bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting the Trend of SARS-CoV-2 Mutation Frequencies Using Historical Data
Authors: Zhou Xinyu , Hu Kevin , Pan Minmin , Li Yajie , Zhang Chi , Cao Sha 
Published: December 2023

AbstractAs the SARS-CoV-2 virus rapidly evolves, predicting the trajectory of viral variations has become a critical yet complex task. A deep understanding of future mutation patterns, in particular the mutations that will prevail in the near future, is vital in steering diagnostics, therapeutics, and vaccine strategies in the coming months.In this study, we developed a model to forecast future SARS-CoV-2 mutation surges in real-time, using historical mutation frequency data from the USA. To improve upon the accuracy of traditional time-series models, we transformed the prediction problem into a supervised learning framework using a sliding window approach. This involved breaking the time series of mutation frequencies into very short segments. Considering the time-dependent nature of the data, we focused on modeling the first-order derivative of the mutation frequency. We predicted the final derivative in each segment based on the preceding derivatives, employing various machine learning methods, including random forest, XGBoost, support vector machine, and neural network models, in this supervised learning setting. Empowered by the novel transformation strategy and the high capacity of machine learning models, we witnessed low prediction error that is confined within 0.1% and 1% when making predictions for future 30 and 80 days respectively. In addition, the method also led to a notable increase in prediction accuracy compared to traditional time-series models, as evidenced by lower MAE, and MSE for predictions made within different time horizons. To further assess the method’s effectiveness and robustness in predicting mutation patterns for unforeseen mutations, we categorized all mutations into three major patterns. The model demonstrated its robustness by accurately predicting unseen mutation patterns when training on data from two pattern categories while testing on the third pattern category, showcasing its potential in forecasting a variety of mutation trajectories.To enhance accessibility and utility, we built our methodology into an R-shiny app (https://swdatpredicts.shinyapps.io/rshiny_predict/), a tool with potential applicability in studying other infectious diseases, thus extending its relevance beyond the current pandemic.
Genome-wide characterization of 54 urinary metabolites reveals molecular impact of kidney function
Authors: Valo Erkka , Richmond Anne , Mutter Stefan , Campbell Archie , Porteous David , Wilson James F ,   FinnDiane Study Group, Groop Per-Henrik , Hayward Caroline , Sandholm Niina 
Published: December 2023

AbstractDissecting the genetic mechanisms underlying urinary metabolite concentrations can provide molecular insights into kidney function and open possibilities for causal assessment of urinary metabolites with risk factors and disease outcomes. Proton nuclear magnetic resonance metabolomics provides a high-throughput means for urinary metabolite profiling, as widely applied for blood biomarker studies. Here we report a genome-wide association study meta-analysed for 3 European cohorts comprising 8,026 individuals, covering both people with type 1 diabetes and general population settings. We identified 52 associations (p<9.3×10-10) for 19 of 54 studied metabolite concentrations. Out of these, 32 were not reported previously for relevant urinary or blood metabolite traits. Subsequent two-sample Mendelian randomization analysis suggests that estimated glomerular filtration rate (eGFR) causally affects 13 urinary metabolite concentrations whereas urinary ethanolamine, an initial precursor for phosphatidylcholine and phosphatidylethanolamine, was associated with higher eGFR lending support for a potential protective role.
Prevalence study of cellular capsid-specific immune responses to AAV2, 4, 5, 8, 9 and rh10 in healthy donors
Authors: Xicluna Rebecca , Avenel Allan , Vandamme Céline , Devaux Marie , Jaulin Nicolas , Couzinie Célia , Le Duff Johanne , Charrier Alicia , Guilbaud Mickaël , Adjali Oumeya , Gernoux Gwladys 
Published: December 2023

ABSTRACTRecombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors forin vivogene transfer as illustrated by the approvals of 7 drugs across Europe and the USA. Nevertheless, pre-existing immunity to AAV capsid in humans remains one of the major limits for a successful clinical translation. Whereas pre-existing humoral response to AAV capsid is well documented, the prevalence of pre-existing capsid-specific T cell responses still needs to be studied and characterized. Here, we investigated the prevalence of AAV-specific circulating T cells towards AAV2, 4, 5, 8, 9 and rh10 in a large cohort of healthy donors using the standard IFNγ ELISpot assay. We observed the highest prevalence of pre-existing cellular immunity to AAV9 serotype followed by AAV8, AAV4, AAV2, AAVrh10 and AAV5 independently of the donors’ serological status. An in-depth analysis of T cell responses towards the 2 most prevalent serotypes 8 and 9 shows that IFNγ secretion is mainly mediated by CD8 T cells for both serotypes. A polyfunctional analysis reveals different cytokine profiles between AAV8 and AAV9. Surprisingly, no IL-2 secretion was mediated by anti-AAV9 immune cells suggesting that these cells may rather be exhausted or terminally differentiated than cytotoxic T cells. Altogether, these results suggest that pre-existing immunity to AAV may vary depending on the serotype and support the necessity of using multiparametric monitoring methods to better characterize anti-capsid cellular immunity and foresee its impact in rAAV-mediated clinical trials.
Spatial propagation of temperate phages within and among biofilms
Authors: Winans James B. , Garcia Sofia L. , Zeng Lanying , Nadell Carey D. 
Published: December 2023

AbstractBacteria form groups comprised of cells and a secreted polymeric matrix that controls their spatial organization. These groups – termed biofilms – can act as refuges from environmental disturbances and from biotic threats, including phages. Despite the ubiquity of temperate phages and bacterial biofilms, live propagation of temperate phages within biofilms has never been characterized on cellular spatial scales. Here, we leverage several approaches to track temperate phages and distinguish between lytic and lysogenic host infections. We determine that lysogeny withinE. colibiofilms initially occurs within a predictable region of cell group packing architecture on the biofilm periphery. Because lysogens are generally found on the periphery of large cell groups, where lytic viral infections also reduce local biofilm cell packing density, lysogens are predisposed to disperse into the passing liquid and are over-represented in biofilms formed from the dispersal pool of the original biofilm-phage system. Comparing our results with those for virulent phages reveals that temperate phages have previously unknown advantages in propagating over long spatial and time scales within and among bacterial biofilms.
Nanotopography boosts cellular uptake by inducing macropinocytosis
Authors: Aramesh Morteza , Yu Di , Essand Magnus , Persson Cecilia 
Published: December 2023

AbstractEfficient cellular uptake of biomolecules, including genetic material, mRNA, proteins, and nanoparticles, requires novel approaches to overcome inherent cellular barriers. This study investigates how nanotopographical cues from nanoporous surfaces impact the uptake efficiency of diverse molecules by cells. The results demonstrate that cellular uptake efficiency increases significantly on nanoporous surfaces compared to flat surfaces. Notably, this process is found to be dependent on the size and morphology of the nanopores, reaching its peak efficacy with blind pores of 400 nm in size. Enhanced genetic transduction on nanoporous surfaces were observed for multiple vectors, including lentiviruses, baculoviruses, and mRNA molecules. The versatile nature of this approach allows co-transfection of cells with multiple mRNA vectors. Moreover, the nanoporous platform was used for efficient and fast manufacturing of CAR-T cells through lentiviral transduction. Furthermore, we pinpoint macropinocytosis as the predominant mechanism driving increased cellular uptake induced by the nanoporous surfaces. The method introduced here for enhancing genetic transduction of cells has applications in immunotherapy research, drug delivery, and cell engineering.
Rewriting regulatory DNA to dissect and reprogram gene expression
Authors: Martyn Gabriella E. , Montgomery Michael T. , Jones Hank , Guo Katherine , Doughty Benjamin R. , Linder Johannes , Chen Ziwei , Cochran Kelly , Lawrence Kathryn A. , Munson Glen , Pampari Anusri , Fulco Charles P. , Kelley David R. , Lander Eric S. , Kundaje Anshul , Engreitz Jesse M. 
Published: December 2023

AbstractRegulatory DNA sequences within enhancers and promoters bind transcription factors to encode cell type-specific patterns of gene expression. However, the regulatory effects and programmability of such DNA sequences remain difficult to map or predict because we have lacked scalable methods to precisely edit regulatory DNA and quantify the effects in an endogenous genomic context. Here we present an approach to measure the quantitative effects of hundreds of designed DNA sequence variants on gene expression, by combining pooled CRISPR prime editing with RNA fluorescencein situhybridization and cell sorting (Variant-FlowFISH). We apply this method to mutagenize and rewrite regulatory DNA sequences in an enhancer and the promoter ofPPIFin two immune cell lines. Of 672 variant-cell type pairs, we identify 497 that affectPPIFexpression. These variants appear to act through a variety of mechanisms including disruption or optimization of existing transcription factor binding sites, as well as creation ofde novosites. Disrupting a single endogenous transcription factor binding site often led to large changes in expression (up to –40% in the enhancer, and –50% in the promoter). The same variant often had different effects across cell types and states, demonstrating a highly tunable regulatory landscape. We use these data to benchmark performance of sequence-based predictive models of gene regulation, and find that certain types of variants are not accurately predicted by existing models. Finally, we computationally design 185 small sequence variants (≤10 bp) and optimize them for specific effects on expressionin silico. 84% of these rationally designed edits showed the intended direction of effect, and some had dramatic effects on expression (–100% to +202%). Variant-FlowFISH thus provides a powerful tool to map the effects of variants and transcription factor binding sites on gene expression, test and improve computational models of gene regulation, and reprogram regulatory DNA.
Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects
Authors: Ghose Ritobrata , Pezzano Fabio , Kourtis Savvas , Sheraj Ilir , Das Shubhamay , Zapater Antoni Gañez , Ghose Upamanyu , Espinar Lorena , Parapatics Katja , Venturini Valeria , Müller André C , Ruprecht Verena , Sdelci Sara 
Published: December 2023

ABSTRACTThe physical microenvironment regulates cell behaviour. However, whether physical confinement rewires the subcellular localisation of organelles and affect metabolism is unknown. Proteomics analysis revealed that cellular confinement induces a strong enrichment of mitochondrial proteins within the nuclear compartment. High-resolution microscopy confirmed that mechanical cell confinement leads to a rapid re-localisation of mitochondria to the nuclear periphery. This nuclear-mitochondrial proximity is mediated by an endoplasmic reticulum-based net that entraps the mitochondria in an actin-dependent manner. Functionally, the mitochondrial proximity results in a nuclear ATP surge, which can be reverted by the pharmacological inhibition of mitochondrial ATP production or via actin depolymerisation. Inhibition of the confinement-derived nuclear ATP surge reveals long-term effects on cell fitness which arise from alterations of chromatin states, delayed DNA damage repair, and impaired cell cycle progression. Together, our data describe a confinement-induced metabolic adaptation that is required to enable prompt DNA damage repair and cell cycle progression by allowing chromatin state transitions.
Sculpting conducting nanopore size and shape throughde novoprotein design
Authors: Berhanu Samuel , Majumder Sagardip , Müntener Thomas , Whitehouse James , Berner Carolin , Bera Asim K. , Kang Alex , Liang Binyong , Khan G Nasir , Sankaran Banumathi , Tamm Lukas K. , Brockwell David J. , Hiller Sebastian , Radford Sheena E. , Baker David , Vorobieva Anastassia A. 
Published: December 2023

AbstractTransmembrane β-barrels (TMBs) are widely used for single molecule DNA and RNA sequencing and have considerable potential for a broad range of sensing and sequencing applications. Current engineering approaches for nanopore sensors are limited to naturally occurring channels such as CsgG, which have evolved to carry out functions very different from sensing, and hence provide sub-optimal starting points. In contrast,de novoprotein design can in principle create an unlimited number of new nanopores with any desired properties. Here we describe a general approach to the design of transmembrane β-barrel pores with different diameter and pore geometry. NMR and crystallographic characterization shows that the designs are stably folded with structures close to the design models. We report the first examples ofde novodesigned TMBs with 10, 12 and 14 stranded β-barrels. The designs have distinct conductances that correlate with their pore diameter, ranging from 110 pS (∼0.5 nm pore diameter) to 430 pS (∼1.1 nm pore diameter), and can be converted into sensitive small-molecule sensors with high signal to noise ratio. The capability to generate on demand β-barrel pores of defined geometry opens up fundamentally new opportunities for custom engineering of sequencing and sensing technologies.One sentence summaryDe novo design enables the generation of stable and quite transmembrane beta-barrel nanopores with tailored sizes, shapes and properties.
Low land-use intensity buffers grasslands against future climate and inter-annual climate variability in a large field experiment
Authors: Korell Lotte , Andrzejak Martin , Berger Sigrid , Durka Walter , Haider Sylvia , Hensen Isabell , Herion Yva , Höfner Johannes , Kindermann Liana , Klotz Stefan , Knight Tiffany M. , Linstädter Anja , Madaj Anna-Maria , Merbach Ines , Michalski Stefan , Plos Carolin , Roscher Christiane , Schädler Martin , Welk Erik , Auge Harald 
Published: December 2023

AbstractClimate and land-use change are key drivers of global change. Full-factorial field experiments in which both drivers are manipulated are essential to understand and predict their potentially interactive effects on the structure and functioning of grassland ecosystems. Here, we present eight years of data on grassland dynamics from the Global Change Experimental Facility (GCEF) in Central Germany. On large experimental plots, temperature and seasonal patterns of precipitation are manipulated by superimposing regional climate model projections onto background climate variability. Climate manipulation is factorially crossed with agricultural land-use scenarios, including intensively used meadows and extensively used (i.e. low-intensity) meadows and pastures. Inter-annual variation of background climate during our study years was high, including three of the driest years on record for our region. The effects of this temporal variability far exceeded the effects of the experimentally imposed climate change on plant species diversity and productivity, especially in the intensively used, species-poor grasslands. These changes in productivity and diversity in response to alterations in climate were due to immigrant species replacing the target forage cultivars. This shift from forage cultivars to immigrant species may impose additional economic costs in terms of a decreasing fodder value and the need for more frequent management measures. In contrast, the extensively used, species-rich grasslands showed weaker responses to both experimentally manipulated future climate and inter-annual climate variability, suggesting that these diverse grasslands are more resistant to climate change than intensively used, species-poor grasslands. We therefore conclude that an extensive management of agricultural grasslands, together with other measures to increase species diversity, can stabilize primary productivity under climate change.
MUT-7 exoribonuclease activity and localisation are mediated by an ancient domain
Authors: Busetto Virginia , Pshanichnaya Lizaveta , Lichtenberger Raffael , Hann Stephan , Ketting René F. , Falk Sebastian 
Published: December 2023

AbstractThe MUT-7 family of 3’-5’ exoribonucleases is evolutionarily conserved across the animal kingdom and plays essential roles in small RNA production in the germline. Most MUT-7 homologs carry a C-terminal domain of unknown function named MUT7-C appended to the exoribonuclease domain. Our analysis shows that the MUT7-C is evolutionary ancient, as a minimal version of the domain exists as an individual protein in prokaryotes. In animals, MUT7-C has acquired an insertion that diverged during evolution, expanding its functions.C. elegansMUT-7 contains a specific insertion within MUT7-C, which allows binding to MUT-8 and, consequently, MUT-7 recruitment to germ granules. In addition, inC. elegansand human MUT-7, the MUT7-C domain contributes to RNA binding and is thereby crucial for nuclease activity. This RNA-binding function most likely represents the ancestral function of the MUT7-C domain. Overall, this study sheds light on MUT7-C and assigns two functions to this previously uncharacterised domain.
The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1
Authors: Honzejkova Karolina , Košek Dalibor , Obsilova Veronika , Obsil Tomas 
Published: December 2023

AbstractApoptosis signal-regulating kinase 1 (ASK1) is a crucial stress sensor, directing cells towards apoptosis, differentiation and senescence via the p38 and JNK signaling pathways. ASK1 dysregulation has been associated with cancer and inflammatory, cardiovascular and neurodegenerative diseases, among others. However, our limited knowledge of the underlying structural mechanism of ASK1 regulation hampers our ability to target this member of the MAP3K protein family towards developing therapeutic interventions for these disorders. Nevertheless, as a multidomain Ser/Thr protein kinase, ASK1 is regulated by a complex mechanism involving dimerization and interactions with several other proteins, including thioredoxin 1 (TRX1). Thus, the present study aims at structurally characterizing ASK1 and its complex with TRX1 using several biophysical techniques. As shown by cryo-EM analysis, in a state close to its active form, ASK1 is a compact and asymmetric dimer, which enables extensive interdomain and interchain interactions. These interactions stabilize the active conformation of the ASK1 kinase domain. In turn, TRX1 functions as a negative allosteric effector of ASK1, modifying the structure of the TRX1-binding domain and changing its interaction with the tetratricopeptide repeats domain. Consequently, TRX1 reduces access to the activation segment of the kinase domain. Overall, our findings not only clarify the role of ASK1 dimerization and inter-domain contacts but also provide key mechanistic insights into its regulation, thereby highlighting the potential of ASK1 protein-protein interactions as targets for antiinflammatory therapy.
Genetic drift drives faster-Z evolution in the salmon louseLepeophtheirus salmonis
Authors: Mongue Andrew J. , Baird Robert B. 
Published: December 2023

AbstractSex chromosome evolution is a particularly complex sub-field of population genetics and there are still unresolved questions about how quickly and adaptively these chromosomes should evolve compared to autosomes. One key limitation to existing knowledge is an intense focus on only a handful of taxa in existing literature, resulting in uncertainty about whether observed patterns reflect general processes or are idiosyncratic to the more widely studied clades. In particular, the Z chromosomes of female heterogametic (ZW) systems tend to be quickly but not adaptively evolving in birds, while in butterflies and moths Z chromosomes tend to be evolving adaptively, but not always faster than autosomes. To understand how these two observations fit into broader evolutionary patterns, we explore, for the first time, patterns of Z chromosome evolution outside of these two well-studied clades. We utilize a publicly available high quality genome, gene expression, population, and outgroup data for the salmon louseLepeophtheirus salmonis, an important aquacultural pest copepod. We find that the Z chromosome is faster evolving than the autosomes, but that this increased effect is driven by drift rather than adaptive evolution. This faster-Z effect seems to be a result of a very low effective population size of the Z chromosome, as well as high rates of female reproductive failure contributing to decreased efficiency of hemizygous selection acting on the Z. These results highlight the usefulness of organismal life history in calibrating population genetic expectations and demonstrate the usefulness of the ever-expanding wealth of modern publicly available genomic data to help resolve outstanding evolutionary questions.
L-Glyceraldehyde inhibits neuroblastoma cell growth via a multi-modal mechanism on metabolism and signaling
Authors: Forbes Martin , Kempa Richard , Mastrobuoni Guido , Rayman Liam , Pietzke Matthias , Bayram Safak , Arlt Birte , Spruessel Annika , Deubzer Hedwig , Kempa Stefan 
Published: December 2023

ABSTRACTGlyceraldehyde (GA) is a 3-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. This phenomenon was extensively studied up until the 1970’s. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits cancer cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and13C-labelling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in the cancer cell. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. This elucidated a specific subset of proteins harbouring oxidoreductase and antioxidant activity. Analysis of nucleotide pools in L-GA treated cells depicted a remarkable and previously unreported phenotype. Nucleotide biosynthesis in neuroblastoma cells is significantly inhibited upon L-GA treatment. Through the application of the antioxidant N-acetyl-cysteine in conjunction with L-GA, metabolic inhibition was partially relieved. We present novel evidence for the multi-modal mechanism of L-GA action in neuroblastoma cells. Specifically, a simple sugar that inhibits the growth of cancer via dysregulating the fragile homeostatic environment inherent to the cancerous cell.