bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping the functional form of the trade-off between infection resistance and reproductive fitness under dysregulated immune signaling
Authors: Critchlow Justin T. , Prakash Arun , Zhong Katherine Y. , Tate Ann T. 
Published: August 2023

AbstractImmune responses benefit organismal fitness by clearing parasites but also exact costs associated with immunopathology and energetic investment. Hosts manage these costs by tightly regulating the induction of immune signaling to curtail excessive responses and restore homeostasis. Despite the theoretical importance of turning off the immune response to mitigate these costs, experimentally connecting variation in the negative regulation of immune responses to organismal fitness remains a frontier in evolutionary immunology. In this study, we used a doseresponse approach to manipulate the RNAi-mediated knockdown efficiency ofcactus(IκBα), a central regulator of Toll pathway signal transduction in flour beetles (Tribolium castaneum). By titratingcactusactivity along a continuous gradient, we derived the shape of the relationship between immune response investment and traits associated with host fitness, including infection susceptibility, lifespan, fecundity, body mass, and gut homeostasis.Cactusknock-down increased the overall magintude of inducible immune responses and delayed their resolution in a dsRNA dose-dependent manner, promoting survival and resistance following bacterial infection. However, these benefits were counterbalanced by dsRNA dose-dependent costs to lifespan, fecundity, body mass, and gut integrity. Our results allowed us to move beyond the qualitative identification of a trade-off between immune investment and fitness to actually derive its functional form. This approach paves the way to quantitatively compare the evolution and impact of distinct regulatory elements on life-history trade-offs and fitness, filling a crucial gap in our conceptual and theoretical models of immune signaling network evolution and the maintenance of natural variation in immune systems.
Colorful Lizards and the Conflict of Collection
Authors: Goodman Colin M. , Claunch Natalie M. , Steele Zachary T. , Episcopio-Sturgeon Diane J. , Romagosa Christina M. 
Published: August 2023

AbstractInvasive species threaten biodiversity and their management is economically burdensome. Research on the indirect effects of introduced species are often focused on indirect ecological effects, with little focus on the more difficult to capture but critically important societal impacts. Often understated are the social costs of invasive species such as conflicts between invasive species managers and public stakeholders. Chameleons are popular in the pet trade and have been introduced throughout Florida, and their presence often attracts private collectors. After locating a population of panther chameleons (Furcifer pardalis) within a suburban neighborhood in central Florida, we administered anonymous questionnaires to residents to explore how this introduction and the ensuing species collection has affected them. Respondents had knowledge of chameleon presence but most expressed low concern about chameleon presence. Respondents who had observed chameleons in the area expressed more concern for their safety given the activities of private collectors. Our study highlights the importance of recognizing the social impacts of species introductions in urban environments, particularly the attention these species can draw and the mixed perception of these species among stakeholders.
Network shape intelligence outperforms AlphaFold2 intelligence in vanilla protein interaction prediction
Authors: Abdelhamid Ilyes , Muscoloni Alessandro , Rotscher Danny Marc , Lieber Matthias , Markwardt Ulf , Cannistraci Carlo Vittorio 
Published: August 2023

AbstractFor decades, scientists and engineers have been working to predict protein interactions, and network topology methods have emerged as extensively studied techniques. Recently, approaches based on AlphaFold2 intelligence, exploiting 3D molecular structural information, have been proposed for protein interaction prediction, they are promising as potential alternatives to traditional laboratory experiments, and their design and performance evaluation is compelling.Here, we introduce a new concept of intelligence termed Network Shape Intelligence (NSI). NSI is modelled via network automata rules which minimize external links in local communities according to a brain-inspired principle, as it draws upon the local topology and plasticity rationales initially devised in brain network science and then extended to any complex network. We show that by using only local network information and without the need for training, these network automata designed for modelling and predicting network connectivity can outperform AlphaFold2 intelligence in vanilla protein interactions prediction. We find that the set of interactions mispredicted by AlphaFold2 predominantly consists of proteins whose amino acids exhibit higher probability of being associated with intrinsically disordered regions. Finally, we suggest that the future advancements in AlphaFold intelligence could integrate principles of NSI to further enhance the modelling and structural prediction of protein interactions.
Transport of metformin metabolites by guanidinium exporters of the Small Multidrug Resistance family
Authors: Lucero Rachael M. , Demirer Kemal , Yeh Trevor Justin , Stockbridge Randy B. 
Published: August 2023

AbstractProteins from the Small Multidrug Resistance (SMR) family are frequently associated with horizontally transferred multidrug resistance gene arrays found in bacteria from wastewater and the human-adjacent biosphere. Recent studies suggest that a subset of SMR transporters might participate in metabolism of the common pharmaceutical metformin by bacterial consortia. Here, we show that both genomic and plasmid-associated transporters of the SMRGdxfunctional subtype export byproducts of microbial metformin metabolism, with particularly high export efficiency for guanylurea. We use solid supported membrane electrophysiology to evaluate the transport kinetics for guanylurea and native substrate guanidinium by four representative SMRGdxhomologues. Using an internal reference to normalize independent electrophysiology experiments, we show that transport rates are comparable for genomic and plasmid-associated SMRGdxhomologues, and using a proteoliposome-based transport assay, we show that 2 proton:1 substrate transport stoichiometry is maintained. Additional characterization of guanidinium and guanylurea export properties focuses on the structurally characterized homologue, Gdx-Clo, for which we examined the pH dependence and thermodynamics of substrate binding and solved an x-ray crystal structure with guanylurea bound. Together, these experiments contribute in two main ways. By providing the first detailed kinetic examination of the structurally characterized SMRGdxhomologue Gdx-Clo, they provide a functional framework that will inform future mechanistic studies of this model transport protein. Second, this study casts light on a potential role for SMRGdxtransporters in microbial handling of metformin and its microbial metabolic byproducts, providing insight into how native transport physiologies are co-opted to contend with new selective pressures.SummaryUsing solid supported membrane electrophysiology, structural biology, and binding assays, we characterize binding and transport of metformin metabolites by bacterial SMR transporters, including proteins associated with horizontal gene transfer in wastewater bacteria that degrade metformin.
Transcriptional suppression of sphingolipid catabolism controls pathogen resistance inC. elegans
Authors: Nasrallah Mohamad A. , Peterson Nicholas D. , Salisbury J. Elizabeth , Liu Pengpeng , Page Amanda L. , Tse Samantha Y. , Wani Khursheed A. , Tocheny Claire E. , Pukkila-Worley Read 
Published: August 2023

ABSTRACTSphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematodeC. elegans, we identified the nuclear hormone receptornhr-66,a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing and RNA sequencing experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes innhr-66loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogenPseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.
WITHDRAWN: L-Carnitine on contrast-induced nephropathy in diabetic rats
Authors: de Oliveira Natalia Abreu , Couto Sheila Marques Fernandes , Borges Fernanda Teixeira , Vattimo Maria de Fátima Fernandes , da Fonseca Cassiane Dezoti 
Published: August 2023

Withdrawal StatementThe authors have withdrawn their manuscript owing to improve the data of manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
MICROGLIAL CELL EXPRESSION OF THE TYPE 2 CANNABINOID RECEPTOR REGULATES IMMUNE-MEDIATED NEUROINFLAMMATION
Authors: Moe Alison , Rayasam Aditya , Sauber Garrett , Shah Ravi K. , Yuan Cheng-Yin , Szabo Aniko , Moore Bob M. , Colonna Marco , Cui Weiguo , Romero Julian , Zamora Anthony E. , Hillard Cecilia J. , Drobyski William R. 
Published: August 2023

ABSTRACTNeuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
An automated convergence diagnostic for phylogenetic MCMC analyses
Authors: Berling Lars , Bouckaert Remco , Gavryushkin Alex 
Published: August 2023

AbstractAssessing convergence of Markov chain Monte Carlo (MCMC) based analyses is crucial but challenging, especially so in high dimensional and complex spaces such as the space of phylogenetic trees (treespace). In practice, it is assumed that the target distribution is the unique stationary distribution of the MCMC and convergence is achieved when samples appear to be stationary. Here we leverage recent advances in computational geometry of the treespace and introduce a method that combines classical statistical techniques and algorithms with geometric properties of the treespace to automatically evaluate and assess practical convergence of phylogenetic MCMC analyses. Our method monitors convergence across multiple MCMC chains and achieves high accuracy in detecting both practical convergence and convergence issues within treespace. Furthermore, our approach is developed to allow for real-time evaluation during the MCMC algorithm run, eliminating any of the chain post-processing steps that are currently required. Our tool therefore improves reliability and efficiency of MCMC based phylogenetic inference methods and makes analyses easier to reproduce and compare. We demonstrate the efficacy of our diagnostic via a well-calibrated simulation study and provide examples of its performance on real data sets. Although our method performs well in practice, a significant part of the underlying treespace probability theory is still missing, which creates an excellent opportunity for future mathematical research in this area.The open source package for the phylogenetic inference framework BEAST2, called ASM, that implements these methods, making them accessible through a user-friendly GUI, is available fromhttps://github.com/rbouckaert/asm/. The open source Python package, called tetres, that provides an interface for these methods enabling their applications beyond BEAST2 can be accessed athttps://github.com/bioDS/tetres/.
Ubiquitin phosphorylation accelerates protein aggregation and promotes neurodegeneration in the aging brain
Authors: Chen Cong , Yi Hua-Wei , Zhang Yi , Wang Tong , Gao Tong-Yao , Lou Zhi-Lin , Wei Tao-Feng , Lu Yun-Bi , Li Ting-Ting , Zhang Wei-Ping , Tang Chun 
Published: August 2023

AbstractSer65-phosphorylated ubiquitin (pUb) was found elevated in neurons of aged and neurodegenerative brains. Yet little is known whether a causative link exists between pUb level and brain aging. Here we show that the knockout ofpink1, a Ub kinase, abolished pUb elevation and decelerated protein aggregation in aged mouse brains and cells with proteasomal inhibition. Conversely, over-expression of PINK1 but not the kinase-dead version increased the pUb level and accelerated protein aggregation by suppressing of proteasomal degradation. Furthermore, PINK1 over-expression in mouse hippocampus neurons increased pUb level and protein aggregation, slowly leading to mitochondrial injury, neurodegeneration, and cognitive impairment. Notably, the neuronal damages induced by PINK1 were rescued by the dominant negative Ub/S65A mutant, while Ub/S65E phosphomimetic mutant caused neuronal death. Together, an incidental increase of Ub phosphorylation can progressively and cumulatively cause the decline of Ub-dependent proteasomal activity, consequenting promotes neurodegeneration in the aging brain.
Species-Agnostic Transfer Learning for Cross-species Transcriptomics Data Integration without Gene Orthology
Authors: Park Youngjun , Muttray Nils Paul , Hauschild Anne-Christin 
Published: August 2023

AbstractNovel hypotheses in biomedical research are often developed or validated in model organisms such as mice and zebrafish and thus play a crucial role, particularly in studying disease mechanisms and treatment responses. However, due to biological differences between species, translating these findings into human applications remains challenging. Moreover, commonly used orthologous gene information is often incomplete, particularly for non-model organisms, and entails a significant information loss during gene-id conversion. To address these issues, we present a novel methodology for species-agnostic transfer learning with heterogeneous domain adaptation. We built on the cross-domain structure-preserving projection and extended the algorithm toward out-of-sample prediction, a common challenge in biomedical sequencing data. Our approach not only allows knowledge integration and translation across various species without relying on gene orthology but also identifies similar GO biological processes amongst the most influential genes composing the latent space for species integration. Subsequently, this enables the identification and functional annotation of genes missing from public orthology databases. Finally, we evaluated our approach with four different single-cell sequencing datasets focusing on out-of-sample prediction and compared it against related machine-learning approaches. In summary, the developed model outperforms all related methods working without prior knowledge when predicting unseen cell types based on other species’ data. The results demonstrate that our novel approach allows knowledge transfer beyond species barriers without the dependency on known gene orthology but utilizing the entire gene sets.
Machine Learning-Driven Phenotype Predictions based on Genome Annotations
Authors: Edirisinghe Janaka N. , Goyal Samaksh , Brace Alexander , Colasanti Ricardo , Gu Tianhao , Sadhkin Boris , Zhang Qizhi , Kamimura Roy , Henry Christopher S. 
Published: August 2023

AbstractOver the past two decades, there has been a remarkable and exponential expansion in the availability of genome sequences, encompassing a vast number of isolate genomes, amounting to hundreds of thousands, and now extending to millions of metagenome-assembled genomes. The rapid and accurate interpretation of this data, along with the profiling of diverse phenotypes such as respiration type, antimicrobial resistance, or carbon utilization, is essential for a wide range of medical and research applications.Here, we leverage sequenced-based functional annotations obtained from the RAST annotation algorithm as predictors and employ six machine learning algorithms (K-Nearest Neighbors, Gaussian Naive Bayes, Support Vector Machines, Neural Networks, Logistic Regression, and Decision Trees) to generate classifiers that can accurately predict phenotypes of unclassified bacterial organisms. We apply this approach in two case studies focused on respiration types (aerobic, anaerobic, and facultative anaerobic) and Gram-stain types (Gram negative and Gram positive). We demonstrate that all six classifiers accurately classify the phenotypes of Gram stain and respiration type, and discuss the biological significance of the predicted outcomes. We also present four new applications that have been deployed in The Department of Energy Systems Biology Knowledgebase (KBase) that enable users to: (i) Upload high-quality data to train classifiers; (ii) Annotate genomes in the training set with the RAST annotation algorithm; (iii) Build six different genome classifiers; and (iv) Predict the phenotype of unclassified genomes. (https://narrative.kbase.us/#catalog/modules/kb_genomeclassification)
The spreading of facultative H3K9me3-heterochromatin drives congenital disease
Authors: Wang Chen , Zhang Wei , Chen Xue-Lin , Wang Wen-Fei , Li Yong-Hao , Chang Jian-Feng , Guo Xiao-Bo , Jing Yuan-Ya , Li Ya-Bin , Lu Xin-Yi , Li Yu-Tong , Liu Kai , Ni Jian-Quan , Sun Fang-Lin 
Published: August 2023

AbstractHeterochromatin marked by trimethylated histone 3 at lysine 9 (H3K9me3) plays fundamental roles in reprogramming to direct cell fate determination in higher eukaryotes. However, the upstream factors that guide the establishment and spreading of H3K9me3-heterochromatin, leading to human developmental malformations, remain elusive. In this study, we found that Cdk13, a member of RNA polymerase II (RNAPII) kinase, suppresses congenital heart syndrome by preventing global facultative H3K9me3-heterochromatin spreading. Additionally, Cdk13 directs the phosphorylation of a large set of heterochromatin proteins at specific sites, which are required for the interaction between HP1 and histone H3K9 methyltransferases. Furthermore, we identified a compound, an inhibitor of heterochromatin regulators, that can alleviate syndromic heart defects inCdk13-mutant mice through the inhibition of H3K9me3-heterochromatin spreading. In summary, this study reveals a novel role and mechanism of Cdk13-triggered facultative H3K9me3-heterochromatin spreading in human genetic disease and paves the way for the treatment of congenital heart syndrome.
Mesothelial cells exhibit characteristics of perivascular cells in anin vitroangiogenesis assay
Authors: Koukorava Chrysa , Ward Kelly , Ahmed Katie , Dauleh Sumaya , Pereira Sofia M , Taylor Arthur , Haddrick Malcolm , Cross Michael J , Wilm Bettina 
Published: August 2023

AbstractMesothelial cells have been shown to have remarkable plasticity towards mesenchymal cell types during development and in disease situations. Here, we have characterized the potential of mesothelial cells to undergo changes towards perivascular cells using an in vitro angiogenesis assay. We demonstrate that GFP-labelled mesothelial cells (GFP-MCs) aligned closely and specifically with endothelial networks formed when human dermal microvascular endothelial cells (HDMECs) were cultured in the presence of VEGF-A165 on normal human dermal fibroblasts (NHDFs) for a 7-day period. The co-culture with GFP-MCs had a positive effect on branch point formation indicating that the cells supported endothelial tube formation. We interrogated the molecular response of the GFP- MCs to the angiogenic co-culture by qRT-PCR and found that the pericyte markerNg2was upregulated when the cells were co-cultured with HDMECs on NHDFs, indicating a change towards a perivascular phenotype. When GFP-MCs were cultured on the NHDF feeder layer, they upregulated the epithelial-mesenchymal transition markerZeb1and lost their circularity while increasing their size, indicating a change to a more migratory cell type. We analysed the pericyte- like behavior of the GFP-MCs in a 3D cardiac microtissue (spheroid) with cardiomyocytes, cardiac fibroblasts and cardiac endothelial cells where the mesothelial cells showed alignment with the endothelial cells. These results indicate that mesothelial cells have the potential to adopt a perivascular phenotype and associate with endothelial cells to potentially support angiogenesis.
Osteocalcin of maternal and embryonic origins synergize to establish homeostasis in offspring
Authors: Pinto Danilo Correa , Delgado Isabella Canal , Yang Haiyang , Clemenceau Alisson , Corvelo André , Narzisi Giuseppe , Musunuri Rajeeva , Berger Julian Meyer , Hendricks Lauren E. , Tokumura Kazuya , Luo Na , Li Hongchao , Oury Franck , Ducy Patricia , Yadav Vijay K. , Li Xiang , Karsenty Gerard 
Published: August 2023

ABSTRACTMany physiological functions regulated by osteocalcin are affected in adult offspring of mothers experiencing an unhealthy pregnancy. Furthermore, osteocalcin signaling during gestation influences cognition and adrenal steroidogenesis in adult mice. Together these observations suggest that osteocalcin functions during pregnancy may be a broader determinant of organismal homeostasis in adult mammals than previously thought. To test this hypothesis, we analyzed in unchallenged wildtype andOsteocalcin-deficient, newborn, and adult mice of various genotypes and origin, and that were maintained on different genetic backgrounds, the functions of osteocalcin in the pancreas, liver and testes and their molecular underpinnings. This analysis revealed that providing mothers are themselvesOsteocalcin-deficient,Osteocalcinhaploinsufficiency in embryos hampers insulin secretion, liver gluconeogenesis, glucose homeostasis, testes steroidogenesis in adult offspring; inhibits cell proliferation in developing pancreatic islets and testes; and disrupts distinct programs of gene expression in these organs and in the brain. This study indicates that through their synergistic regulation of multiple physiological functions, osteocalcin ofmaternal and embryonic origins contributes to the establishment and maintenance of organismal homeostasis in newborn and adult offspring.