bluuebunny/crossref_metadata_2025_split huggingface dataset:
High variability of migration strategies in a re-established Trumpeter Swan population
Authors: Wolfson David W. , Knapik Randall T. , Thomas Anna Buckardt , Harms Tyler M. , Kearns Laura J. , Kiss Brian W. , Poole Timothy F. , Fowler Drew N. , Finger Taylor A. , Matteson Sumner W. , Moriarty John J. , Mayo Tiffany , Smith Margaret , Herwig Christine M. , Andersen David E. , Fieberg John R. 
Published: June 2024

AbstractBackgroundThe Interior Population (IP) of trumpeter swans (Cygnus buccinator), formerly extirpated by market hunting, was re-established in eastern North America by releasing individuals from both migratory and non-migratory populations. Their current annual movement patterns are largely unknown. Our goal was to describe their seasonal movements and quantify the proportion of the IP that is migratory, the extent and phenology of seasonal movements, and associations between movement patterns and breeding status and breeding location.MethodsWe deployed 113 GPS-GSM transmitters on IP trumpeter swans in six U.S. states and one Canadian province across the current IP breeding range. Using data from 252 ‘swan-years’, we estimated dates of migration events by segmenting the annual cycle using piecewise regression models fit to each yearly time-series of displacement from the breeding site. We fit a latent-state model to characterize population-level associations between breeding latitude and maximum extent of migration, and linear mixed models to quantify associations between individual characteristics (e.g., breeding status, sex) and migration phenology.ResultsAt the individual level, 59% of swans moved to distant non-breeding-period areas (long-distance migration, defined as moving >100 km from the breeding site), 16% exhibited regional migration (25-100 km from breeding site), 19% exhibited non-migratory but local movements (<25 km from breeding site), and 6% exhibited multiple migration strategies. Swans breeding at more-northern latitudes departed their territories earlier in autumn and returned later in the spring than those breeding at more southern latitudes. Breeding swans departed later in the autumn than non-breeders, but breeding status did not have a strong association with arrival in the spring.ConclusionIP trumpeter swans are partial migrants, with a continuum of strategies each year, from local movements to long-distance migration. Much of the variability in movement patterns was related to factors tied to natural history demands (e.g., breeding status) and response to environmental conditions (e.g., through associations with breeding latitude).
Corticosteroids prevent pathological angiogenesis yet compromise reparative vascular remodeling in the retina
Authors: Hata Masayuki , Hata Maki , Dejda Agnieszka , Pilon Frédérique , Diaz Roberto , Fournier Frédérik , Joyal Jean-Sebastien , Cagnone Gael , Ochi Yotaro , Crespo-Garcia Sergio , Wilson Ariel , Sapieha Przemyslaw 
Published: June 2024

AbstractTissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system (CNS), this is observed through a predominantly innate immune response in retinal vascular diseases such as age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. Here we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen-induced retinopathy, we report that broad spectrum corticosteroid drugs such as dexamethasone suppress initial formation of pathological pre-retinal neovascularization in early stages of disease, yet blunt successive waves of reparative inflammation and hence prevent beneficial vascular remodeling. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1 (CX3CR1)-expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing Lyz-M (lysozyme 2) are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus-faced properties of anti-inflammatory drugs should be considered when treating retinal vascular disease and particularly in stages associated with persistent neovascularization.
The CYP1A1 connection between enterolactone and breast cancer risk
Authors: Hatwik Juana , Sonia Ningthoujam , Limaye Anil M. 
Published: June 2024

AbstractEnterolactone (EL), a mammalian enterolignan, is a gut microbe-generated plant-lignan derivative. Although observational data are controversial, meta-analyses have affirmed that plant lignan-rich diets, or high serum EL reduce breast cancer risk, or the associated mortality, in post-menopausal women. However, the mechanistic basis is unknown. Here we show that EL antagonizes AHR to reduceCYP1A1mRNA expression in MCF-7 breast cancer cells. Intriguingly, it increases CYP1A1 protein, a mediator of xenobiotic response, which is frequently expressed in breast tumors, and implicated in cell proliferation and survival. EL’s effect on CYP1A1 expression is similar to estrogen, and mediated via ERα. But, by virtue of partial ERα agonism/antagonism, EL attenuates estrogen-mediated increase in CYP1A1 protein. These data suggest potential mechanisms underlying EL’s beneficial effects in breast cancer. In the face of xenobiotic exposure, its AHR antagonism may reduce the generation of cancer-inducing genotoxic agents. With declining levels of estrogen in post-menopausal women, EL may antagonize estrogen-mediated induction of CYP1A1 protein, and the associated proliferation of mammary epithelial cells.
Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure
Authors: Weiss Rachel C. , Pyles Kelly D. , Cho Kevin , Brennan Michelle , Fisher Jonathan S. , Patti Gary J. , McCommis Kyle S. 
Published: June 2024

AbstractBackgroundHeart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown.MethodsWe performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of U-13C-glucose. Cardiac glycogen was assessed biochemically and by transmission electron microscopy. Cardiac uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the CS-Mpc2-/- heart failure. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed low-fat or ketogenic diet.ResultsFailing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, yet these hearts displayed increased enrichment from U-13C-glucose and increased glycolytic metabolite pool sizes.13C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ∼6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic13C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin-II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet.ConclusionsOur results indicate that loss of MPC in the heart causes glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is reduced by consumption of a ketogenic diet.
Background compensation revisited: Conserved phase response curves in frequency controlled homeostats with coherent feedback
Authors: Ruoff Peter 
Published: June 2024

AbstractBackground compensation is the ability of a controlled variable to respond to an applied perturbation in an unchanged manner and independent of different but constant background signals which act in parallel to the perturbation. We found that background compensation occurs by ‘coherent feedback’ mechanisms where additional control variables feed directly back to the controlled variable. This paper extends a previous study on background compensation to include phase responses in frequency controlled coherent feedback oscillators. While the frequency resetting amplitude in coherent feedback oscillators is found to be dependent on the inflow/outflow perturbation of the controlled variable and thereby become phase dependent, the frequency resetting itself and the corresponding phase response curves are found to be background compensated. It is speculated that this type of background compensation may be an additional way how ambient noise can be ‘ignored’ by organisms.
Efficient positioning of QTL and Secondary Limit thresholds in a clinical trial risk-based monitoring
Authors: Shnaydman Vladimir 
Published: June 2024

AbstractIn the high-stakes world of clinical trials, where a company’s multimillion-dollar drug development investment is at risk, the increasing complexity of these trials only compounds the challenges. Therefore, the development of a robust risk mitigation strategy, as a crucial component of comprehensive risk planning, is not just important but essential for effective drug development, particularly in the RBQM ecosystem. This emphasis on the urgency and significance of risk mitigation strategy can help the audience understand the gravity of the topic.The paper introduces a novel framework for deriving an efficient risk mitigation strategy at the planning stage of a clinical trial and establishing operational rules (thresholds). This approach combines optimization and simulation models, offering a fresh perspective on risk management in clinical trials. The optimization model aims to derive an efficient contingency budget and allocate limited mitigation resources across mitigated risks. The simulation model aims to efficiently position the QTL/KRI and Secondary Limit thresholds for each risk to be aligned with risk assessment and contingency resources.A compelling case study vividly illustrates the practical application and effectiveness of the proposed technique. This real-world example not only demonstrates the framework’s potential but also instills confidence in its successful implementation, reassuring the audience of its practicality and effectiveness.
In Silico-Driven Engineering ofHalomonas elongataL-Asparaginase: Towards Enhanced Proteolytic Resistance in Lymphoblastic Leukemia
Authors: Ghadikolaei Maryam Samadaei , Asad Sedigheh , Hassan-Zadeh Vahideh 
Published: June 2024

AbstractThe shortened L-asparaginase’s half-life in leukemia patients due to elevated serum proteases, poses a challenge. This study aimed to enhance the stability ofHalomonas elongataL-asparaginase against trypsin. Employing the trRosetta server, we modeled the enzyme’s 3D structure with a quality score of 96.5, revealing predominant secondary structure of random coils (42%), alpha helices (33%), and extended strands (20%) organized in two domains. Molecular docking unveiled a triad alignment among residues Thr16, Ser65, and Asp97 with L-asparagine. Site selection for mutation considered secondary structure prediction, dimerization analysis, trypsin cleavage site determination and epitope mapping. A library of enzyme variants was constructed through site saturation mutagenesis which led to the identification of the Arg206 to Thr, resulting in a 1.7-fold increased enzyme-specific activity (2400 U/mg) and heightened trypsin resistance. The mutant displayed a half-life of 3.47 hin human serum, approximately 50% longer than the wild type.In silicoanalyses confirmed structural stability, reduced flexibility, and enhanced substrate binding, contributing to increased proteolysis resistance and enzymatic activity. The Arg206Thr mutant exhibited anti-proliferative activity (IC50of 1.45 U/ml) on leukemia cell line K562, suggesting potential therapeutic implications.
Plasma proteomics in the UK Biobank reveals youthful brains and immune systems promote healthspan and longevity
Authors: Oh Hamilton Se-Hwee , Le Guen Yann , Rappoport Nimrod , Urey Deniz Yagmur , Rutledge Jarod , Brunet Anne , Greicius Michael D. , Wyss-Coray Tony 
Published: June 2024

ABSTRACTOrgan-derived plasma protein signatures derived from aptamer protein arrays track organ-specific aging, disease, and mortality in humans, but the robustness and clinical utility of these models and their biological underpinnings remain unknown. Here, we estimate biological age of 11 organs from 44,526 individuals in the UK Biobank using an antibody-based proteomics platform to model disease and mortality risk. Organ age estimates are associated with future onset of heart failure (heart age HR=1.83), chronic obstructive pulmonary disease (lung age HR=1.39), type II diabetes (kidney age HR=1.58), and Alzheimer’s disease (brain age HR=1.81) and sensitive to lifestyle factors such as smoking and exercise, hormone replacement therapy, or supplements. Remarkably, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity. These findings support the use of plasma proteins for monitoring organ health and the efficacy of drugs targeting organ aging disease.
Transposable Element (TE) insertion predictions from RNAseq inputs and TE impact on RNA splicing and gene expression inDrosophilabrain transcriptomes
Authors: Azad Md Fakhrul , Tong Tong , Lau Nelson C. 
Published: June 2024

ABSTRACTRecent studies have suggested that Transposable Elements (TEs) residing in introns frequently splice into and alter primary gene coding transcripts. To re-examine the exonization of TEs into protein-coding gene transcripts, we re-analyzed aDrosophilaneuron circadian rhythm RNAseq dataset and a deep long RNA fly midbrain RNAseq dataset using our Transposon Insertion and Depletion Analyzer (TIDAL) program. Our TIDAL results were able to predict several TE insertions from RNAseq data that were consistent with previous published studies. However, we also uncovered many discrepancies in TE-exonization calls, such as reads that mainly support intron retention of the TE and little support for chimeric mRNA spliced to the TE. We then deployed rigorous gDNA-PCR and RT-PCR procedures on TE-mRNA fusion candidates to see how many of bioinformatics predictions could be validated. By testing aw1118strain from which the deeper long RNAseq data was derived from and comparing to anOreRstrain, only 9 of 23 TIDAL candidates (<40%) could be validated as a novel TE insertion by gDNA-PCR, indicating that deeper study is needed on using RNAseq as inputs into current TE-insertion prediction programs. Of these validated calls, the RT-PCR results only supported TE-intron retention. Lastly, in theDscam2andBxgenes of thew1118strain that contained intronic TEs, gene expression was 2-3 times higher than theOreRgenes lacking the TEs. This study’s validation approach indicates that chimeric TE-mRNAs are infrequent and cautions that more optimization is required in bioinformatics programs to call TE insertions using RNAseq datasets.
Bola-amphiphilic dendrimer empowers imatinib to target metastatic ovarian cancer stem cellsviaβ-catenin-HRP2 signaling axis
Authors: Shi Zeyu , Artemenko Margarita , Zhang Ming , Yi Canhui , Chen Peng , Lin Shuting , Bian Zhancun , Lian Baoping , Meng Fanzhen , Chen Jiaxuan , Roussel Tom , Li Ying , Chan Karen K. L. , Ip Philip P. C. , Lai Hung-Cheng , Liu Xiaoxuan , Peng Ling , Wong Alice S. T. 
Published: June 2024

ABSTRACTOvarian cancer is the leading cause of death among all gynecological malignancies, and drug resistance renders the current chemotherapy agents ineffective for patients with advanced metastatic tumors. We report an effective treatment strategy for targeting metastatic ovarian cancer involving a nanoformulation (Bola/IM) – bola-amphiphilic dendrimer (Bola)-encapsulated imatinib (IM) – to target the critical mediator of ovarian cancer stem cells (CSCs) CD117 (c-Kit). Bola/IM offered significantly more effective targeting of CSCs compared to IM alone, through a novel and tumor-specific β-catenin/HRP2 axis, allowing potent inhibition of cancer cell survival, stemness and metastasis in metastatic and drug-resistant ovarian cancer cells. Promising results were also obtained in clinically relevant patient-derived ascites and organoids, alongside high tumor-oriented accumulation and favorable pharmacokinetic properties in mouse models. Furthermore, Bola/IM displayed synergistic anticancer activity when combined with the first-line chemotherapeutic drug cisplatin in patient-derived xenograft mouse models, without any adverse effects. Our findings support the use of Bola/IM as a nanoformulation to empower IM, providing targeted and potent treatment of metastatic ovarian cancer. Our study thus represents a significant advancement towards addressing the unmet medical need for improved therapies targeting this challenging disease.
In vivorat-brain mapping of multiple gray matter water populations using nonparametric D(ω)-R1-R2 distributions MRI
Authors: Yon Maxime , Narvaez Omar , Topgaard Daniel , Sierra Alejandra 
Published: June 2024

AbstractMassively Multidimensional Diffusion MRI combines tensor-valued encoding, oscillating gradients, and diffusion-relaxation correlation to provide multicomponent sub-voxel parameters depicting the tissue microstructure. This method was successfully implementedex vivoin micro-imaging systems and in clinical conditions but with a reduced diffusion frequency (ω) range due to the use of classical tensor-valued encoding. We demonstrate here its preclinicalin vivoimplementation with a protocol of 389 contrast images probing a wide diffusion frequency range of 18 to 92 Hz atb-values up to 2.1 ms/µm2enabled by the use of modulated gradient waveforms and combined with multislice high-resolution and low-distortion EPI acquisition with segmented and full reversed phase-encode acquisition. This framework allows the identification of diffusionω-dependence in the rat cerebellum and olfactory bulb gray matter (GM) and the parameter distributions are shown to resolve two water pools in GM with different diffusion coefficients, shapes,ω-dependence, relaxation rates, and spatial repartition whose attribution to specific microstructure could modify the current understanding of the origin of restriction in GM.
Maternal Immune Activation imprints translational dysregulation and differential MAP2 phosphorylation in descendant neural stem cells
Authors: Martín-Guerrero Sandra M. , Martín-Estebané María , Lara Ordóñez Antonio J. , Cánovas Miguel , Martín-Oliva David , González-Maeso Javier , Cutillas Pedro R. , López-Giménez Juan F. 
Published: June 2024

ABSTRACTAlterations induced by maternal immune activation (MIA) during gestation impact the subsequent neurodevelopment of progeny, a process that in humans, has been linked to the development of several neuropsychiatric conditions. To undertake a comprehensive examination of the molecular mechanisms governing MIA, we have devised an in vitro model based on neural stem cells (NSCs) sourced from fetuses carried by animals subjected to Poly I:C treatment. These neural progenitors demonstrate proliferative capacity and can be effectively differentiated into both neurons and glial cells. Transcriptomic, proteomic, and phosphoproteomic analyses conducted on these cellular models, in conjunction with counterparts from control treatments, revealed discernible shifts in the expression levels of a specific subset of proteins implicated in neuronal function. Noteworthy, we found an absence of congruence between these alterations at the transcriptomic level, suggesting that differences in protein translation contribute to the observed dysregulation. Furthermore, the phosphoproteomic data highlighted a discernible discrepancy in the basal phosphorylation of proteins between differentiated cells from both experimental groups, particularly within proteins associated with cytoskeletal architecture and synaptic functionality, notably those belonging to the MAP family. Observed alterations in MAP phosphorylation were found to potentially have functional consequences as they correlate with changes in neuronal plasticity and the establishment of neuronal synapses. Our data agrees with previous published observations and further underscore the importance of MAP2 phosphorylation state on its function and the impact that this protein has in neuronal structure and function.
Opportunities to improve the recommendation of plant varieties under the Recommended List (RL) system
Authors: Yang Chin Jian , Russell Joanne , Mackay Ian , Powell Wayne 
Published: June 2024

AbstractRecommended List (RL) is the UK plant variety recommendation system introduced in 1944 for supporting growers in making decisions on variety choices. The current analysis for RL is largely based on published works on trial designs and statistical analyses in the 1980s. Given the statistical advances that have been developed and adopted elsewhere, it is timely to review and update the methods for data analysis in RL. In addition, threats from climate change challenge the prediction of variety performance in future environments. Better variety recommendations, particularly for matching varieties to specific environments can be achieved through improved modeling of effects from genetics, environments and genetic by environment interactions. Here, we evaluated grain yield data from 153 spring barley varieties that were trialed for RL from 2002 to 2019. Our results show that the available methods for predicting variety performance are poor and inconsistent across environments without any clearly superior method. However, these shortcomings can be easily overcome by switching the statistical model for analyzing RL data to one that fits variety effects as random and accounts for genetic relationships among varieties. Lastly, we also discuss other possible approaches for analyzing RL data and highlight the relevance of genomics in both variety registration and recommendation.