bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer
Authors: Bowen Mikayla Borthwick , Melendez Brenda , Zhang Qian , Moreno Diana , Peralta Leah , Chan Wai Kin , Jeter Collene , Tan Lin , Zal M. Anna , Lorenzi Philip L. , Dunner Kenneth , Yang Richard K , Broaddus Russell R. , Celestino Joseph , Gokul Nisha , Whitley Elizabeth , Schmandt Rosemarie , Lu Karen , Kim Hyun-Eui , Yates Melinda S. 
Published: June 2024

AbstractLynch syndrome (LS) is defined by inherited mutations in DNA mismatch repair genes, includingMSH2,and carries 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, specific mechanisms for LS-associated endometrial carcinogenesis are not well understood. Here, we assessed the effects of MSH2 loss on EC pathogenesis using a novel mouse model (PR-CreMsh2flox/flox, abbreviated Msh2KO), primary cell lines established from this model, human tissues, and human EC cell lines with isogenic MSH2 knockdown. Beginning at eight months of age, 30% of Msh2KO mice exhibited endometrial atypical hyperplasia (AH), a precancerous lesion. At 12 to 16 months of age, 47% of Msh2KO mice exhibited either AH or ECs with histologic features similar to human LS-related ECs. Transcriptomic profiling of EC from Msh2KO mice revealed a transcriptomic signature for mitochondrial dysfunction. Studiesin vitroandin vivorevealed mitochondrial dysfunction based upon two mechanisms: marked mitochondrial content reduction, along with pronounced disruptions to the integrity of retained mitochondria. Human LS-related ECs also exhibited mitochondrial content reduction compared with non-LS-related ECs. Functional studies revealed metabolic reprogramming of MSH2-deficient EC cellsin vitro, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. We are the first to identify mitochondrial dysfunction and metabolic disruption as a consequence of MSH2 deficiency-related EC. Mitochondrial and metabolic aberrations should be evaluated as novel biomarkers for endometrial carcinogenesis or risk stratification and could serve as targets for cancer interception in women with LS.SignificanceThis is the first study to report mitochondrial dysfunction contributing to MSH2-deficient endometrial cancer development, identifying a noncanonical pathway for MSH2 deficient carcinogenesis, which also imparts vulnerability to metabolic targeting.
Immune Checkpoint Blockade Delays Cancer and Extends Survival in Murine DNA Polymerase Mutator Syndromes
Authors: Sawant Akshada , Shi Fuqian , Lopes Eduardo Cararo , Hu Zhixian , Abdelfattah Somer , Baul Jennele , Powers Jesse , Hinrichs Christian S. , Rabinowitz Joshua D. , Chan Chang S. , Lattime Edmund C. , Ganesan Shridar , White Eileen 
Published: June 2024

AbstractMutations in polymerasesPold1andPoleexonuclease domains in humans are associated with increased cancer incidence, elevated tumor mutation burden (TMB) and response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond. Here we generatedPold1andPoleproofreading mutator mice and show that ICB treatment of mice with high TMB tumors did not improve survival as only a subset of tumors responded. Similarly, introducing the mutator alleles into mice with Kras/p53 lung cancer did not improve survival, however, passaging mutator tumor cellsin vitrowithout immune editing caused rejection in immune-competent hosts, demonstrating the efficiency by which cells with antigenic mutations are eliminated. Finally, ICB treatment of mutator mice earlier, before observable tumors delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the use of ICB in individuals at high risk for cancer prevention.HighlightsGermline somatic and conditionalPold1andPoleexonuclease domain mutations in mice produce a mutator phenotype.Spontaneous cancers arise in mutator mice that have genomic features comparable to human tumors with these mutations.ICB treatment of mutator mice with tumors did not improve survival as only a subset of tumors respond.Introduction of the mutator alleles into an autochthonous mouse lung cancer model also did not produce immunogenic tumors, whereas passaging mutator tumor cellsin vitrocaused immune rejection indicating efficient selection against antigenic mutationsin vivo.Prophylactic ICB treatment delayed cancer onset, improved survival, and selected for tumors with no aneuploidy.Graphical Abstract
Epstein-Barr virus induced 3 attributes to TLR7-mediated splenomegaly and bicytopenia
Authors: Iseki Masanori , Sakamoto Yuma , Takezaki Daiki , Matsuda Yoshihiro , Inoue Mariko , Morizane Shin , Mukai Tomoyuki 
Published: June 2024

AbstractEpstein-Barr virus induced 3 (EBI3) is a gene induced by stimulation of toll-like receptors (TLRs) and functions as a component of a heterodimer cytokine IL-27. IL-27 regulates both innate and acquired immune responses; however, their functionin vivois still largely unknown. Splenomegaly, an enlargement of the spleen, is known to be induced by chronic infectious diseases, including infectious mononucleosis due to EB virus infection. Repeated treatment of imiquimod (IMQ; a TLR7 agonist) has been reported to induce splenomegaly and cytopenia due to increased splenic function. Although immune cell activation is speculated to be involved in the pathogenesis of chronic infection-mediated splenomegaly, the detailed molecular mechanism is unknown. Here, we demonstrated that IMQ induced marked splenomegaly and severe bicytopenia (anemia and thrombocytopenia) in the wild-type mice. Myeloid cells, not lymphoid cells, were increased in the enlarged spleen. Extramedullary hematopoiesis was observed in the enlarged spleen of the IMQ-treated mice. RNA-seq analysis revealed that type I interferon (IFN)-related genes were upregulated in the spleen and peripheral blood in IMQ-treated mice.Ebi3deficiency partially retrieved these IMQ-induced pathological changes. We found thatIl27as well asEbi3genes were elevated by IMQ in the spleen and peripheral blood. Further, IL-27 stimulation upregulated type I IFN-related genes in bone marrow-derived macrophage culture in the absence of type I IFN. Collectively, EBI3 contributes to TLR7-induced splenomegaly and bicytopenia, presumably via IL-27.
Structural and biochemical analysis of ligand binding in yeast Niemann-Pick type C1-related protein
Authors: Nel Lynette , Thaysen Katja , Jamecna Denisa , Olesen Esben , Szomek Maria , Langer Julia , Frain Kelly May , Höglinger Doris , Wüstner Daniel , Pedersen Bjørn P. 
Published: June 2024

AbstractIn eukaryotes, integration of sterols into the vacuolar/lysosomal membrane is critically dependent on the Niemann-Pick type C (NPC) system. The system consists of an integral membrane protein, called NCR1 in yeast, and NPC2, a luminal soluble protein that transfers sterols to the N-terminal domain (NTD) of NCR1 before membrane integration. Both proteins have been implicated in sterol homeostasis of yeast and humans. Here, we investigate sterol and lipid binding of the NCR1/NPC2 transport system and determine crystal structures of the sterol-binding NTD. The NTD binds both ergosterol and cholesterol, with nearly identical conformations of the binding pocket. Apart from sterols, the NTD can also bind fluorescent analogs of phosphatidylinositol, phosphatidylcholine and phosphatidylserine as well as sphingosine and ceramide. We confirm the multi-lipid scope of the NCR1/NPC2 system using photo-crosslinkable and clickable lipid analogs, namely pac-cholesterol, pac-sphingosine and pac-ceramide. Finally, we reconstitute the transfer of pac-sphingosine from NPC2 to the NTDin vitro. Collectively, our results support that the yeast NPC system can work as versatile machinery for vacuolar homeostasis of structurally diverse lipids, besides ergosterol.Summary blurbResults of X-ray crystallography and binding assays with different lipids expand our knowledge of the substrate scope of the Niemann-Pick type C1-related proteins NCR1 and NPC2 in yeast.GRAPHICAL ABSTRACT
Kinetic landscape of single virus-like particles highlights the efficacy of SARS-Cov-2 internalization
Authors: Atemin Aleksandar , Ivanova Aneliya , Peppel Wiley , Stamatov Rumen , Gallegos Rodrigo , Durden Haley , Uzunova Sonya , Vershinin Michael D. , Saffarian Saveez , Stoynov Stoyno S. 
Published: June 2024

AbstractThe efficiency of virus internalization into target cells is a major determinant of infectivity. SARS-CoV-2 internalization occurs via S-protein-mediated cell binding followed either by direct fusion with the plasma membrane or endocytosis and subsequent fusion with the endosomal membrane. Despite the crucial role of virus internalization, the precise kinetics of the processes involved remains elusive. We developed a pipeline, which combines live-cell microscopy and advanced image analysis, for measuring the rates of multiple internalization-associated molecular events of single SARS-CoV-2-virus-like particles (VLPs), including endosome ingression, pH change, and nucleocapsid release. Our live-cell imaging experiments demonstrate that only a few minutes after binding to the plasma membrane, VLPs ingress into Rab5-negative endosomes via Dynamin-dependent scission. Less than two minutes later, the pH of VLPs drops below 5 followed by an increase in VLP speed, yet these two events are not interrelated. Nucleocapsid release from the VLPs occurs with similar kinetics to the pH drop, suggesting that VLP fusion occurs during endosome acidification. Neither Omicron mutations nor abrogation of the S protein polybasic cleavage site altered the rate of VLP internalization events, indicating that they do not affect these processes. Finally, we observe that VLP internalization occurs two to three times faster in VeroE6 than in A549 cells, which may contribute to the greater susceptibility of the former cell line to SARS-CoV-2 infection. Taken together, our precise measurements of the kinetics of VLP internalization-associated processes shed light on their contribution to the effectiveness of SARS-CoV-2 propagation in cells. Time-lapse videos of the studied internalization events can be accessed in the dedicatedCOVIDynamics database.
Residual force enhancement decreases when scaling from the single muscle fibre to joint level in humans
Authors: Hinks Avery , Jacob Kaitlyn B. E. , Patterson Makenna A. , Dalton Benjamin E. , Power Geoffrey A. 
Published: June 2024

AbstractResidual force enhancement (rFE), defined as increased isometric force following active lengthening compared to a fixed-end isometric contraction at the same muscle length and level of activation, is present across all scales of muscle. While rFE is always present at the cellular level, often rFE ‘non-responders’ are observed during joint-level voluntary contractions. We compared rFE between the joint level and single fibre level (vastus lateralis biopsies) in 16 young males.In-vivovoluntary knee-extensor rFE was measured by comparing steady-state isometric torque between a stretch-hold (maximal activation at 150°, stretch to 70°, hold) and a fixed-end isometric contraction, with ultrasonographic recording of vastus lateralis fascicle length (FL). Fixed-end contractions were performed at 67.5°, 70°, 72.5°, and 75°; the joint angle that most closely matched FL of the stretch-hold contraction’s isometric steady-state was used to calculate rFE. The starting and ending FLs of the stretch-hold contraction were expressed as % optimal FL, determined via torque-angle relationship. In single fibre experiments, the starting and ending fibre lengths were matched relative to optimal length determined fromin-vivotesting, yielding an average sarcomere excursion of ∼2.2-3.4µm. There was a greater magnitude of rFE at the single fibre (∼20%) than joint level (∼5%) (P=0.004), with ‘non-responders’ only observed at the joint level. By comparing rFE across scales within the same participants, we show the development of the rFE non-responder phenomenon is upstream of rFE’s cellular mechanisms, with rFE only lost rather than gained when scaling from single fibres to the joint level.
Genetic burden of dysregulated cytoskeletal organisation in the pathogenesis of pulmonary fibrosis
Authors: Wang Dapeng , Ni Yujie , Liu Bin , Ding Huan , John Alison , Wain Louise V , Johnson Simon R. , Maher Toby M , Molyneaux Philip L , Renzoni Elizabeth , Saini Gauri , Wells Athol U , Morris-Rosendahl Deborah , Jenkins R Gisli , Stewart Iain 
Published: June 2024

AbstractBackgroundPulmonary fibrosis (PF) is a shared characteristic of chronic interstitial lung diseases of mixed aetiology. Previous studies on PF highlight a pathogenic role for common and rare genetic variants. This study aimed to identify rare pathogenic variants that are enriched in distinct biological pathways and dysregulated gene expression.MethodsRare variants were identified using whole genome sequencing (WGS) from two independent PF cohorts, the PROFILE study and the Genomics England 100K (GE100KGP) cohort, with the gnomAD database as a reference. Four pathogenic variant categories were defined: loss of function variants, missense variants, protein altering variants, and protein truncating variants. Gene burden testing was performed for rare variants defined as having a minor allele frequency <0.1%. Overrepresentation analysis of gene ontology terms and gene concept network analysis were used to interpret functional pathways. Integration of publicly available transcriptomic datasets was performed using weighted gene co-expression network analysis of idiopathic pulmonary fibrosis (IPF) lung tissue compared with healthy controls.ResultsBurden testing was performed on 507 patients from the PROFILE study and 451 PF patients from GE100KGP cohort, compared with 76,156 control participants from the gnomAD database. Ninety genes containing significantly more pathogenic rare variants in cases than in controls were observed in both cohorts. Fifty-six genes included missense variants and 87 genes included protein altering variants. For missense variants,HMCN1, encoding hemicentin-1, andRGPD1, encoding a protein with a RanBD1 domain, were highly associated with PF in both PROFILE (p=5.70E-22 and p=4.48E-51, respectively) and GE100KGP cohorts (p=2.27E-24 and p=1.59E-36, respectively). 56 of 90 genes with significant burden were observed within modules correlated with disease in transcriptomic analysis, includingHMCN1andRGPD1. Enriched functional categories from genetic and transcriptomic analyses included pathways involving extracellular matrix constituents, cell adhesion properties and microtubule organisation.ConclusionsRare pathogenic variant burden testing and weighted gene co-expression network analysis of transcriptomic data provided complementary evidence for pathways regulating cytoskeletal dynamics in PF pathogenesis. Functional validation of candidates could provide novel targets for intervention strategies.
No effect of menstrual cycle phase on eccentric exercise-induced neuromuscular impairments and the magnitude of the repeated bout effect
Authors: Rilling Amelia , Power Geoffrey A. 
Published: June 2024

AbstractNeuromuscular function is impaired following an unaccustomed bout of eccentric exercise, however, through the repeated bout effect (RBE) the muscle is protected from damage following a subsequent bout of eccentric exercise. As a result of unaccustomed eccentric contractions, structural muscle damage occurs in both sexes. However, the inflammatory response may be mitigated in females due to estradiol, thereby attenuating the secondary effects of muscle damage and potentially limiting the magnitude of the RBE. We investigated the relationship between menstrual cycle phase and oral contraceptive use on neuromuscular impairments following the first bout of exercise, and the magnitude of the RBE. Thirteen female participants performed two bouts of 150 maximal eccentric voluntary contractions of the elbow flexors four weeks apart. Normally menstruating females participated during the late follicular phase (day 10-14) of their menstrual cycle, as determined through cycle tracking, when estradiol is near peak, and progesterone is lower. Oral contraceptive users were tested on their placebo pill days (lower estradiol). Neuromuscular function was assessed for Bout 1 before the eccentric protocol and then again 48 hours following, and this was repeated 4 weeks later for Bout 2. Eccentric exercise-induced muscle weakness and soreness did not differ between groups following Bout 1 (p=0.885), and the magnitude of the RBE (p<0.05) was similar between groups (p=0.995). Females in the late follicular phase (classified as high estradiol) and females on combined oral contraceptives (low estradiol) had similar impairments in neuromuscular function following the first bout of eccentric exercise, and a similar RBE.
Sex-specific immunocompetence: resistance and tolerance can both be futile but not under the same circumstances
Authors: Brenninger Franziska A. , Kovalov Viktor , Kokko Hanna 
Published: June 2024

AbstractImmunocompetence evolution can involve a ‘resistance is futile’ scenario, if parasite encounter rates are so high that high investment in resistance only marginally delays infection. Here, we investigate two understudied aspects of ‘futility’. First, immunocompetence is usefully categorized as reducing the rate of becoming infected (resistance) or reducing the negative fitness consequences of infection once it happened (tolerance). We compare the prospects of futility for resistance, tolerance, and their joint occurrence, showing that resistance futility arises with respect to parasite encounter rates, while tolerance futility arises with respect to parasite virulence. However, if the same host trait improves pleiotropically both resistance and tolerance, futility disappears altogether and immunity investment remains profitable when increasing parasite encounter rates, virulence, or both. Second, we examine how sexual selection strength impacts these findings. If one sex (typically males) is near the faster end of a fast-slow continuum of life histories, then life history patterns reflecting futility can evolve sex-specificity. The solutions often feature sexual dimorphism in immunocompetence, but not always in the direction of strong sexual selection yielding low immunity: sexual selection can select for faster and ‘sicker’ lives, but if sexual selection also causes traits that impact parasite encounter rates, the results are strongly dependent on whether futility (along any axis) plays a role.Lay SummaryIntuition suggests that investment into immunity is higher, when hosts frequently encounter parasites. While there are examples that confirm this, in other cases, hosts have been shown to abandon immune defenses under high parasite pressure. We reconcile these findings by modelling the optimal host resource allocation towards immunity under varying parasite pressure and strength of sexual selection. Our results show two axes along which immunity investments are futile and should therefore be abandoned in favor of investing into reproduction: resisting infection becomes futile under high parasite abundance, while tolerating the harmful effects of infection is not beneficial under ever increasing parasitic virulence. However, investments of organisms that are capable of both resistance and tolerance mechanisms yield fitness payoffs also when parasites are highly virulent and abundant. This work highlights the impact of parasites and immune defenses on optimal immunity investment levels in hosts, an insight which also complements theory on sex-specific immunity.
Elevated rates of molecular evolution genome-wide in mutualist legumes and rhizobia
Authors: Harrison L. T , Stinchcombe J. R , Frederickson M. E 
Published: June 2024

AbstractRates of molecular evolution vary greatly among even closely related species. Although theory predicts that antagonistic interactions between species increase rates of molecular evolution, predictions for how mutualism affects evolutionary rates are mixed. Here, we compared rates of molecular evolution between 1) mutualistic and non-mutualistic legumes, 2) an independent set of symbiotic rhizobia and their non-symbiotic close relatives, and 3) symbiotic and non-symbiotic clades withinEnsifer, a diverse genus of bacteria with various lifestyles. We assembled transcriptomesde novofor 12 legume species and then calculated dN/dS ratios at orthologous genes in all species to determine if genes in mutualistic plants evolve faster or slower than in their non-mutualistic relatives. We also calculated dN/dS ratios in symbiosis genes known to be important for nodulation with rhizobia. We found that mutualists have higher rates of molecular evolution genome-wide compared to non-mutualist legumes. We next calculated dN/dS ratios in 14 bacteria species across the proteobacteria phylogeny that differ in whether they associate mutualistically with plants, using previously published data. We found that in most pairs, symbiotic rhizobia show higher dN/dS values compared to their non-symbiotic relatives. Finally, within a bacterial genus with many well-characterized mutualist species (Ensifer), we calculated dN/dS ratios in symbiotic and non-symbiotic clades and found that symbiotic lineages have higher rates of molecular evolution genome-wide, but not at genes on the symbiotic plasmid pSymB. Our results suggest that although mutualism between legumes and rhizobia is associated with elevated rates of molecular evolution genome-wide, symbiosis genes may be evolutionarily stagnant.
Combining Scalable Organ Chip Platform with Deep Learning-Based Imaging Analysis for Cancer Therapeutic Screening
Authors: Yuan Yu-Chieh , Xu Beibei , McCormack Jenna , Huang XuHai , Ma Jingzhe , Marshall Thomas , Sun Yacong , Singh Hardeep , Fanelli Alyssa , Gilbride Paige , Qian Xiaohua , Xie Zhiyong , Si Longlong , Xie Xin , Bai Haiqing 
Published: June 2024

AbstractFunctional precision oncology represents an emerging approach to genomic approaches by testing treatment options directly on patient-derived models. Current assays, including the use of patient-derived xenograft (PDX) and patient-derived organoid (PDOs), faces major barriers in clinical use due to technical challenges, such as standardization, cost, assay time, scalability, and faithful mimicry of patient tumor microenvironment (TME). Here, we introduce an Organ Chip (OC) device constructed entirely from thermoplastic materials, free of porous membrane or other barrier structures, and optimized for high-content imaging (HCI). This automation-compatible device supports tissue-specific extracellular matrices and coculture for a wide spectrum of organ and disease types, including the TME. As a proof-of-concept, we demonstrate the growth of pancreatic, lung, and colon cancer cell lines and primary lung cancer cells and the testing of cancer drugs in these models. HCI-based phenotypic profiling enabled accurate quantification of drug response, with better performance than traditional biochemical assays. Moreover, we developed a deep-learning method for assessing drug responses using bright field images. The integration of a low-cost, scalable, and faithful OC models with automatic high-content image analysis represents a significant stride towards functional precision oncology and cancer drug discovery.