bluuebunny/crossref_metadata_2025 huggingface dataset:
Cmai: Predicting Antigen-Antibody Interactions from Massive Sequencing Data
Authors: Song Bing , Wang Kaiwen , Na Saiyang , Yao Jia , Fattah Farjana J , von Itzstein Mitchell S. , Yang Donghan M. , Liu Jialiang , Xue Yaming , Liang Chaoying , Guo Yuzhi , Raman Indu , Zhu Chengsong , Dowell Jonathan E , Homsi Jade , Rashdan Sawsan , Yang Shengjie , Gwin Mary E , Hsiehchen David , Gloria-McCutchen Yvonne , Raj Prithvi , Bai Xiaochen , Wang Jun , Conejo-Garcia Jose , Xie Yang , Gerber David E. , Huang Junzhou , Wang Tao
Published: July 2024

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.
Sulfur Amino Acid Restriction Enhances Exercise Capacity in Mice by Boosting Fat Oxidation in Muscle
Authors: Mann Charlotte G , MacArthur Michael R , Zhang Jing , Gong Songlin , AbuSalim Jenna E , Hunter Craig J. , Lu Wenyun , Agius Thomas , Longchamp Alban , Allagnat Florent , Rabinowitz Joshua , Mitchell James R , De Bock Katrien , Mitchell Sarah J
Published: July 2024

Dietary restriction of the sulfur-containing amino acids methionine and cysteine (SAAR) improves body composition, enhances insulin sensitivity, and extends lifespan; benefits seen also with endurance exercise. Yet, the impact of SAAR on skeletal muscle remains largely unexplored. Here we demonstrate that one week of SAAR in sedentary, young, male mice increases endurance exercise capacity. Indirect calorimetry showed that SAAR increased lipid oxidation at rest and delayed the onset of carbohydrate utilization during exercise. Transcriptomic analysis revealed increased expression of genes involved in fatty acid catabolism especially in glycolytic muscle following SAAR. These findings were functionally supported by increased fatty acid circulatory turnover flux and muscle β-oxidation. Reducing lipid uptake from circulation through endothelial cell (EC)-specific CD36 deletion attenuated the running phenotype. Mechanistically, VEGF-signaling inhibition prevented exercise increases following SAAR, without affecting angiogenesis, implicating noncanonical VEGF signaling and EC CD36-dependent fatty acid transport in regulating exercise capacity by influencing muscle substrate availability.
Human erythroid progenitors express antigen presentation machinery
Authors: Clements Rebecca L. , Kennedy Elizabeth A. , Song David , Campbell Ariana , An Hyun Hyung , Amses Kevin R. , Miller-Ensminger Taylor , Addison Mary M. , Eisenlohr Laurence C. , Chou Stella T. , Jurado Kellie Ann
Published: July 2024

Early-life immune exposures can profoundly impact lifelong health. However, functional mechanisms underlying fetal immune development remain incomplete. Erythrocytes are not typically considered active immune mediators, primarily because erythroid precursors discard their organelles as they mature, thus losing the ability to alter gene expression in response to stimuli. Erythroid progenitors and precursors circulate in human fetuses and neonates. Although there is limited evidence that erythroid precursors are immunomodulatory, our understanding of the underlying mechanisms remains inadequate. To define the immunobiological role of fetal and perinatal erythroid progenitors and precursors, we analyzed single cell RNA-sequencing data and found that transcriptomics support erythroid progenitors as putative immune mediators. Unexpectedly, we discovered that human erythroid progenitors constitutively express Major Histocompatibility Complex (MHC) class II antigen processing and presentation machinery, which are hallmarks of specialized antigen presenting immune cells. Furthermore, we demonstrate that erythroid progenitors internalize and cleave foreign proteins into peptide antigens. Unlike conventional antigen presenting cells, erythroid progenitors express atypical costimulatory molecules and immunoregulatory cytokines that direct the development of regulatory T cells, which are critical for establishing maternal-fetal tolerance. Expression of MHC II in definitive erythroid progenitors begins during the second trimester, coinciding with the appearance of mature T cells in the fetus, and is absent in primitive progenitors. Lastly, we demonstrate physical and molecular interaction potential of erythroid progenitors and T cells in the fetal liver. Our findings shed light on a unique orchestrator of fetal immunity and provide insight into the mechanisms by which erythroid cells contribute to host defense.
Interspecies interactions alter the antibiotic sensitivity ofPseudomonas aeruginosa
Authors: Koumans C.I.M. , Tandar S.T. , Liakopoulos A. , van Hasselt J.G.C.
Published: July 2024

Polymicrobial infections are infections that are caused by multiple pathogens, and are common in patients with cystic fibrosis (CF). Although polymicrobial infections are associated with poor treatment responses in CF, the effects of the ecological interactions between co-infecting pathogens on antibiotic sensitivity and treatment outcome are poorly characterized. To this end, we systematically quantified the impact of these effects on the antibiotic sensitivity ofPseudomonas aeruginosafor nine antibiotics in the presence of thirteen secondary cystic fibrosis-associated bacterial and fungal pathogens through time-kill assays. We fitted pharmacodynamic models to these kill curves for each antibiotic-species combination and found that interspecies interactions changing the antibiotic sensitivity ofP. aeruginosaare abundant. Interactions that lower antibiotic sensitivity are more common than those that increase it, with generally more substantial reductions than increases in sensitivity. For a selection of co-infecting species, we performed pharmacokinetic-pharmacodynamic modelling ofP. aeruginosatreatment. We predicted that interspecies interactions can either improve or reduce treatment response to the extent that treatment is rendered ineffective from a previously effective antibiotic dosing schedule and vice versa. In summary, we show that quantifying the ecological interaction effects as pharmacodynamic parameters is necessary to determine the abundance and the extent to which these interactions affect antibiotic sensitivity in polymicrobial infections.

Importance

In cystic fibrosis (CF) patients, chronic respiratory tract infections are often polymicrobial, involving multiple pathogens simultaneously. Polymicrobial infections are difficult to treat as they often respond unexpectedly to antibiotic treatment, which might possibly be explained because co-infecting pathogens can influence each other’s antibiotic sensitivity, but it is unknown to what extent such effects occur. To investigate this, we systematically quantified the impact of co-infecting species on antibiotic sensitivity, focusing onP. aeruginosa, a common CF pathogen. We studied for a large set co-infecting species and antibiotics whether changes in antibiotic response occur. Based on these experiments, we used mathematical modeling to simulateP. aeruginosa’s response to colistin and tobramycin treatment in the presence of multiple pathogens. This study offers comprehensive data on altered antibiotic sensitivity of P. aeruginosa in polymicrobial infections, serves as a foundation for optimizing treatment of such infections, and consolidates the importance of considering co-infecting pathogens.
FKBP12-BOUND CALCINEURIN CONTROL TMEM16A ACTIVITY
Authors: Guzmán-Hernández María Luisa , Huerta Miriam , López-Romero Ana E. , Morán-Zendejas Rita , Betanzos Abigail , Pérez-Cornejo Patricia , Arreola Jorge
Published: July 2024

The Ca2+-dependent Cl-channel TMEM16A activity is vital for mammals. Critical functions such as blood pressure, pain, fluid and electrolyte secretion, peristalsis, and electrical activity depend on TMEM16A Cl-fluxes. Ciclosporin A (CsA) and FK506, two immunosuppressants that inhibit calcineurin (CaN), down-regulate TMEM16A function. However, the underlying mechanism remains undetermined. CsA binds to cyclophilin 1, whereas FK506 binds to FKBP12, and both complexes subsequently inhibit CaN, a phosphatase that maintains TMEM16A function. Here, we show that TMEM16A-EGFP and mRFP-FKBP12 colocalize in HEK-AD293 cells stimulated with the Ca2+ionophore ionomycin, FKBP12 co-immunoprecipitated with TMEM16A expressed in CaN-depleted HEK-AD293 cells, ionomycin favoured TMEM16A and FKBP12 interaction in a bimolecular fluorescence complementation assay in live cells, and TMEM16A currents recorded from CaN-depleted HEK-AD293 cells were insensitive to CsA and FK506. These data support the idea that FKBP12 works as an auxiliary protein of TMEM16A, thus enabling the interaction of CaN under physiological conditions. This heteromerization is essential to sustain TMEM16A activity. On the contrary, disrupting the Ca2+-stimulated CaN-FKBP12-TMEM16A heterotrimer or inhibiting CaN with CsA or FK506 does not preclude TMEM16A activation but decreases activity.
Comprehensive evaluation of phosphoproteomic-based kinase activity inference
Authors: Müller-Dott Sophia , Jaehnig Eric J. , Munchic Khoi Pham , Jiang Wen , Yaron-Barir Tomer M. , Savage Sara R. , Garrido-Rodriguez Martin , Johnson Jared L. , Lussana Alessandro , Petsalaki Evangelia , Lei Jonathan T. , Dugourd Aurelien , Krug Karsten , Cantley Lewis C. , Mani D.R. , Zhang Bing , Saez-Rodriguez Julio
Published: July 2024

Kinases play a central role in regulating cellular processes, making their study essential for understanding cellular function and disease mechanisms. To investigate the regulatory state of a kinase, numerous methods have been, and continue to be, developed to infer kinase activities from phosphoproteomics data. These methods usually rely on a set of kinase targets collected from various kinase-substrate libraries. However, only a small percentage of measured phosphorylation sites can usually be attributed to an upstream kinase in these libraries, limiting the scope of kinase activity inference. In addition, the inferred activities from different methods can vary making it crucial to evaluate them for accurate interpretation. Here, we present a comprehensive evaluation of kinase activity inference methods using multiple kinase-substrate libraries combined with different inference algorithms. Additionally, we try to overcome the coverage limitations for measured targets in kinase substrate libraries by adding predicted kinase-substrate interactions for activity inference. For the evaluation, in addition to classical cell-based perturbation experiments, we introduce a tumor-based benchmarking approach that utilizes multi-omics data to identify highly active or inactive kinases per tumor type. We show that while most computational algorithms perform comparably regardless of their complexity, the choice of kinase-substrate library can highly impact the inferred kinase activities. Hereby, manually curated libraries, particularly PhosphoSitePlus, demonstrate superior performance in recapitulating kinase activities from phosphoproteomics data. Additionally, in the tumor-based evaluation, adding predicted targets from NetworKIN further boosts the performance, while normalizing sites to host protein levels reduces kinase activity inference performance. We then showcase how kinase activity inference can help in characterizing the response to kinase inhibitors in different cell lines. Overall, the selection of reliable kinase activity inference methods is important in identifying deregulated kinases and novel drug targets. Finally, to facilitate the evaluation of novel methods in the future, we provide both benchmarking approaches in the R package benchmarKIN.

Graphical Abstract
Vaginal Microbiota Transplantation (VMT) for treatment of vaginal dysbiosis without the use of antibiotics – A Double-Blinded Randomized Controlled Trial in healthy women with vaginal dysbiosis
Authors: Wrønding Tine , Vomstein Kilian , DeLong Kevin , Lundgaard Agnete Troen , Mollerup Sarah , Mortensen Brynjulf , Bosma Elleke F. , Hellerung Ann Marie , Engel Emilie Vester , Wiil Klara Dortea , Heintz Julie Elm , Halkjær Sofie Ingdam , Hugerth Luisa W , Hartwig Tanja Schlaikjær , Petersen Andreas Munk , Thomsen Anne Bloch , Westergaard David , Freiesleben Nina La Cour , Westh Henrik , van Hylckama Vlieg Johan E.T. , Ensign Laura M. , Nielsen Henriette Svarre
Published: July 2024

Here we describe the first double-blinded, randomized, placebo-controlled trial (RCT) on vaginal microbiota transplantation (VMT) without antibiotics in women withbothsymptomatic and asymptomatic vaginal dysbiosis. Forty-nine women were randomly assigned to VMT or placebo. The trial did not show a significant conversion to our predefinedLactobacillus-dominated microbiome. However, in participants not initially converting, antiseptic pretreatment before a subsequent VMT led to a 50% conversion rate, associated with an anti-inflammatory shift in gene expression. Metagenomic sequencing and strain-level genetic analysis confirmed donor engraftment in five of 10 women who showed microbiome conversion. Extensive exploration of the microbiome, immune response and metadata revealed differences in baseline energy metabolism in participants who later experienced donor engraftment. Treatments for vaginal dysbiosis are urgently needed and given that VMT can lead to donor engraftment and change the vaginal immune profile, future studies should focus on optimizing this treatment for various women’s health diseases.
Changes in vaginalUreaplasmaandLactobacillusdue to antibiotic regimen for premature rupture of membranes
Authors: Kawaguchi Haruna , Nakura Yukiko , Yamamoto Ryo , Hayashi Shusaku , Takeuchi Makoto , Ishii Keisuke , Yanagihara Itaru
Published: July 2024

Preterm premature rupture of membranes (PPROM) is associated with preterm delivery and neonatal complications. PPROM is often complicated by intra-amniotic inflammation and/or microbial invasion of the amniotic cavity withUreaplasmaorMycoplasma. Various prophylactic antibiotic therapies have been proposed to prolong latency between PPROM and delivery, reduce the risk of clinical chorioamnionitis, and improve neonatal complications. However, information on the potential of azithromycin administration to reduce the microbial load of vaginalUreaplasmaandMycoplasmaremains lacking. This prospective cohort study included singleton pregnancies managed with prophylactic antibiotics for PPROM at less than 36 weeks of gestation. All patients received the standard antibiotic regimen for PPROM, which consisted of a single oral azithromycin and intravenous ampicillin every for 2 days followed by 5 days of oral amoxicillin. Vaginal swabs samples were collected when PPROM was confirmed and after the antibiotic regimen administration. The main outcome measures were to investigate the changes in vaginalUreaplasma, Mycoplasma,andLactobacillus spp.due to the antibiotic regimen. In addition, the association between the presence and changes in vaginalUreaplasmaandMycoplasma, pregnancy outcomes, and neonatal complications were examined. Out of 82 eligible PPROM, 51 had positive vaginalUreaplasma. Thirty-six patients (52.2%) completed the antibiotic regimen. Among those with positive vaginalUreaplasmawho completed the antibiotic regimen, 75% experienced an increase in vaginalUreaplasmalevels. For those who delivered before completing all antibiotic doses, 40% had increased vaginalUreaplasmalevels. Furthermore, the antibiotic regimen resulted in decreasedLactobacillus spp.in almost all cases. However, vaginalUreaplasmachanges were not found to be associated with neonatal sepsis or bronchopulmonary dysplasia. This suggests thatUreaplasmabecame resistant to azithromycin. Future studies are needed to revalidate current antibiotic therapy for PPROM.
Neural Stem Cell Relay from B1 to B2 cells in the adult mouse Ventricular-Subventricular Zone
Authors: Cebrian-Silla Arantxa , Assis Nascimento Marcos , Mancia Walter , Gonzalez-Granero Susana , Romero-Rodriguez Ricardo , Obernier Kirsten , Steffen David M , Lim Daniel. A. , Garcia-Verdugo Jose Manuel , Alvarez-Buylla Arturo
Published: July 2024

Neurogenesis and gliogenesis continue in the Ventricular-Subventricular Zone (V-SVZ) of the adult rodent brain. B1 cells are astroglial cells derived from radial glia that function as primary progenitors or neural stem cells (NSCs) in the V-SVZ. B1 cells, which have a small apical contact with the ventricle, decline in numbers during early postnatal life, yet neurogenesis continues into adulthood. Here we found that a second population of V-SVZ astroglial cells (B2 cells), that do not contact the ventricle, function as NSCs in the adult brain. B2 cell numbers increase postnatally, remain constant in 12-month-old mice and decrease by 18 months. Transcriptomic analysis of ventricular-contacting and non-contacting B cells revealed key molecular differences to distinguish B1 from B2 cells. Transplantation and lineage tracing of B2 cells demonstrate their function as primary progenitors for adult neurogenesis. This study reveals how NSC function is relayed from B1 to B2 progenitors to maintain adult neurogenesis.
Lydicamycins Induce Morphological Differentiation in Actinobacterial Interactions
Authors: Jarmusch Scott A. , Schostag Morten D. , Yang Zhijie , Wang Jinglin , Anderson Aaron J.C. , Weber Tilmann , Ding Ling
Published: July 2024

Streptomycesare major players in soil microbiomes, however, interactions involvingStreptomycesand other actinobacteria are rarely described. The complex developmental cycle of actinobacteria necessitates a multi-omics approach to unravel the web of information. This study resulted from the observation of induced morphogenesis between two environmental isolates from the same site,Kitasatosporasp. P9-2B1 andStreptomycessp. P9-2B2. When co-cultivated on potato dextrose agar (PDA), P9-2B2 induced a wave-like sporulation in strain P9-2B1. Using massspectrometry imaging, we revealed that a suite of lydicamycins were present in this induced sporulation zone. Lydicamycin deficient mutants were generated using CRISPR Base-Editing and the inducible sporulation ceased, confirming their role in triggering morphological differentiation. In agar diffusion assays, pure lydicamycin was inhibitory when added concurrently with bacterial inoculation and induced sporulation with delayed addition. Subsequent testing of additional environmental isolates resulted in the same inducible sporulation wave phenomenon, includingStreptomyces coelicolorM145 and M1146. Using transcriptomics, we observed the differential expression of genes related to early aerial mycelium development four days into cocultivation and the transitional genes responsible for development of spores on day 9. Along with these differentially expressed genes, we also observed numerous overall stress responses, specifically cell envelope stress responses. These findings uncovered actinobacteria interactions mediated by lydicamycins, pointing to a potential role of certain groups of bioactive metabolites in nature.

Importance

Shifting away from an antibiotic discovery mindset, uncovering the chemical ecology of secondary metabolites is key to maximizing their biotechnological application. The reduced complexity of dual cultures allows for in depth analysis and investigation of these interactions via multi-omics provides orthogonal data leading to more robust conclusions. This study provides insight into the role of lydicamycins in dual cultures with other actinobacteria and provides an integral roadmap for future chemical ecology work between microorganisms, especially through the use of mass spectrometry imaging.
Optimizing alkalinity control in Recirculating Aquaculture Systems (RAS): a dynamic modelling approach
Authors: Montjourides Marie Aline , Roblitz Susanna , Dahle Hakon
Published: July 2024

Maintaining good water quality is essential for successful fish production in land-based recirculating aquaculture systems (RAS). Numerous interdependent factors influence water quality parameters, making it difficult to evaluate which operational strategies are most favorable. Mathematical models and model simulations have proven to be powerful tools to evaluate how RAS design and operation are linked to RAS dynamics, but these models rarely implement pH and carbonate species as dynamic variables. Here, we present a dynamic model for RAS (dynRAS) that combines rates of TAN (total ammonia nitrogen) removal, fish growth, and CO2 and TAN excretion, with a reaction model for pH and the carbonate system formulated based on the law of mass action. A novel aspect of our approach is the incorporation of a dosage system modelled by a Hill-function, enabling the exploration of diverse dosing strategies for pH and alkalinity management. The model was validated based on empirical data from a pilot scale RAS system operated with a feeding regime involving 12 hours of feeding per day. We found that model simulations could be used to accurately predict diurnal cycling patterns in RAS water quality parameters. Furthermore, we made use of simulations to assess how diurnal cycling varies with changing pH and alkalinity levels. Model results emphasize the complexity of pH and alkalinity control in RAS in relation to overall water quality management. Based on our simulations, we argue that what should be considered as optimal pH and alkalinity in RAS depends on the state of the system. Accordingly, optimal pH and alkalinity thresholds may vary between different RAS units and between different time points of a rearing cycle. More generally, we demonstrate how modelling and model simulations can be an effective way of getting insights into the dynamics of complex RAS interactions and provide a valuable tool to efficiently explore effects of different operational strategies on water quality parameters.
Castanet: a pipeline for rapid analysis of targeted multi-pathogen genomic data
Authors: Mayne Richard , Secret Shannah , Geoghegan Cyndi , Trebes Amy , Kean Kai , Reid Kaitlin , Lin Gu-Lung , Ansari M. Azim , de Cesare Mariateresa , Bonsall David , Elliott Ivo , Piazza Paolo , Brown Anthony , Bray James , Knight Julian C. , Harvala Heli , Breuer Judith , Simmonds Peter , Bowden Rory J. , Golubchik Tanya
Published: July 2024

Motivation

Target enrichment strategies generate genomic data from multiple pathogens in a single process, greatly improving sensitivity over metagenomic sequencing and enabling cost-effective, high throughput surveillance and clinical applications. However, uptake by research and clinical laboratories is constrained by an absence of computational tools that are specifically designed for the analysis of multi-pathogen enrichment sequence data. Here we present the Castanet pipeline: an analysis pipeline for end-to-end processing and consensus sequence generation for use with multi-pathogen enrichment sequencing data. Castanet is designed to work with short-read data produced by existing targeted enrichment strategies, but can be readily deployed on any BAM file generated by another methodology. It is packaged with usability features, including graphical interface and installer script.

Results

In addition to genome reconstruction, Castanet reports method-specific metrics that enable quantification of capture efficiency, estimation of pathogen load, differentiation of low-level positives from contamination, and assessment of sequencing quality. Castanet can be used as a traditional end-to-end pipeline for consensus generation, but its strength lies in the ability to process a flexible, pre-defined set of pathogens of interest directly from multi-pathogen enrichment experiments. In our tests, Castanet consensus sequences were accurate reconstructions of reference sequences, including in instances where multiple strains of the same pathogen were present. Castanet performs effectively on standard laptop computers and can process the entire output of a 96-sample enrichment sequencing run (50M reads) using a single batch process command, in<2 h.

Availability and Implementation

Source code freely available under GPL-3 license athttps://github.com/MultipathogenGenomics/castanet, implemented in Python 3.10 and supported in Ubuntu Linux 22.04 and other Bash-like environments. The data for this study have been deposited in the European Nucleotide Archive (ENA) at EMBL-EBI under accession number PRJEB77004.
IGF2BP3 promotes the progression of gastric cancer by activating cGMP-PKG signaling pathway via targeting FBXO32
Authors: Si Yi , Tian Bo , Zhang Rui , Xuan Mingda , Liu Kunyi , Jiao Jiao , Han Shuangshuang , Li Hongfei , Hu Yanhong , Zhao Hongyan , He Wenjing , Wang Jia , Liu Ting , Yu Weifang
Published: July 2024

N6-methyladenosine (m6A) represents the most prevalent chemical modification on eukaryotic mRNA, with an accumulating body of literature indicating its pivotal significance in the pathogenesis of human cancers. Nevertheless, the precise molecular interplay between the m6A reader protein IGF2BP3 and gastric cancer remains to be thoroughly delineated. Our study uncovered that the expression of IGF2BP3 in gastric cancer tissues is markedly elevated in comparison to adjacent normal tissues, and this upregulation is tightly correlated with the incidence of lymph node metastasis, more advanced TNM stages, and deeper invasion depth of tumor in patients.In vitroexperiments demonstrated that IGF2BP3 potentiates the proliferative, migratory, and invasive capacities of gastric cancer cells, while concurrently inhibiting apoptosis and augmenting the intracellular levels of aerobic glycolysis.In vivoexperiments revealed that IGF2BP3 contributes to the growth of gastric cancer. Mechanistically, IGF2BP3 can increase the expression of FBXO32 protein by recognizing and binding to the m6A binding site on FBXO32 mRNA and further activate the downstream cGMP-PKG signaling pathway, thereby modulating various biological functions of gastric cancer cells and ultimately promoting the progression of gastric cancer. In summary, our findings suggest that IGF2BP3 upregulates the expression of FBXO32 protein in an m6A dependent manner and subsequently activates the cGMP-PKG signaling pathway, ultimately leading to the onset and progression of gastric cancer. Consequently, the targeting of the IGF2BP3/FBXO32/cGMP-PKG axis emerges as a promising therapeutic modality for the treatment of gastric cancer.
Unravelling complex hybrid and polyploid evolutionary relationships using phylogenetic placement of paralogs from target enrichment data
Authors: Walden Nora , Kiefer Christiane , Koch Marcus A.
Published: July 2024

Phylogenomic datasets comprising hundreds of genes have become the standard for plant systematics and phylogenetics. However, large scale phylogenomic studies often exclude polyploids and hybrids due to the challenges in assessing paralog status of targeted loci and incorporating them into tree reconstruction methods. Using a target enrichment dataset of 1081 genes from 452 samples from the Brassicaceae tribe Arabideae, including many hybrid and high ploidy taxa, we developed a novel approach to disentangle the evolutionary history of this phylogenetically and taxonomically challenging clade. Our approach extends beyond commonly used gene tree-species tree reconciliation techniques by using phylogenetic placement, a method adopted from metagenomics, of paralogous sequences into a diploid tree. We call this approach Paralog PhyloGenomics (PPG), and show how it allows for the simultaneous assessment of the origins of ancient and recent hybrids and autopolyploids, and the detection of nested polyploidization events. Additionally, we demonstrate how synonymous substitution rates provide further evidence for the mode of polyploidization, specifically to distinguish between allo- and autopolyploidization, and to identify hybridization events involving a ghost lineage. Our approach will be a valuable addition to phylogenomic methods available for the study of polyploids.
Linking selection to demography in experimental evolution of active death in a unicellular organism
Authors: Zeballos Nathalie , Rieu Oceane , Fereol Stanislas , Leung Christelle , Chevin Luis-Miguel
Published: July 2024

Deciphering how natural selection emerges from demographic differences among genotypes, and reciprocally how evolution affects population dynamics, is key to understanding population responses to environmental stress. This is especially true in non-trivial ecological scenarios, such as programmed cell death (PCD) in unicellular organisms, which can lead to massive population decline in response to stress. To understand how selection may operate on this trait, we exposed monocultures and mixtures of two closely related strains of the microalgaDunalliela salina, one of which induces PCD, to multiple cycles of hyper-osmotic shocks, and tracked demography and selection throughout. Population dynamics were consistent between mixtures and monocultures, suggesting that selection on PCD does not involve strong ecological interactions. The PCD-inducing strain was maintained throughout the experiment despite an initial decline, by a combination of fast population rebound following each decline, and density-dependent competition dynamics near the stationary phase that were independent of these initial population fluctuations. As result of PCD maintenance, population decline in response to environmental stress was not counter-selected in our experiment, but persisted over 13 cycles of salinity. Our results highlight how analysing the demographic underpinnings of fitness and competition can shed light on the mechanisms underlying selection and eco-evolutionary dynamics.
GenomeDelta: detecting recent transposable element invasions without repeat library
Authors: Pianezza Riccardo , Haider Anna , Kofler Robert
Published: July 2024

To evade repression by the host defense, transposable elements (TEs) are occasionally horizontally transferred (HT) to naive species. TE invasions triggered by HT may be much more abundant than previously thought. For example, previous studies inDrosophila melanogasterfound 11 TE invasions over 200 the past years. A major limitation of current approaches for detecting recent invasions is the necessity for a repeat-library, which is notoriously difficult to generate. To address this, we developed GenomeDelta, a novel approach for identifying sample-specific sequences, such as recently invading TEs, without prior knowledge of the sequence. It can thus be used with model and non-model organisms. As input, GenomeDelta requires a long-read assembly and short-read data. It will find sequences in the assembly that are not represented in the short read data. Beyond identifying recent TE invasions, GenomeDelta can detect sequences with spatially heterogeneous distributions, recent insertions of viral elements and recent lateral gene transfers. We thoroughly validated GenomeDelta with simulated and real data from extant and historical specimens. Finally, we demonstrate that GenomeDelta can reveal novel biological insights: we discovered the three most recent TE invasions inDrosophila melanogasterand a novel TE with a geographically heterogeneous distribution inZymoseptoria tritici.
EstroGene2.0: A multi-omic database of response to estrogens, ER-modulators, and resistance to endocrine therapies in breast cancer
Authors: Li Zheqi , Chen Fangyuan , Chen Li , Liu Jiebin , Tseng Danielle , Hadi Fazal , Omarjee Soleilmane , Kishore Kamal , Kent Joshua , Kirkpatrick Joanna , D’Santos Clive , Lawson Mandy , Gertz Jason , Sikora Matthew J. , McDonnell Donald P. , Carroll Jason S. , Polyak Kornelia , Oesterreich Steffi , Lee Adrian V.
Published: July 2024

Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing drugs and to develop new ER-modulators. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed substantial diversity in response to different classes of ER-modulators including SERMs, SERDs, SERCA and LDD/PROTAC. Notably, endocrine resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signaling, which is recapitulated clinically. Furthermore, dissecting multipleESR1-mutant cell models revealed the different clinical relevance of genome-edited versus ectopic overexpression model engineering and identified high-confidence mutant-ER targets, such asNPY1R.These examples demonstrate how EstroGene2.0 helps investigate breast cancer’s response to endocrine therapies and explore resistance mechanisms.
The coevolution of learning schedules and teaching enhances cumulative knowledge and drives a teacher-innovator syndrome
Authors: Maisonneuve Ludovic , Lehmann Laurent , Mullon Charles
Published: July 2024

Natural selection shapes how individuals learn and acquire knowledge from their environment. Under the right conditions, this can lead to the evolution of learning schedules—how individuals allocate resources to acquire knowledge throughout their lifespan—that promote the accumulation of knowledge across generations (“cumulative knowledge” or “cumulative culture”). In spite of having been observed across multiple taxa, the role of parental teaching in this evolutionary process remains understudied. Using mathematical modelling, we show that learning schedules and parental teaching coevolve, resulting in greater time spent learning individually and innovating, as well as greater inter-generational transfer of knowledge from parent to offspring. These outcomes together enhance cumulative knowledge. Our analyses further reveal that within populations, selection typically favours an association between teaching and individual learning whereby some individuals innovate and teach within the family (“knowledge producers” with extensive knowledge), while others teach less and learn socially outside of the family (“knowledge scroungers” with less knowledge). Overall, our findings indicate that the coevolution of learning schedules and teaching promotes knowledge accumulation within and between generations, and favours diversity within and between populations in knowledge acquisition, possession and transmission.
Active surveillance for influenza A virus in swine reveals within-farm reassortment and cocirculation of distinct subtypes and genetic clades
Authors: Thomas Megan N. , Janzen Garrett M. , Markin Alexey , Sharma Aditi , Hewitt Kelly , Li Ganwu , Baker Amy L. , Gauger Phillip C. , Anderson Tavis K.
Published: July 2024

Influenza A virus (IAV) is one of the three most frequently detected respiratory pathogens in swine. A passive IAV in swine surveillance system in the United States (U.S.) provides aggregated national metrics to quantify spatial and temporal changes in genetic diversity.

However, swine production is not homogenous: production systems vary in size and management strategies that affect the transmission and evolution of IAV. To assess the impact of fine-scale variation in swine production on IAV transmission, we conducted active surveillance on sow farms and linked nurseries from 4 U.S. production systems for up to 14 monthly collections. From IAV-positive samples, we obtained 85 complete HA sequences, and of these, we successfully assembled 62 whole genomes with associated epidemiological information. To infer transmission and evolution, we conducted Bayesian phylodynamic analyses and detected six genetic clades from four HA lineages: the H1 1A classical swine, the H1 1B human-seasonal, and the H3 2010.1 and 1990.4 lineages. The 1B and H3 1990.4 strains showed evidence of transmission from sow farm to nursery. In contrast, 1A and H3 2010.1 viruses were detected in nurseries without detection in a linked sow farm. We also detected seven separate human-to- swine transmission events in the H1N1 pandemic clade (1A.3.3.2) in sow and nursery sites. Our data demonstrated that nursery sites were infected with IAV that was both linked and unlinked to the sow farm. These data suggest that control efforts may be impacted by subclinical IAV transmission in the breeding herd, the mixing of sow farm sources at the nursery, regional spread of new strains, and human-to-swine transmission. Regular surveillance activities within production systems provide the ability to match vaccine components to circulating diversity, thereby minimizing the opportunity for novel reassorted viruses to emerge and impact animal health.
Atf4 protects islet β-cell identity and function under acute glucose-induced stress but promotes β-cell failure in the presence of free fatty acid
Authors: Yagan Mahircan , Najam Sadia , Hu Ruiying , Wang Yu , Dadi Prasanna , Xu Yanwen , Simmons Alan J. , Stein Roland , Adams Christopher M. , Jacobson David A. , Lau Ken , Liu Qi , Gu Guoqiang
Published: July 2024

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes (T2D) via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here thatAtf4expression in β-cells is dispensable for glucose homeostasis in young mice, but it is required for β-cell function during aging and under obesity-related metabolic stress. Henceforth, agedAtf4-deficient β-cells display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced loss-of identity and dysfunction. At molecular level,Atf4-deficient β-cells down-regulate genes involved in protein translation, reducing β-cell identity gene products under high glucose. They also upregulate several genes involved in lipid metabolism or signaling, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest thatAtf4activation is required for β-cell identity and function under high glucose, but this paradoxically induces β-cell failure in the presence of high levels of free fatty acids. Different branches of Atf4 activity could be manipulated for protecting β-cells from metabolic stress-induced failure.

Highlights

Atf4 is dispensable in β-cells in young mice

Atf4 protects β-cells under high glucose

Atf4 exacerbate fatty acid-induced β-cell defects

Atf4 activates translation but depresses lipid-metabolism
Muskelin acts as a substrate receptor of the highly regulatedDrosophilaCTLH E3 ligase during the maternal-to-zygotic transition
Authors: Briney Chloe A. , Henriksen Jesslyn C. , Lin Chenwei , Jones Lisa A. , Benner Leif , Rains Addison B. , Gutierrez Roxana , Gafken Philip R. , Rissland Olivia S.
Published: July 2024

The maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache is replaced with newly made zygotic gene products. We have previously shown that inDrosophilathe deposited RNA-binding proteins ME31B, Cup, and Trailer Hitch (TRAL) are ubiquitylated by the CTLH E3 ligase and cleared. However, the organization and regulation of the CTLH complex remain poorly understood in flies. In particular,Drosophilalacks an identifiable substrate adaptor, and the mechanisms restricting degradation of ME31B and its cofactors to the MZT are unknown. Here, we show that the developmental specificity of the CTLH complex is mediated by multi-pronged regulation, including transcriptional control by the transcription factor OVO and autoinhibition of the E3 ligase. One major regulatory target is the subunit Muskelin, which we demonstrate acts as a substrate adaptor for theDrosophilaCTLH complex. Although conserved, Muskelin has structural roles in other species, suggesting a surprising functional plasticity. Finally, we find that Muskelin has few targets beyond the three known RNA binding proteins, showing exquisite target specificity. Thus, multiple levels of integrated regulation restrict the activity of the embryonic CTLH complex to early embryogenesis, seemingly with the goal of regulating three important RNA binding proteins.
Organoid Models Derived from Primary Tumors and Patient-Derive Xenograft Tumors Reflect Platinum Sensitivity of Ovarian Cancer Patients
Authors: Nikeghbal Parisa , Burke Danielle , Steinkamp Mara P.
Published: July 2024

Ovarian cancer (OC) remains the deadliest gynecological cancer, primarily due to late stage diagnosis and high rates of chemotherapy resistance and recurrence. Lack of representative preclinical models exacerbates the challenges of discovering effective therapies to treat platinum-resistant OC. Patient-derived xenograft (PDX) models maintain the genetic characteristics of the original tumor, but require considerable development time and have limited screening capabilities. Organoid models mimic the tumor’s 3D structure and preserve intra-tumoral heterogeneity, so are ideal for drug screening. The purpose of this study was to determine if PDX-derived organoids (PDXOs) can reflect patient responses to chemotherapy similar to organoids derived from primary patient tumors (PDOs). In drug response assays, PDXOs and PDOs demonstrated similar sensitivity to standard chemotherapy. Furthermore, both PDXOs and PDOs reliably reflected patient response based on the clinical designation of platinum sensitivity. Seven out of eight models derived from six platinum-sensitive cases showed a significant reduction in cell viability when treated with carboplatin, paclitaxel, or the combination therapy. Six of seven organoid models derived from four platinum-resistant or refractory patients demonstrated little to no reduction in cell viability with carboplatin or combination treatment. In these platinum-resistant models, response to single agent paclitaxel was mixed, suggesting that organoid models could predict response to second-line paclitaxel. This study demonstrates that PDXOs can effectively mirror patient responses to chemotherapy, underscoring their potential as valuable, renewable models for screening novel therapies and developing personalized treatment strategies in OC.
Reduced leaf numbers due to shade avoidance allows sugar beet to maintain biomass under drought stress
Authors: Ballenger Joe , Adjesiwor Albert T. , Ewers Brent , Weinig Cynthia , Kniss Andrew R.
Published: July 2024

The physical environment is complex even in managed agroecosystems, and plants often experience multiple stressors such as light competition and drought simultaneously. Phenotypic responses to multiple stressors may exhibit tradeoffs or constraints, such that harvestable yield is reduced In this study, we investigate how sugar beets respond to combinations of neighbor presence, resource competition, and water stress, and test the hypothesis that shade avoidance cues from neighboring vegetation may cause yield loss similar to, or even greater than, resource depletion by neighboring vegetation. Sugar beets were grown in 19L pails surrounded by Kentucky bluegrass (Poa pratiensis). Competition treatments included “shade avoidance only” whereB. vulgarisleaves were exposed to reflected light from neighbors without shading or root competition, “shade avoidance plus root interaction” where crop and competitor roots interacted, and “no competition” as a control. Sugar beets in each competition treatment were subjected to 3 levels of irrigation: 100% of estimated evapotranspiration (ET), 80% ET and 60% ET. When grown without drought stress (100% ET), the shade avoidance treatment had 16% less root biomass compared to the no competition control (P = 0.007); however, under the most severe drought treatment (60% ET) root biomass was similar between the shade avoidance and no competition treatments (P = 0.48). Under 60% ET, plants in the shade avoidance only treatment produced 15% fewer leaves (P < 0.001) but 14% greater leaf area (P = 0.049) compared to the no competition control. The reduced number of leaves produced due to shade avoidance resulted in less structural tissue to be maintained under drought stress, and thus provides a potential benefit to ‘shade avoidance’ responses that are not directly related to avoiding shade.
Deep mutational scanning reveals sequence to function constraints for SWEET family transporters
Authors: Narayanan Krishna K. , Weigle Austin T. , Xu Lingyun , Mi Xuenan , Zhang Chen , Chen Li-Qing , Procko Erik , Shukla Diwakar
Published: July 2024

Protein science is entering a transformative phase enabled by deep mutational scans that provide an unbiased view of the residue level interactions that mediate function. However, it has yet to be extensively used to characterize the mutational and evolutionary landscapes of plant proteins. Here, we apply the method to explore sequence-function relationships within the sugar transporter AtSWEET13. DMS results describe how mutational interrogation throughout different regions of the protein affects AtSWEET13 abundance and transport function. Our results identify novel transport-enhancing mutations that are validated using the FRET sensor assays. Extending DMS results to phylogenetic analyses reveal the role of transmembrane helix 4 (TM4) which makes the SWEET family transporters distinct from prokaryotic SemiSWEETs. We show that transmembrane helix 4 is intolerant to motif swapping with other clade-specific SWEET TM4 compositions, despite accommodating single point-mutations towards aromatic and charged polar amino acids. We further show that the transfer learning approaches based on physics and ML basedIn silicovariant prediction tools have limited utility for engineering plant proteins as they were unable to reproduce our experimental results. We conclude that DMS can produce datasets which, when combined with the right predictive computational frameworks, can direct plant engineering efforts through derivative phenotype selection and evolutionary insights.