bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute irradiation alters the heterogeneity among medullary thymic epithelial cells
Authors: Horie Kenta , Namiki Kano , Miyauchi Maki , Ishikawa Tatsuya , Hayama Mio , Maruyama Yuya , Miyao Takahisa , Murata Shigeo , Akiyama Nobuko , Akiyama Taishin 
Published: April 2023

AbstractThe thymus has the ability to regenerate from acute injury caused by radiation, infection, and stressors. In addition to thymocytes, thymic epithelial cells in the medulla (mTECs), which are crucial for T cell self-tolerance by ectopically expressing and presenting thousands of tissue-specific antigens (TSAs), are damaged by these insults and recover thereafter. However, given recent discoveries on the high heterogeneity of mTECs, it remains to be determined whether the frequency and properties of mTEC subsets are restored during thymic recovery from radiation damage. Here we demonstrate that acute total body irradiation with a sublethal dose induces aftereffects on heterogeneity and gene expression of mTECs. Single-cell RNA-sequencing (scRNA-seq) analysis showed that irradiation reduces the frequency of mTECs expressing AIRE, which is a critical regulator of TSA expression, 15 days after irradiation. In contrast, transit-amplifying mTECs (TA-mTECs), which are progenitors of AIRE-expressing mTECs, and Ccl21a-expressing mTECs, were less affected. Interestingly, detailed analysis of scRNA-seq data suggested that the proportion of a unique mTEC cluster expressing Ccl25 and high level of TSAs was severely decreased by irradiation. Overall, we propose that acute irradiation disturbs the heterogeneity and properties of mTECs, and may thereby impair TSA expression for thymic T cell selection.
An mRNA-LNP-based Lassa virus vaccine induces protective immunity in mice
Authors: Hashizume Mei , Takashima Ayako , Iwasaki Masaharu 
Published: April 2023

AbstractThe mammarenavirus Lassa virus (LASV) causes the life-threatening hemorrhagic fever disease, Lassa fever. The lack of licensed medical countermeasures against LASV underscores the urgent need for the development of novel LASV vaccines, which has been hampered by the requirement for a biosafety level 4 facility to handle live LASV. Here, we investigated the efficacy of mRNA-lipid nanoparticle (mRNA-LNP)-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or the nucleoprotein (LCMnp) of the prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), in mice using recombinant (r) LCMV expressing a modified LASgpc and wild-type rLCMV. Two doses of LASgpc- or LCMnp-mRNA-LNP administered intravenously or intramuscularly protected mice from a lethal challenge with rLCMVs. Negligible levels of LASgpc-specific antibodies were induced in mRNA-LNP-immunized mice, but robust LASgpc- and LCMnp-specific CD8+T cell responses were detected. Our findings and surrogate mouse models of LASV infection provide a critical foundation for the rapid development of mRNA-LNP-based LASV vaccines.
Cell Painting-based bioactivity prediction boosts high-throughput screening hit-rates and compound diversity
Authors: Haslum Johan Fredin , Lardeau Charles , Karlsson Johan , Turkki Riku , Leuchowius Karl-Johan , Smith Kevin , Müllers Erik 
Published: April 2023

AbstractEfficiently identifying bioactive compounds towards a target of interest remains a time- and resource-intensive task in early drug discovery. The ability to accurately predict bioactivity using morphological profiles has the potential to rationalize the process, enabling smaller screens of focused compound sets.Towards this goal, we explored the application of deep learning with Cell Painting, a high-content image-based assay, for compound bioactivity prediction in early drug screening. Combining Cell Painting data and unrefined single-concentration activity readouts from high-throughput screening (HTS) assays, we investigated to what degree morphological profiles could predict compound activity across a set of 140 unique assays.We evaluated the performance of our models across different target classes, assay technologies, and disease areas. The predictive performance of the models was high, with a tendency for better predictions on cell-based assays and kinase targets. The average ROC-AUC was 0.744 with 62% of assays reaching ≥0.7, 30% reaching ≥0.8 and 7% reaching ≥0.9 average ROC-AUC, outperforming commonly used structure-based predictions in terms of predictive performance and compound structure diversity. In many cases, bioactivity prediction from Cell Painting data could be matched using brightfield images rather than multichannel fluorescence images. Experimental validation of our predictions in follow-up assays confirmed enrichment of active compounds.Our results suggest that models trained on Cell Painting data can predict compound activity in a range of high-throughput screening assays robustly, even with relatively noisy HTS assay data. With our approach, enriched screening sets with higher hit rates and higher hit diversity can be selected, which could reduce the size of HTS campaigns and enable primary screening with more complex assays.
Coordination of host and endosymbiont gene expression governs endosymbiont growth and elimination in the cereal weevilSitophilusspp
Authors: Ferrarini Mariana Galvão , Vallier Agnès , Vincent-Monégat Carole , Dell’Aglio Elisa , Gillet Benjamin , Hughes Sandrine , Hurtado Ophélie , Condemine Guy , Zaidman-Rémy Anna , Rebollo Rita , Parisot Nicolas , Heddi Abdelaziz 
Published: April 2023

AbstractBackgroundInsects living in nutritionally poor environments often establish long-term relationships with intracellular bacteria that supplement their diets and improve their adaptive and invasive powers. Even though these symbiotic associations have been extensively studied on physiological, ecological and evolutionary levels, few studies have focused on the molecular dialogue between host and endosymbionts to identify genes and pathways involved in endosymbiosis control and dynamics throughout host development.ResultsWe simultaneously analyzed host and endosymbiont gene expression during the life cycle of the cereal weevilSitophilus oryzae, from larval stages to adults, with a particular emphasis on emerging adults where the endosymbiontSodalis pierantoniusexperiences a contrasted growth-climax-elimination dynamics. We unraveled a constant arms race in which different biological functions are intertwined and coregulated across both partners. These include immunity, metabolism, metal control, apoptosis, and bacterial stress response.ConclusionsThe study of these tightly regulated functions, which are at the center of symbiotic regulations, provides evidence on how hosts and bacteria finely tune their gene expression and respond to different physiological challenges constrained by insect development in a nutritionally limited ecological niche.Graphical Abstract
GENOME REPORT: Chromosome-scale genome assembly of the African spiny mouse (Acomys cahirinus)
Authors: Nguyen Elizabeth Dong , Fard Vahid Nikoonejad , Kim Bernard Y. , Collins Sarah , Galey Miranda , Nelson Branden R. , Wakenight Paul , Gable Simone M. , McKenna Aaron , Bammler Theo K. , MacDonald Jim , Okamura Daryl M. , Shendure Jay , Beier David R. , Ramirez Jan Marino , Majesky Mark W. , Millen Kathleen J. , Tollis Marc , Miller Danny E. 
Published: April 2023

ABSTRACTThere is increasing interest in the African spiny mouse (Acomys cahirinus) as a model organism because of its ability for regeneration of tissue after injury in skin, muscle, and internal organs such as the kidneys. A high-quality reference genome is needed to better understand these regenerative properties at the molecular level. Here, we present an improved reference genome forA. cahirinusgenerated from long Nanopore sequencing reads. We confirm the quality of our annotations using RNA sequencing data from four different tissues. Our genome is of higher contiguity and quality than previously reported genomes from this species and will facilitate ongoing efforts to better understand the regenerative properties of this organism.
Melanin enhances metastatic melanoma colonization by inhibiting ferroptosis
Authors: Groenewoud Arwin , Zhao Gangyin , Gelmi Maria-Chiara , Yin Jie , Lamers Gerda E. M. , Doorn Remco van , Verdijk Rob. M. , Jager Martine J. , Engel Felix B. , Snaar-Jagalska B. Ewa 
Published: April 2023

AbstractMelanoma associated death is mainly caused by metastatic disease. Increased melanin levels are associated with decreased melanoma patient survival, yet the contribution of melanin to this process is unknown. Here we show that melanin protects circulating melanoma cells from ferroptosis, enhancing their metastatic potential. We observed that melanin levels in patient-derived uveal melanoma cells as well as cutaneous and conjunctival melanoma cell lines correlate with their metastatic potential in zebrafish xenografts. We find strong associations of the melanin biosynthesis geneTYRP1, ferroptosis related enzymeGPX4and mitochondrial anion channel (VDAC1) with reduced melanoma-specific survival in TCGA data of cutaneous melanoma. Modulation of melanin levels significantly impacts melanoma metastatic potential, increasing or decreasing in concordance with melanin levels. Furthermore, melanin depletion significantly sensitized melanoma cells to ferroptosis leading to a decreased metastatic capacity and enhanced efficacy of ferroptosis induction based anti-cancer therapeutic strategies. Collectively, our results reveal that combined inhibition of melanin biosynthetic enzymes and induction of ferroptosis has potential as a treatment strategy of metastatic melanoma.Graphical abstract
Biogeography and the evolution of acoustic communication in the polyploid North American gray treefrog complex
Authors: Booker William W. , Lemmon Emily Moriarty , Lemmon Alan R. , Ptacek Margaret B. , Hassinger Alyssa T. B. , Schul Johannes , Gerhardt H. Carl 
Published: April 2023

AbstractAfter polyploid species are formed, interactions between diploid and polyploid lineages may generate additional diversity in novel cytotypes and phenotypes. In anurans, mate choice by acoustic communication is the primary method by which individuals identify their own species and assess suitable mates. As such, the evolution of acoustic signals is an important mechanism for contributing to reproductive isolation and diversification in this group. Here, we estimate the biogeographic history of the North American gray treefrog complex, consisting of the diploidHyla chrysoscelisand the tetraploidHyla versicolor, focusing specifically on the geographic origin of whole genome duplication and the expansion of lineages out of glacial refugia. We then test for lineage-specific differences in mating signals by applying comparative methods to a large acoustic data set collected over 52 years that includes>1500 individual frogs. Along with describing the overall biogeographic history and call diversity, we found evidence that the geographic origin ofH. versicolorand the formation of the midwestern polyploid lineage are both associated with glacial limits, and that the southwestern polyploid lineage is associated with a shift in acoustic phenotype relative to the diploid lineage with which they share a mitochondrial lineage. InH. chrysoscelis, we see that acoustic signals are largely split by Eastern and Western lineages, but that northward expansion along either side of the Appalachian Mountains is associated with further acoustic diversification. Overall, results of this study provide substantial clarity on the evolution of gray treefrogs as it relates to their biogeography and acoustic communication.
Role of DNA-DNA sliding friction and non-equilibrium dynamics in viral genome ejection and packaging
Authors: Fizari Mounir , Keller Nicholas , Jardine Paul J. , Smith Douglas E. 
Published: April 2023

ABSTRACTMany viruses eject their DNA via a nanochannel in the viral shell, driven by internal forces arising from the high-density genome packing. The speed of DNA exit is controlled by friction forces that limit the molecular mobility, but the nature of this friction is unknown. We introduce a method to probe the mobility of the tightly confined DNA by measuring DNA exit from phage phi29 capsids with optical tweezers. We measure extremely low initial exit velocity, a regime of exponentially increasing velocity, stochastic pausing that dominates the kinetics, and large dynamic heterogeneity. Measurements with variable applied force provide evidence that the initial velocity is controlled by DNA-DNA sliding friction, consistent with a Frenkel-Kontorova model for nanoscale friction. We confirm several aspects of the ejection dynamics predicted by theoretical models. Features of the pausing suggest it is connected to the phenomenon of “clogging” in soft-matter systems. Our results provide evidence that DNA-DNA friction and clogging control the DNA exit dynamics, but that this friction does not significantly affect DNA packaging.
Drug discovery for heart failure targeting myosin-binding protein C
Authors: Bunch Thomas A. , Guhathakurta Piyali , Thompson Andrew R. , Lepak Victoria C. , Carter Anna L , Thomas Jennifer J. , Thomas David D. , Colson Brett A. 
Published: April 2023

ABSTRACTCardiac MyBP-C (cMyBP-C) interacts with actin-myosin to fine-tune cardiac muscle contractility. Phosphorylation of cMyBP-C, which reduces binding of cMyBP-C to actin or myosin, is often decreased in heart failure (HF) patients, and is cardioprotective in model systems for HF. Therefore, cMyBP-C is a potential target for HF drugs that mimic phosphorylation and/or perturb its interactions with actin or myosin. We labeled actin with fluorescein-5-maleimide (FMAL), and the C0-C2 fragment of cMyBP-C (cC0-C2) with tetramethyl rhodamine (TMR). We performed two complementary high-throughput screens (HTS) on an FDA-approved drug library, to discover small molecules that specifically bind to cMyBP-C and affect its interactions with actin or myosin, using fluorescence lifetime (FLT) detection. We first excited FMAL and detected its FLT, to measure changes in fluorescence resonance energy transfer (FRET) from FMAL (donor) to TMR (acceptor), indicating binding and/or structural changes in the protein complex. Using the same samples, we then excited TMR directly, using a longer wavelength laser, to detect the effects of compounds on the environmentally sensitive FLT of TMR, to identify compounds that bind directly to cC0-C2. Secondary assays, performed on selected modulators with the most promising effects in the primary HTS assays, characterized specificity of these compounds for phosphorylated versus unphosphorylated cC0-C2 and for cC0-C2 versus C1-C2 of fast skeletal muscle (fskC1-C2). A subset of identified compounds modulated ATPase activity in cardiac and/or skeletal myofibrils. These assays establish feasibility for discovery of small-molecule modulators of the cMyBP-C-actin/myosin interaction, with the ultimate goal of developing therapies for HF.
A comparison of the Netherlands, Norway and UK Familial Hypercholesterolemia screening programmes with implications for target setting and the UK’s NHS Long Term Plan
Authors: Page Christopher , Zheng Huiru , Wang Haiying , Rai Taranjit Singh , O’Kane Maurice , Hart Pádraig , McKee Shane , Watterson Steven 
Published: April 2023

AbstractWe sought to determine the most efficacious and cost-effective strategy to follow when developing a national screening programme by comparing and contrasting the national screening programmes of Norway, the Netherlands and the UK. Comparing the detection rates and screening profiles between the Netherlands, Norway, the UK and constituent nations (England, Northern Ireland, Scotland and Wales) it is clear that maximising the number of relatives screened per index case leads to identification of the greatest proportion of an FH population. The UK has stated targets to detect 25% of the population of England with FH across the 5 years to 2024 with the NHS Long Term Plan. However, this is grossly unrealistic and, based on pre-pandemic rates, will only be reached in the year 2096. We also modelled the efficacy and cost-effectiveness of two screening strategies: 1) Universal screening of 1-2-year-olds, 2) electronic healthcare record screening, in both cases coupled to reverse cascade screening. We found that index case detection from electronic healthcare records was 56% more efficacious than universal screening and, depending on the cascade screening rate of success, 36%-43% more cost-effective per FH case detected. The UK is currently trialling universal screening of 1–2-year-olds to contribute to national FH detection targets. Our modelling suggests that this is not the most efficacious or cost-effective strategy to follow. For countries looking to develop national FH programmes, screening of electronic healthcare records, coupled to successful cascade screening to blood relatives is likely to be a preferable strategy to follow.
Respiratory Syncytial Virus (RSV) Hospital Admission Rates and Patients’ Characteristics Before the Age of Two in England, 2015-2019
Authors: Fonseca Maria João , Hagenaars Saskia , Bangert Mathieu , Flach Clare , Hudson Richard 
Published: April 2023

AbstractBackgroundA granular understanding of respiratory syncytial virus (RSV) burden in England is needed to prepare for new RSV prevention strategies. We estimated the rates of RSV hospital admissions in infants before age two in England and describe baseline characteristics.MethodsA birth cohort of all infants born between 01/03/2015 and 28/02/2017 (n=449,591) was established using Clinical Practice Research Datalink-Hospital Episode Statistics. Case cohorts included infants with an admission for 1) RSV-coded, 2) bronchiolitis-coded, 3) any respiratory tract infection (RTI)-coded <24 months and 4) RSV-predicted by an algorithm <12 months. Baseline characteristics were described in case and comparative cohorts (infants without corresponding admission). Cumulative incidence and admission rates were calculated. Multiple linear regression was used to estimate the proportion of RTI healthcare visits attributable to RSV.ResultsThe RSV-coded/RSV-predicted case cohorts were composed of 4,813/12,694 infants (cumulative incidence: 1.1%/2.8%). Case cohort infants were more likely to have low birth weight, comorbidities and to be born during RSV season than comparative cohort infants, yet >77% were term healthy infants and >54% born before the RSV season. During the first year of life, 11.6 RSV-coded and 34.4 RSV-predicted hospitalizations occurred per 1,000 person-years. Overall, >25% of unspecified lower RTI admissions were estimated to be due to RSV.ConclusionsIn England, one in 91 infants had an RSV-coded admission, likely underestimated by ∼3-fold. Most infants were term healthy infants born before the RSV season. To decrease the total burden of RSV at the population level, immunization programs need to protect all infants.
Site-specific length-biomass relationships of arctic arthropod families are critical for accurate ecological inferences
Authors: Versluijs Tom S.L. , Zhemchuzhnikov Mikhail K. , Kutcherov Dmitry , Roslin Tomas , Schmidt Niels Martin , van Gils Jan. A. , Reneerkens Jeroen 
Published: April 2023

AbstractArthropods play an essential role in terrestrial ecosystems, not least by forming the food base for insectivorous birds. To better understand such trophic interactions, it is essential to monitor seasonal trajectories in arthropod biomass. Because obtaining direct measurements of the body mass of individual specimens is laborious, these data are often indirectly acquired by utilizing allometric length-biomass relationships based on a correlative parameter, such as body length. Studies on insectivorous birds have often used such relationships with a low taxonomic resolution and/or small sample size and/or adopted regressions calibrated in different biomes. Despite the scientific interest in the ecology of arctic arthropods, no site-specific family-level length-biomass relationships have hitherto been published. Here we present 27 family-specific length-biomass relationships from two sites in the High Arctic: Zackenberg in northeast Greenland and Knipovich in north Taimyr, Russia. We show that length-biomass regressions from different sites within the same biome did not affect estimates of phenology but did result in substantially different estimates of arthropod biomass. Estimates of daily biomass at Zackenberg were on average 24% higher when calculated using regressions for Knipovich compared to using regressions for Zackenberg. Our results illustrate that the use of allometric relationships from different sites can significantly alter the biological interpretation of, for instance, the interaction between insectivorous birds and their arthropod prey. We conclude that length-biomass relationships should be locally established rather than being based on global relationships.SubjectsEcology, Entomology, Terrestrial ecology
Featural representation and internal noise underlie the eccentricity effect in contrast sensitivity
Authors: Xue Shutian , Fernández Antonio , Carrasco Marisa 
Published: April 2023

AbstractHuman visual performance for basic visual dimensions (e.g., contrast sensitivity and acuity) peaks at the fovea and decreases with eccentricity. The eccentricity effect is related to the larger surface area of the visual cortex corresponding to the fovea, but it is unknown if differential feature tuning contributes to this eccentricity effect. Here, we investigated two system-level computations underlying the eccentricity effect: featural representation (tuning) and internal noise. Observers (both sexes) detected a Gabor embedded in filtered white noise which appeared at the fovea or one of four perifoveal locations. We used psychophysical reverse correlation to estimate the weights assigned by the visual system to a range of orientations and spatial frequencies (SFs) in noisy stimuli, which are conventionally interpreted as perceptual sensitivity to the corresponding features. We found higher sensitivity to task-relevant orientations and SFs at the fovea than the perifovea, and no difference in selectivity for either orientation or SF. Concurrently, we measured response consistency using a double-pass method, which allowed us to infer the level of internal noise by implementing a noisy observer model. We found lower internal noise at the fovea than perifovea. Finally, individual variability in contrast sensitivity correlated with sensitivity to and selectivity for task-relevant features as well as with internal noise. Moreover, the behavioral eccentricity effect mainly reflects the foveal advantage in orientation sensitivity compared to other computations. These findings suggest that the eccentricity effect stems from a better representation of task-relevant features and lower internal noise at the fovea than at the perifovea.SignificancePerformance in many visual tasks worsens with eccentricity. Many studies attribute this eccentricity effect to retinal and cortical factors, like higher cone density and a larger cortical surface area representing the foveal than peripheral locations. We investigated whether system-level computations for task-relevant visual features also underlie this eccentricity effect. Measuring contrast sensitivity in visual noise, we showed that the fovea better represents task-relevant orientation and spatial frequency and has lower internal noise than the perifovea, and that individual variability in these two computations correlates with that in performance. These findings reveal that both representations of these basic visual features and internal noise underlie the difference in performance with eccentricity.