bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in endocrine-resistant breast cancer cells
Authors: Ward Ashley V. , Riley Duncan , Cosper Kirsten E. , Finlay-Schultz Jessica , Brechbuhl Heather M. , Libby Andrew E. , Hill Kaitlyn B. , Varshney Rohan R. , Kabos Peter , Rudolph Michael C. , Sartorius Carol A. 
Published: June 2024

AbstractBackgroundLipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER+ breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor.MethodsER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived. Global gene expression and lipidomic profiling were performed to compare parental and endocrine resistant cells. Lipid storage was assessed using Oil Red O (ORO) staining. The FASN inhibitor TVB-2640 was tested for its impact on lipid storage and cell growth.13C2-acetate tracing was used to evaluate FASN activity and the efficacy of TVB-2640.ResultsEndocrine resistant cells showed significant enrichment in lipid metabolism pathways and distinct lipidomic profiles, characterized by elevated triglyceride levels and enhanced cytoplasmic lipid droplets.13C2-acetate tracing revealed increased FASN activity in endocrine resistant cells, which was effectively reduced by TVB-2640. While TVB-2640 reduced lipid storage in most but not all cell lines, this did not correlate with decreased cell growth.Polyunsaturated fatty acids (PUFAs) containing 6 or more double bonds were elevated in endocrine resistant cells and remained unaffected or increased with TVB-2640.ConclusionEndocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer.
Antibacterial effectors inDictyostelium discoideum: specific activity against different bacterial species
Authors: Munoz-Ruiz Raphael , Lamrabet Otmane , Jauslin Tania , Guilhen Cyril , Bourbon Alixia , Cosson Pierre 
Published: June 2024

ABSTRACTDictyostelium discoideumis a phagocytic amoeba continuously eating, killing and digesting bacteria. Previous studies have detected inD. discoideumcell extracts a bacteriolytic activity effective againstKlebsiella pneumoniaebacteria.In this study we characterized bacteriolytic activities found inD. discoideumcell extracts against five different bacteria (K. pneumoniae,Escherichia coli,Pseudomonas aeruginosa,Staphylococcus aureus, andBacillus subtilis).We first analyzed the bacteriolytic activity against these five bacteria in parallel over a range of pH values. We then measured the remaining bacteriolytic activity inD. discoideum kil1andmodAKO mutants. We also performed partial fractionation ofD. discoideumextracts and assessed activity against different bacteria. Together our results indicate that optimal bacteriolytic activity against different bacteria results from the action of different effectors. Proteomic analysis allowed us to propose a list of potential bacteriolytic effectors.IMPORTANCEMany antibacterial effectors have been characterized over the last decades, and their biological importance, mode of action and specificity is often still under study. Here we characterizedin vitrobacteriolytic activity inD. discoideumextracts against five species of gram-negative and gram-positive bacteria. Our results reveal that optimal lysis of different bacteria mobilizes different effectors. Proteomic analysis generated a list of potential bacteriolytic effectors. This work opens the way for future analysis of the role of individual effectors in livingD. discoideumcells.
Studies ofCrHCF244reveal similarities and differences inpsbAtranslation betweenChlamydomonas reinhardtiiandArabidopsis thaliana
Authors: Wang Xiaozhuo , Wang Guannan , Cheramie Lexi A. , Zhao Cuiping , Dassanayake Maheshi , Moroney James V. , Vinyard David J. 
Published: June 2024

AbstractTranslation ofpsbA, the chloroplast gene that encodes the D1 subunit of Photosystem II (PSII), is important for both PSII biogenesis and repair. The translation of thepsbAtranscript in the chloroplast is under the control of nuclear gene products. Using aChlamydomonasforward genetic screen and whole genome sequencing, we found a mutant defective in PSII activity and mapped the causative gene to be the homolog ofArabidopsis High Fluorescence(HCF244) gene, orCrHCF244. We then demonstrated that CrHCF244 is required forpsbAtranslation in the alga, consistent with the function of HCF244 inArabidopsis. TheArabidopsis HCF244gene also complemented the algal mutant. These results experimentally support the functional conservation of the homologs in green algae and land plants. However, these studies also revealed differences inpsbAtranslation inChlamydomonasandArabidopsis. Loss of HCF244 inArabidopsisresults in a large decrease in chlorophyll. In contrast, there is no significant loss of chlorophyll inChlamydomonaswhenCrHCF244is knocked out. This observation supports the uncoupling of D1 translation and chlorophyll association in algae as reported recently in anohp2mutant, which is defective in chlorophyll delivery. Intriguingly, theCrHCF244mutant also exhibited a relatively high rate of suppressor mutants, pointing to the presence of alternative pathway(s) for D1 translation control. The characterization of both the conserved aspects and the differences inpsbAtranslation control between algae and plants will help elucidate how this process is regulated.HighlightWe identified CrHCF244 as a translation factor ofpsbAinChlamydomonas. Characterization of this protein and genetic examinations of other previously identifiedpsbAtranslation factors inChlamydomonasreveal similarities and differences inpsbAtranslation betweenChlamydomonasandArabidopsis.
The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn’s disease
Authors: Guisado Daniela , Talware Sayali , Wang Xiaoli , Davis Andrew , Fozilov Elbek , Etra Aaron , Colombel Jean-Frederic , Schaniel Christoph , Tastad Christopher , Levine John E. , Ferrara James L. M. , Chuang Ling-Shiang , Sabic Ksenija , Singh Shishir , Marcellino Bridget K. , Hoffman Ronald , Cho Judy , Cohen Louis J. 
Published: June 2024

ABSTRACTBackgroundTreatment strategies for Crohn’s disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune “reset”). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts.MethodsImmunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment.ResultsOur study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT.ConclusionsThese studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.
Data-driven modeling ofE. colitranscriptional regulation
Authors: Dalldorf Christopher G. , Hughes Griffith , Li Gaoyuan , Palsson Bernhard O. , Zielinski Daniel C. 
Published: June 2024

AbstractThe growth of bacterial gene expression datasets has offered unprecedented coverage of achievable transcriptomes, reflecting diverse activity states of the transcription regulatory network. Machine learning methods like Independent Component Analysis (ICA) can decompose gene expression datasets into regulatory modules and condition-specific regulator activities. Here, we present a workflow to utilize inferred regulator activities to construct quantitative models of promoter regulation inE. coli. Resulting models are validated by predicting condition-specific TF effector concentrations and binding site motif strength based on differential gene expression data alone. We show how reconstructed promoter models can capture multi-scale regulation and disentangle regulator interactions, including resolving the apparent paradox whereargRexpression is positively correlated with its regulon despite being a repressor. We applied the workflow for all regulator-linked components extracted by ICA, demonstrating the scalability of the workflow to capture theE. coliTRN. This work suggests a path toward systematic, quantitative reconstruction of transcription regulatory networks driven by the large-scale databases that are now available for many organisms.
A phased chromosome-level genome assembly provides insights into the evolution of sex chromosomes inAmaranthus tuberculatus
Authors: Raiyemo Damilola A. , Cutti Luan , Patterson Eric L. , Llaca Victor , Fengler Kevin , Montgomery Jacob S. , Morran Sarah , Gaines Todd A. , Tranel Patrick J. 
Published: June 2024

SummaryAmaranthus tuberculatus(waterhemp) is a troublesome weed species of agronomic importance that is dioecious with an XY sex-determination system. The evolution of sex chromosomes, the contiguity of sex-determining region (SDR) and the expression pattern of genes within the SDR remain poorly understood.We assembled the genome of a maleA. tuberculatus, phased the genome into two chromosome-level haplotypes, and performed restriction site-associated DNA genome- wide association (RAD-GWA) analysis, comparative genomics, adaptive evolution analysis, and, with existing data, transcriptomic profiling to characterize the species’ sex chromosomes.Comparative analysis enabled the identification of a ∼32.8 Mb SDR on chromosome 1 that is gene-poor, abundant in long terminal repeat (LTR) retrotransposons, and harbors two inversions. Synteny analysis revealed that chromosome 1 likely originated from the fusion of two ancestral chromosomes, and mRNA data indicated 93 genes out of the 531 protein-coding genes within the SDR of haplome 2 were differentially expressed between mature male and female flowers, with several of the genes enriched for Gene Ontology (GO) terms involved in floral development.Beyond adding to our understanding of sex chromosome evolution, the genomic resource provided here will be valuable for addressing further questions on adaptive trait evolution inAmaranthus.
A High-quality Oxford Nanopore Assembly of the Hourglass Dolphin (Lagenorhynchus cruciger) Genome
Authors: McGrath Nick , le Roux Jamie , Whibley Annabel , Alexander Alana , Stewart Ramari Oliphant , Johnstone Muriel , Stockin Karen A. , Silander Olin K. 
Published: June 2024

AbstractThe hourglass dolphin (Lagenorhynchus cruciger) is a small cetacean species of the Southern Ocean, with significance to iwi Māori (Māori tribes) of Aotearoa New Zealand as taonga (treasured/valued). Due to the remoteness and difficulty of surveying Antarctic waters, it remains one of the least-studied dolphin species. A recent stranding of an hourglass dolphin represented a rare opportunity to generate a genome assembly as a resource for future study into the conservation and evolutionary biology of this species. In this study, we present a high-quality genome assembly of an hourglass dolphin individual using a single sequencing platform, Oxford Nanopore Technologies, coupled with computationally efficient assembly methods. Our assembly strategy yielded a genome of high contiguity (N50 of 8.07 Mbp) and quality (98.3% BUSCO completeness). Compared to other Delphinoidea reference genomes, this assembly has fewer missing BUSCOs than any exceptOrcinus orca, more single-copy complete BUSCOs than any exceptPhocoena sinus, and 20% fewer duplicated BUSCOs than the average Delphinoidea reference genome. This suggests that it is one of the most complete and accurate marine mammal genomes to date. This study showcases the feasibility of a cost-effective mammalian genome assembly method, allowing for genomic data generation outside the traditional confines of academia and/or resource-rich genome assembly hubs, and facilitating the ability to uphold Indigenous data sovereignty. In the future the genome assembly presented here will allow valuable insights into the past population size changes, adaptation, vulnerability to future climate change of the hourglass dolphin and related species.
THE DUAL-SPECIFICITY KINASE DYRK1A INTERACTS WITH THE HEPATITIS B VIRUS GENOME AND REGULATES THE PRODUCTION OF VIRAL RNA
Authors: Pastor Florentin , Charles Emilie , Di Vona Chiara , Chapelle Maëlys , Rivoire Michel , Passot Guillaume , Chabot Benoit , de la Luna Susana , Lucifora Julie , Durantel David , Salvetti Anna 
Published: June 2024

ABSTRACTThe genome of Hepatitis B virus (HBV) persists in infected hepatocytes as a nuclear episome (cccDNA) that is responsible for the transcription of viral genes and viral rebound, following antiviral treatment arrest in chronically infected patients. Beside pegylated interferon-alpha, there is currently no clinically approved therapeutic protocol able to target cccDNA [1]. The development of alternative strategies aiming at permanently abrogating HBV RNA production requires a thorough understanding of cccDNA transcriptional and post-transcriptional regulation. In a previous study, we discovered that 1C8, a compound that inhibits the phosphorylation of some cellular RNA-binding proteins (RBPs), could decrease the level of HBV RNAs. Here, we aimed at identifying kinases responsible for this effect. Among the kinases targeted by 1C8, we focused on DYRK1A, a dual-specificity kinase that controls the transcription of cellular genes by phosphorylating transcription factors, histones, chromatin regulators as well as RNA polymerase II. The results of a combination of genetic and chemical approaches using HBV-infected hepatocytes, indicated that DYRK1A positively regulates the production of HBV RNAs. In addition, we found that DYRK1A associates with cccDNA, and stimulates the production of HBV nascent RNAs. Finally, reporter gene assays showed that DYRK1A up-regulates the activity of the HBV enhancer 1/X promoter in a sequence-dependent manner. Altogether, these results indicate that DYRK1A is a proviral factor that may participate in the the HBV life cycle by stimulating the production of HBx, a viral factor absolutely required to trigger the complete cccDNA transcriptional program.
Meta TCT: Towards Interpretable Treatment Effects in Clinical Trials for Progressive Diseases
Authors: Stijven Florian , Mallinckrodt Craig , Molenberghs Geert , Alonso Ariel , Dickson Sam , Hendrix Suzanne 
Published: June 2024

AbstractIn progressive diseases, like Alzheimer’s disease, treatments that slow progression should start early in the disease course to longer maintain higher levels of functioning. In corresponding clinical trials, the treatment effect is usually expressed in terms of mean differences on a clinical scale. Early in the disease course, however, treatment effects expressed on a clinical scale are often small but may nonetheless correspond to an important slowing of disease progression. This complicates the appreciation of the relevance of observed treatment effects. For example, it may be difficult to determine whether a 2-point improvement on a clinical scale is relevant for clinical practice. In this paper, we propose the meta Time-Component Tests (meta TCT). This new approach leads to estimators of treatment effects on the time scale, in terms of time saved or percentage slowing of progression, that are easy to interpret. This approach is based on estimates obtained from an arbitrary model for longitudinal data and is, therefore, very flexible. Asymptotic properties of the Meta TCT estimators are derived and evaluated in an extensive simulation study. Meta TCT is then applied to a phase 2/3 clinical trial for Alzheimer’s disease, which was first analyzed with a mixed model. In this trial, meta TCT leads to important additional insights into the treatment effect. We believe that meta TCT will facilitate the estimation of interpretable treatment effects in clinical trials for progressive diseases, and that this, in turn, will fine-tune the evaluation of the clinical relevance of new treatments.
Inequalities in relative cancer survival by race, immigration status, income, and education for 22 cancer sites in Canada, a cohort study
Authors: Malagón Talía , Botting-Provost Sarah , Moore Alissa , El-Zein Mariam , Franco Eduardo L. 
Published: June 2024

AbstractIntroductionThere is a paucity of disaggregated data to monitor cancer health inequalities in Canada. We used data linkage to estimate site-specific cancer relative survival by race, immigration status, household income, and education level in Canada.MethodsWe pooled the Canadian Census Health and Environment Cohorts, which are linked datasets of 5.9 million respondents of the 2006 long-form census and 6.5 million respondents of the 2011 National Household Survey. Individual-level respondent data from these surveys were probabilistically linked with the Canadian Cancer Registry up to 2015 and with the Canadian Vital Statistics Database up to 2019. We used propensity score matching and Poisson models to calculate age-standardized relative survival by equity stratifiers for all cancers combined and for 22 individual cancer sites for the period 2006-2019.ResultsThere were 757,485 primary cancer cases diagnosed over follow-up included in survival analyses; the age-standardized period relative survival was 72.5% at 5 years post-diagnosis. Relative survival was higher in immigrants (74.6%, 95%CI 74.3-74.8) than in Canadian-born persons (70.4%, 95%CI 70.2-70.6), and higher in racial groups with high proportions of immigrants. There was a marked social gradient by household income and education level, with 11-12% lower relative survival in cancer patients in the lowest household income and education levels than in the highest levels. Socioeconomic gradients were observed for most cancer sites, though the magnitude varied.ConclusionsDespite the availability of universal healthcare in Canada, the observed differences in relative survival suggest there remain important inequities in cancer control and care.
Gone but not forgotten: dynamics of sperm storage and potential ejaculate digestion in the black soldier flyHermetia illucens
Authors: Manas Frédéric , Piterois Harmony , Labrousse Carole , Beaugard Laureen , Uzbekov Rustem , Bressac Christophe 
Published: June 2024

AbstractWhen it comes to describe reproduction in internally fertilized species, understanding the dynamics of sperm storage is crucial to unravel the complexity of post-copulatory sexual selection processes. This physiological process goes from sperm transfer to its use for fertilization. In this framework, the spatiotemporal dynamics of sperm storage were described in the black soldier fly (BSF) with fluorescence and transmission electron microscopy (TEM). Besides being of great economic interest, BSF females have highly compartmentalized spermathecae. Spermatozoa were counted both during and after mating in two successive spermathecae compartments: the fishnet canals and the reservoirs. In addition to seminal fluids, male transfers a sperm plug in the fishnet canals, then only some spermatozoa reach the reservoirs over 2 days. TEM observations of the fishnet canals revealed potential digestive functions, explaining the decline in the number and the viability of spermatozoa that have not been stored in the reservoirs. After one mating, females laid up to three fertile clutches, evidencing no constraints on sperm quantity or quality. Spermatic and ultrastructural investigations strongly suggest that BSF ejaculate acts both as a sperm plug and a as nuptial gift, reinforcing the interest in studying this insect as a model for sexual selection.
Early development of the glucocorticoid stress response in dyeing poison frog tadpoles
Authors: Surber-Cunningham Lisa L. , Jimenez Lucas S. , Mobo Lauren W. , Westrick Sarah E. , Fischer Eva K. 
Published: June 2024

AbstractIn vertebrates, the glucocorticoid “stress” response (corticosterone or cortisol) through the hypothalamic-pituitary-adrenal (HPA) axis influences many essential functions, including behavior, metabolism, immunity, and ontogenetic transitions. During development, stress responses can be adaptive if they facilitate antipredator behavior and modulate developmental speed to adjust to environmental conditions; however, these same responses can be maladaptive when energetic costs become too high and developmental speed trades-off with size and health at maturity. Thus, the timing of HPA-axis development may be aligned with specific developmental challenges and opportunities presented by a species’ life history strategy. In anurans (frogs and toads), corticosterone plays critical roles in development and behavior, and concentrations can fluctuate in response to environmental stressors. Given the role of corticosterone in ontogenetic changes and behaviors, we studied the development of the HPA axis in tadpoles of the dyeing poison frog (Dendrobates tinctorius), a species with a unique life history that includes transport to water after hatching on land and aggressive and cannibalistic behavior. We measured the excretion rate and whole-body concentration of corticosterone and the corticosterone response to adrenocorticotropic hormone (ACTH) in free-swimming tadpoles after transport and throughout metamorphosis. We found no significant differences across development in excretion rates or whole-body concentration of corticosterone, nor corticosterone response to ACTH, indicating that that the glucocorticoid response develops early in ontogeny. This pattern differs from those in other species of tadpoles, suggesting the unique ecological pressures faced byD. tinctoriushave shaped the development of its HPA axis. More broadly, this study illustrates how life history strategies and tradeoffs impact the timing of the HPA axis development.