bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbiome Metabolome Integration Platform (MMIP): a web-based platform for microbiome and metabolome data integration and feature identification
Authors: Gautam Anupam , Bhowmik Debaleena , Basu Sayantani , Zeng Wenhuan , Lahiri Abhishake , Huson Daniel H. , Paul Sandip 
Published: April 2023

AbstractA microbial community maintains its ecological dynamics via metabolite crosstalk. Hence knowledge of the metabolome, alongside its populace, would help us understand the functionality of a community and also predict how it will change in atypical conditions. Methods that employ low-cost metagenomic sequencing data can predict the metabolic potential of a community, that is, its ability to produce or utilize specific metabolites. These, in turn, can potentially serve as markers of biochemical pathways that are associated with different communities. We developed MMIP (Microbiome Metabolome Integration Platform), a web-based analytical and predictive tool that can be used to compare the taxonomic content, diversity variation and the metabolic potential between two sets of microbial communities from targeted amplicon sequencing data. MMIP is capable of highlighting statistically significant taxonomic, enzymatic and metabolic attributes as well as learning-based features associated with one group in comparison with another. Further MMIP can predict linkages among species or groups of microbes in the community, specific enzyme profiles, compounds or metabolites associated with such a group of organisms. With MMIP, we aim to provide a user-friendly, online web-server for performing key microbiome-associated analyses of targeted amplicon sequencing data, predicting metabolite signature, and using learning-based linkage analysis, without the need for initial metabolomic analysis, and thereby helping in hypothesis generation.
Identifying the limits where variation in consumer stable isotope values reflect variation in diet
Authors: Arnoldi Jean-François , Bortoluzzi Jenny Rose , Rowlands Hugh , Harrod Chris , Parnell Andrew , Payne Nicholas , Donohue Ian , Jackson Andrew L 
Published: April 2023

AbstractAnalysis of stable isotopes in cosumbers is used commonly to study their ecological and/or environmental niche. There is, however, considerable debate regarding how isotopic values relate to diet and how other sources of variation confound this link, which can undermine the utility.From the analysis of a simple, but general, model of isotopic incorporation in consumer organisms, we examine the relationship between isotopic variance among individuals, and diet variability within a consumer population.We show that variance in consumer isotope values is directly proportional to variation in diet (through Simpson indices), to the number of isotopically distinct food sources in the diet, and to the baseline variation within and among the isotope values of the food sources. Additionally, when considering temporal diet variation within a consumer we identify the interplay between diet turnover rates and tissue turnover rates that controls the sensitivity of stable isotopes to detect diet variation.Our work demonstrates that variation in the stable isotope values of consumers reflect variation in their diet. This relationship, however, can be confounded with other factors to the extent that they may mask the signal coming from diet. We show how simple quantitative corrections can recover a direct 1:1 correlation in some situations, and in others we can adjust our interpretation in light of the new understanding arising from our models. Our framework provides guidance for the design and analysis of empirical studies where the goal is to infer niche width from stable isotope data.
Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer
Authors: Pellecchia Simona , Franchini Melania , Viscido Gaetano , Arnese Riccardo , Gambardella Gennaro 
Published: April 2023

ABSTRACTEpidermal growth factor receptor (EGFR)-targeted therapies have demonstrated variable and unpredictable clinical responses in triple negative breast cancer (TNBC). To elucidate the underlying mechanisms of this variability, we employ cellular barcoding and single-cell transcriptomics to reconstruct the subclonal dynamics of EGFR-amplified TNBC cells in response to afatinib, a tyrosine kinase inhibitor (TKI) that irreversibly inhibits EGFR. Integrated lineage tracing analysis revealed a rare pre-existing subpopulation of cells with distinct biological signature, including elevated expression levels of IGFBP2 (Insulin-Like Growth Factor Binding Protein 2). We show that IGFBP2 overexpression is sufficient to render TNBC cells tolerant to afatinib treatment by activating the compensatory IGF1-R signalling pathway. Finally, based on reconstructed mechanisms of resistance, we employ deep learning techniques to predict the afatinib sensitivity of TNBC cells. Our strategy proved effective in reconstructing the complex signalling network driving EGFR-targeted therapy resistance, offering new insights for the development of individualized treatment strategies in TNBC.
Logic-Based Modeling of Inflammatory Macrophage Crosstalk with Glomerular Endothelial Cells in Diabetic Kidney Disease
Authors: Patidar Krutika , Ford Versypt Ashlee N. 
Published: April 2023

ABSTRACTDiabetic kidney disease is a complication in one out of three patients with diabetes. Aberrant glucose metabolism in diabetes leads to structural and functional damage in glomerular tissue and a systemic inflammatory immune response. Complex cellular signaling is at the core of metabolic and functional derangement. Unfortunately, the mechanism underlying the role of inflammation in glomerular endothelial cell dysfunction during diabetic kidney disease is not fully understood. Mathematical models in systems biology allow the integration of experimental evidence and cellular signaling networks to understand mechanisms involved in disease progression. This study developed a logic-based ordinary differential equations model to study inflammatory crosstalk between macrophages and glomerular endothelial cells during diabetic kidney disease progression using a protein signaling network stimulated with glucose and lipopolysaccharide. This modeling approach reduced the biological parameters needed to study signaling networks. The model was fitted to and validated against available biochemical data fromin vitroexperiments. The model identified mechanisms for dysregulated signaling in macrophages and glomerular endothelial cells during diabetic kidney disease. In addition, the influence of signaling interactions on glomerular endothelial cell morphology through selective knockdown and downregulation was investigated. Simulation results showed that partial knockdown of VEGF receptor 1, PLC-γ, adherens junction proteins, and calcium partially recovered the intercellular gap width between glomerular endothelial cells. These findings contribute to understanding signaling and molecular perturbations that affect the glomerular endothelial cells in the early stage of diabetic kidney disease.NEW & NOTEWORTHYThe work provides a novel analysis of signaling crosstalk between macrophages and glomerular endothelial cells in the early stage of diabetic kidney disease. A logic-based mathematical modeling approach identified vital signaling molecules and interactions that regulate glucose-mediated inflammation in the glomerular endothelial cells and cause endothelial dysfunction in the diabetic kidney. Simulated interactions among vascular endothelial growth factor receptor 1, nitric oxide, calcium, and junction proteins significantly affect the intercellular gap between glomerular endothelial cells.
Urbanization and a green corridor do not impact genetic divergence in common milkweed (Asclepias syriaca)
Authors: Breitbart Sophie T. , Agrawal Anurag A. , Wagner Helene H. , Johnson Marc T.J. 
Published: April 2023

AbstractUrbanization is altering landscapes globally at an unprecedented rate. While ecological differences between urban and rural environments often promote phenotypic divergence among populations, it is unclear to what degree these trait differences arise from genetic divergence as opposed to phenotypic plasticity. Furthermore, little is known about how specific landscape elements, such as green corridors, impact genetic divergence in urban environments. We tested the hypotheses that: 1) urbanization, and 2) proximity to an urban green corridor influence genetic divergence inAsclepias syriaca(common milkweed) populations for phenotypic traits. Using seeds from 52 populations along three urban-to-rural subtransects in the Greater Toronto Area, one of which followed a green corridor, we grew ∼1000 plants in a common garden and observed >20 ecologically-important traits associated with plant defense/damage, reproduction, and growth over four years. We found significant heritable variation for eight traits withinA. syriacapopulations and weak phenotypic divergence among populations. However, neither urbanization nor an urban green corridor influenced genetic divergence in individual traits or multivariate phenotype. These findings contrast with the expanding literature demonstrating that urbanization promotes rapid evolutionary change and offer preliminary insights into the eco- evolutionary role of green corridors in urban environments.
µPhos: a scalable and sensitive platform for functional phosphoproteomics
Authors: Oliinyk Denys , Will Andreas , Schneidmadel Felix R. , Humphrey Sean J. , Meier Florian 
Published: April 2023

AbstractMass spectrometry has revolutionized cell signaling research by vastly simplifying the identification and quantification of many thousands of phosphorylation sites in the human proteome. Defining the cellular response to internal or external perturbations in space and time is crucial for further illuminating functionality of the phosphoproteome. Here we describe µPhos, an accessible phosphoproteomics platform that permits phosphopeptide enrichment from 96-well cell culture experiments in < 8 hours total processing time. By minimizing transfer steps and reducing liquid volumes to < 200 µL, we demonstrate increased sensitivity, over 90% selectivity, and excellent quantitative reproducibility. Employing highly sensitive trapped ion mobility mass spectrometry, we quantify more than 20,000 unique phosphopeptides in a human cancer cell line using 20 µg starting material, and confidently localize > 5,000 phosphorylation sites from 5 µg. This depth covers key intracellular signaling pathways, rendering sample-limited applications and extensive perturbation experiments with hundreds of samples viable.Abstract Figure
Characterization of proteoform post-translational modifications by top-down and bottom-up mass spectrometry in conjunction with UniProt annotations
Authors: Chen Wenrong , Ding Zhengming , Zang Yong , Liu Xiaowen 
Published: April 2023

AbstractMany proteoforms can be produced from a gene due to genetic mutations, alternative splicing, post-translational modifications (PTMs), and other variations. PTMs in proteoforms play critical roles in cell signaling, protein degradation, and other biological processes. Mass spectrometry (MS) is the primary technique for investigating PTMs in proteoforms, and two alternative MS approaches, top-down and bottom-up, have complementary strengths. The combination of the two approaches has the potential to increase the sensitivity and accuracy in PTM identification and characterization. In addition, protein and PTM knowledgebases, such as UniProt, provide valuable information for PTM characterization and validation. Here, we present a software pipeline called PTM-TBA (PTM characterization by Top-down, Bottom-up MS and Annotations) for identifying and localizing PTMs in proteoforms by integrating top-down and bottom-up MS as well as UniProt annotations. We identified 1,662 mass shifts from a top-down MS data set of SW480 cells, 545 (33%) of which were matched to 12 common PTMs, and 351 of which were localized. PTM-TBA validated 346 of the 1,662 mass shifts using UniProt annotations or a bottom-up MS data set of SW480 cells.
Impact of diet on jejunal microbiota composition during broiler development with special focus onEnterococcus hiraeandEnterococcus faecium
Authors: Stege Paul B. , Schokker Dirkjan , Harders Frank , Kar Soumya K. , Stockhofe Norbert , Perricone Vera , Rebel Johanna M. J. , de Jong Ingrid C. , Bossers Alex 
Published: April 2023

AbstractModern broiler breeds allow for high feed efficiency and rapid growth, but come at a cost of increased susceptibility to pathogens and disease. Broiler growth rate, feed efficiency, and health are furthermore affected by the composition of the gut microbiota, which in turn is influenced by diet composition. In this study we therefore assessed how diet composition alters the broiler jejunal gut microbiota. A total of 96 broiler chickens were divided into four diet groups: control, coated butyrate supplementation, medium chain fatty acid supplementation, or a high-fibre low-protein content. Diet groups were sub-divided into age groups (4, 12 and 33 days of age) resulting in groups of 8 broilers per diet per age. The jejunum content jejunum was used for metagenomic shotgun sequencing to determine the microbiota composition on species level. Among all diet groups, a total of 104 differential abundant bacterial species were detected. Most notably were the changes in the jejunal microbiota induced by butyrate supplementation when compared to the control diet, resulting in the reduced relative abundance of mainlyEnterococcus faeciumand the opportunistic pathogenEnterococcus hiraein broilers 4 days post-hatch. At this early stage of development, the immune system is still immature thereby highlighting the importance to study the relation of diet and the jejunal microbiota. Future studies should furthermore elucidate how diet can be used to promote a beneficial microbiota in the early stages of broiler development.
Genetic modifiers of APOBEC-induced mutagenesis
Authors: Mertz Tony M. , Rice-Reynolds Elizabeth , Nguyen Ly , Wood Anna , Bray Nicholas , Mitchell Debra , Lobachev Kirill , Roberts Steven A. 
Published: April 2023

AbstractThe cytidine deaminases APOBEC3A and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we utilized a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. Also, we determined whether each deletion was epistatic with UNG1 loss, which indicated whether the encoded factors participate in the error-free bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single stranded DNA (ssDNA). Additionally, we determined that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, which results in extremely high A3B-induced mutagenesis, (2) defective CTF18-RFC complex function, which results in high levels of A3B induced mutations specifically on the leading strand template that synergistically increase with loss of UNG1, and (3) defective HR-mediated bypass of APOBEC-induced lesions, which were epistatic with Ung1 loss and result from increased Rev1-mediated C-to-G substitutions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancer tumors display 3- to 4-fold more APOBEC-induced mutations. Mirroring our results in yeast, for BRCA1/2 deficient tumors Rev1-mediated C-to-G substitutions are solely responsible for increased APOBEC-signature mutations and these mutations occur on the lagging strand during DNA replication. Together these results identify important factors that influence the dynamics of DNA replication and likely the abundance of APOBEC-induced mutation during tumor progression as well as a novel mechanistic role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.
The role of plasmids in the gut microbiome during the first year of life
Authors: He Wanli , Russel Jakob , Klincke Franziska , Nesme Joseph , Sørensen Søren Johannes 
Published: April 2023

AbstractPlasmids are extrachromosomal self-replicating genetic elements that play a key role in bacterial ecology and evolution by shuttling diverse host-beneficial traits between bacteria. However, our understanding of plasmids is still limited, particularly in the human gut microbiota, and little is known about how they are acquired and become established in infants. In this study, we explored a longitudinal fecal metagenomic dataset obtained from 98 Swedish children who were followed during their first year of life. For this, we developed a bioinformatics pipeline for the complete sequence assembly and annotation of plasmids, together with the identification of plasmid contigs. We found that gut plasmids in these children were extremely diverse, particularly in the first four months of life, and this diversity decreased with maturation of the gut microbiota. Members of generaBacteroidesandBifidobacteriumwere identified as major hosts of transmissible plasmids and important hubs of horizontal gene transfer in the early human gut microbiota. Additionally, we discovered that plasmids played a substantial role in expanding the gene repertoires of their bacterial hosts: approximately a quarter of unannotated plasmid genes were found only on plasmids and not on chromosomes. Together, our results provide the first characterization of the early acquisition and development of plasmids in the infant gut microbiome. Their diversity and abundance in the first months of life could benefit a variable and rapidly proliferating microbiota by providing increased adaptability in a highly competitive environment.
Safe delivery of AAV vectors to the liver of small weaned pigs by ultrasound-guided percutaneous transhepatic portal vein injection
Authors: Rothgangl Tanja , Hruzova Martina , Gnannt Ralph , Aeberhard Nadja , Kissling Lucas , Grisch-Chan Hiu Man , Klassa Sven , Rimann Nicole , Marquart Kim F. , Ioannidi Eleonora , Wolf Anja , Kupatt Christian , Sidler Xaver , Häberle Johannes , Schwank Gerald , Thöny Beat 
Published: April 2023

AbstractOne challenge for liver-directed gene therapy is sufficient vector delivery to the target tissue while minimizing loss of the applied vector dose to other tissues. Infusion via peripheral veins is the least invasive approach; however, it results in systemic diffusion and substantial vector dilution. Here, we describe a safe and minimally invasive method to deliver adeno-associated virus (AAV) vectors to the liver of small weaned pigs by ultrasound-guided percutaneous trans-hepatic portal vein injection. 4-week-old piglets were infused with ∼2.5×1014vector genomes comprising a dual-rAAV2/9 vector system with a split adenine base editor forin vivoinactivation ofPCSK9to reduce LDL-cholesterol levels. Animals had no signs of discomfort and tolerated the procedure well. However, despite 45% editing of the target site with the applied adenine base editor system in cultivated porcine cells, we only found low amounts of AAV vector genomes and neither detectable transgene-expression nor successful editing in the treated pig livers. We hypothesize that rapid proliferation of pig hepatocytes caused AAV vector dilution, leading to a loss of the vectors from the nucleus, and hence insufficient base editor protein expression for achieving detectable editing rates. Nonetheless, ultrasound-guided percutaneous transhepatic injection to the portal vein is well-tolerated in piglets and has potential for human (neonate) application.
Aging exerts a limited influence on the perception of self-generated and externally generated touch
Authors: Timar Lili , Job Xavier , de Xivry Jean-Jacques Orban , Kilteni Konstantina 
Published: April 2023

AbstractTouch generated by our voluntary movements is attenuated both at the perceptual and neural level compared to touch of the same intensity delivered to our body by another person or machine. This somatosensory attenuation phenomenon relies on the integration of somatosensory input and predictions about the somatosensory consequences of our actions. Previous studies have reported increased somatosensory attenuation in elderly people, proposing an overreliance on sensorimotor predictions to compensate for age-related declines in somatosensory perception; however, recent results have challenged this direct relationship. In a preregistered study, we used a force-discrimination task to assess whether aging increases somatosensory attenuation and whether this increase is explained by decreased somatosensory precision in elderly individuals. Although 94% of our sample (n = 108, 21–77 years old) perceived their self-generated touches as weaker than externally generated touches of identical intensity (somatosensory attenuation) regardless of age, we did not find a significant increase in somatosensory attenuation in our elderly participants (65–77 years old), but a trend when considering only the oldest subset (69-77 years old). Moreover, we did not observe a significant age-related decline in somatosensory precision or a significant relationship of age with somatosensory attenuation. Together, our results suggest that aging exerts a limited influence on the perception of self-generated and externally generated touch and indicate a less direct relationship between somatosensory precision and attenuation in the elderly individuals than previously proposed.New and NoteworthySelf-generated touch is attenuated compared to externally generated touch of identical intensity. This somatosensory attenuation has been previously shown to be increased in elderly participants, but it remains unclear whether it is related to age-related somatosensory decline. In our preregistered study, we observed a trend for increased somatosensory attenuation in our oldest participants (≥69 years), but we found no evidence of an age-related decline in somatosensory function or a relationship of age with somatosensory attenuation.