L. , Abraham Paul 
Published: November 2023

AbstractEctomycorrhizal fungi establish mutually beneficial relationships with trees, trading nutrients for carbon.Suillusare ectomycorrhizal fungi that are critical to the health of boreal and temperate forest ecosystems. Comparative genomics has identified a high number of non-ribosomal peptide synthetase and terpene biosynthetic gene clusters (BGC) potentially involved in fungal competition and communication. However, the functionality of these BGCs is not known. This study employed co-culture techniques to activate BGC expression and then used metabolomics to investigate the diversity of metabolic products produced by threeSuillusspecies (S. hirtellusEM16,S. decipiensEM49, andS. cothurnatusVC1858), core members of the Pine microbiome. After 28 days of growth on solid media, liquid chromatography–tandem mass spectrometry identified a diverse range of extracellular metabolites (exometabolites) along the interaction zone betweenSuillusco-cultures. Prenol lipids were among the most abundant chemical classes. Out of the 62 unique terpene BGCs predicted by genome mining, 116 putative terpenes were identified across the threeSuillusspecies using metabolomics. Notably, some terpenes were significantly more abundant in co-culture conditions. For example, we identified a metabolite matching to isomers isopimaric acid, sandaracopimaric acid, and abietic acid, which can be found in pine resin and play important roles in host defense mechanisms andSuillusspore germination. This research highlights the importance of combining genomics and metabolomics to advance our understanding of the chemical diversity underpinning fungal signaling and communication.ImportanceUsing a combination of genomics and metabolomics, this study’s findings offer new insights into the signaling and communication ofSuillusfungi, which serve a critical role in forest ecosystems.
Using Deep Learning to Decipher the Impact of Telomerase Promoter Mutations on the Morpholome
Authors: Nevarez Andres J. , Mudla Anusorn , Diaz Sabrina A. , Hao Nan 
Published: November 2023

AbstractMelanoma showcases a complex interplay of genetic alterations and cellular morphological changes during metastatic transformation. While pivotal, the role of specific mutations in dictating these changes still needs to be fully elucidated. Telomerase promoter mutations (TPMs) significantly influence melanoma’s progression, invasiveness, and resistance to various emerging treatments, including chemical inhibitors, telomerase inhibitors, targeted therapy, and immunotherapies. We aim to understand the morphological and phenotypic implications of the two dominant monoallelic TPMs, C228T and C250T, enriched in melanoma metastasis. We developed isogenic clonal cell lines containing the TPMs and utilized dual-color expression reporters steered by the endogenous Telomerase promoter, giving us allelic resolution. This approach allowed us to monitor morpholomic variations induced by these mutations. TPM-bearing cells exhibited significant morpholome differences from their wild-type counterparts, with increased allele expression patterns, augmented wound-healing rates, and unique spatiotemporal dynamics. Notably, the C250T mutation exerted more pronounced changes in the morpholome than C228T, suggesting a differential role in metastatic potential. Our findings underscore the distinct influence of TPMs on melanoma’s cellular architecture and behavior. The C250T mutation may offer a unique morpholomic and systems-driven advantage for metastasis. These insights provide a foundational understanding of how a non-coding mutation in melanoma metastasis affects the system, manifesting in cellular morpholome.