bluuebunny/crossref_metadata_2025_split huggingface dataset:
Putting life history theory to the test - the estimation of reproductive values from field data
Authors: Borger Mirjam J. , Komdeur Jan , Richardson David S. , Weissing Franz J. 
Published: March 2022

AbstractQuantifying fitness is important to understand adaptive evolution. Reproductive values are useful for making fitness comparisons involving different categories of individuals, like males and females. By definition, the reproductive value of a category is the expectedper capitacontribution of the members of that category to the gene pool of future generations. Life history theory reveals how reproductive values can be determined via the estimation of life-history parameters, but this requires intricate algebraic calculations. Recently, a more intuitive, pedigree-based method has become popular, which estimates the genetic contributions of individuals to future generations by tracking their descendants down the pedigree. Here we compare both methods. We implement various life-history scenarios (for which the “true” reproductive values can be calculated) in individual-based simulations, use the simulation data to estimate reproductive values with both methods, and compare the results with the true target values. We show that the pedigree-based estimation of reproductive values is either systematically biased (and hence inaccurate), or very imprecise. This holds even for simple life histories and under idealized conditions. In contrast, the traditional algebraic method estimates reproductive values with high accuracy and precision.Lay SummaryTo study evolution in empirical systems it is important to accurately and precisely measure fitness. Here, using simulations, we compare two methods for estimating fitness and test their accuracy and precision. One estimates life-history parameters and calculates a fitness proxy using complex algebra. The other method estimates genetic contribution to future generations by tracking descendants down the pedigree. We conclude that the pedigree method is unreliable, while the algebraic method is accurate and precise.
Tradeoffs in bacterial physiology determine the efficiency of antibiotic killing
Authors: Bren Anat , Glass David S. , Kohanim Yael Korem , Mayo Avi , Alon Uri 
Published: March 2022

AbstractAntibiotics can kill or stop the growth of bacteria, and their effectiveness depends on many factors. It is important to understand the relation between bacterial physiology, the environment and antibiotic action. While many of the mechanistic details of antibiotic action are known, the connection between death rate and bacterial physiology is poorly understood. Death rate in antibiotics has often been shown to rise linearly with growth rate; however, it remains unclear how environmental factors, in concert with whole-cell physiological properties, affect bactericidal activity. To address this, we developed a high-throughput assay to precisely measure antibiotic-mediated bacterial death. We found that death rate is linear in growth rate, but the slope depends on environmental conditions. Specifically, stressors lower the death rate compared to a non-stressed environment with the same growth rate. To understand the role of stress, we developed a mathematical model of bacterial death based on resource allocation that takes into account a newly defined stress-response sector; we identify this sector using RNA-seq. Our model accurately predicts the death rate and minimal inhibitory concentration of antibiotics across a wide range of conditions, including a previously unknown increase in the stress response and protection from death at very low levels of cAMP. The present death-growth model suggests conditions that may improve antibiotic efficacy.
URB597 induces aggression in adult Lister Hooded rats
Authors: Warren William G. , Hale Ed , Papagianni Eleni P. , Cassaday Helen J. , Stevenson Carl W. , Stubbendorff Christine 
Published: March 2022

AbstractThe endocannabinoid system has been implicated in both social and cognitive processing. The endocannabinoid metabolism inhibitor, URB597, dose-dependently improves non-social memory in adult Wistar and Sprague Dawley rats, whereas its effect on social interaction (SI) is affected by both rat strain and drug dose. Lister Hooded rats consistently respond differently to drug treatment in general compared with albino strains. This study sought to investigate the effects of different doses of URB597 on social and non-social memory in Lister Hooded rats, as well as analysing the behavioural composition of the SI.Males were tested for novel object recognition (NOR), social preference (between an object and an unfamiliar rat), social novelty recognition (for a familiar vs unfamiliar rat) and SI with an unfamiliar rat. URB597 (0.1 or 0.3 mg/kg) or vehicle was given 30 minutes before testing. During SI testing, total interaction time was assessed along with time spent on aggressive and explorative behaviours.Lister Hooded rats displayed expected non-social and social memory and social preference, which was not affected by URB597. During SI, URB597 did not affect total interaction time. However, the high dose increased aggression, compared to vehicle, and decreased anogenital sniffing, compared to the low dose of URB597. In summary, URB597 did not affect NOR, social preference or social recognition memory but did have subtle behavioural effects during SI in Lister hooded rats.These findings highlight the importance of considering strain as well as the composition of behaviour when investigating drug effects on social behaviour.
Multi-omics profiling of collagen-induced arthritis mouse model reveals early metabolic dysregulation via SIRT1 axis
Authors: Li Lingzi , Freitag Janina , Asbrand Christian , Munteanu Bogdan , Wang Bei-Tzu , Zezina Ekaterina , Didier Michel , Thill Gilbert , Rocher Corinne , Herrmann Matthias , Biesemann Nadine 
Published: March 2022

AbstractRheumatoid arthritis (RA) is characterized by joint infiltration of immune cells and synovial inflammation which leads to progressive disability. Current treatments improve the disease outcome, but the unmet medical need is still high. New discoveries over the last decade have revealed the major impact of cellular metabolism on immune cell functions. So far, a comprehensive understanding of metabolic changes during disease development, especially in the diseased microenvironment, is still limited. Therefore, we studied the longitudinal metabolic changes during the development of murine arthritis integrating metabolomics and bulk RNA-seq data. We identified an early change in macrophage pathways which was accompanied by oxidative stress, a drop in NAD+ level and induction of glucose transporters. We discovered inhibition of SIRT1, a NAD-dependent histone deacetylase and confirmed its dysregulation in human macrophages and synovial tissue of RA patients. Mining this database should enable the discovery of novel metabolic targets and therapy opportunities in RA.
Structural basis for APE1 processing DNA damage in the nucleosome
Authors: Weaver Tyler M. , Hoitsma Nicole M. , Spencer Jonah J. , Gakhar Lokesh , Schnicker Nicholas J. , Freudenthal Bret D. 
Published: March 2022

AbstractGenomic DNA is continually exposed to endogenous and exogenous factors that promote DNA damage. Eukaryotic genomic DNA is packaged into nucleosomes, which present a barrier to accessing and effectively repairing DNA damage. The mechanisms by which DNA repair proteins overcome this barrier to repair DNA damage in the nucleosome and protect genomic stability is unknown. Here, we determine how the base excision repair (BER) endonuclease AP-endonuclease 1 (APE1) recognizes and cleaves DNA damage in the nucleosome. Kinetic assays determined that APE1 cleaves solvent-exposed AP sites in the nucleosome with 3 - 6 orders of magnitude higher efficiency than occluded AP sites. A cryo-electron microscopy structure of APE1 bound to a nucleosome containing a solvent-exposed AP site identified that APE1 uses a DNA sculpting mechanism for AP site recognition, where APE1 bends the nucleosomal DNA to access the AP site. Notably, additional biochemical and structural characterization of occluded AP sites identified contacts between the nucleosomal DNA and histone octamer that prevent efficient processing of the AP site by APE1. These findings provide a rationale for the position-dependent activity of BER proteins in the nucleosome and suggests the ability of BER proteins to sculpt nucleosomal DNA drives efficient BER in chromatin.
Type I interferons govern Zika virus resistance of human macrophages and microglia
Authors: Hanrath Aidan T. , Hatton Catherine F. , Gothe Florian , Browne Cathy , Vowles Jane , Leary Peter , Cockell Simon J. , Cowley Sally A. , James William S. , Hambleton Sophie , Duncan Christopher J. A. 
Published: March 2022

AbstractThe role of the human type I interferon (IFN-I) system in restricting Zika virus (ZIKV) is uncertain. Here, genetic and pharmacological ablation of IFN-I signalling enhanced ZIKV replication and cytopathicity in macrophages and microglia, key cells in ZIKV transmission and pathogenesis. Thus, despite the extensive IFN-I countermeasures employed by ZIKV, IFN-I dictates the outcome of infection in macrophages. Therapeutic manipulation of the IFN-I system may bring clinical benefit in ZIKV.
Tailoring CRISPR-Cas Immunity for the Degradation of Antibiotic Resistance Genes
Authors: Li Xin , Bao Nan , Yan Zhen , Yuan Xian-Zheng , Wang Shu-Guang , Xia Peng-Fei 
Published: March 2022

AbstractThe evolution and dissemination of antibiotic resistance genes (ARGs) are prompting severe health and environmental issues. While environmental processes are key barriers preventing the spread of ARGs, they are often sources of ARGs at the same time, as ARGs may be required and accumulate in the biological treatment units. An upgrading of environmental biotechnology is imperative and urgent. ARGs confer antibiotic resistance based on the DNA sequences rather than the chemistry of DNA molecules. An ARG can be considered degraded if its sequence was disrupted. Therefore, we present here that CRISPR-Cas immunity, an archaeal and bacterial immune system for eliminating invading foreign DNAs, can be repurposed and tailored for the degradation of ARGs. By deploying an artificial IncP machinery, the designed system, namely VADER, can be successfully delivered via bacterial conjugation. Then, we propose a new sector for ARG degradation to be implemented as a complement to the biological units in the framework of environmental processes. In this endeavor, a prototype conjugation reactor at a 10-mL-scale was devised, and 100% of the target ARG were eliminated in the transconjugated microbes receiving VADER in the reactor. By generating a nexus of synthetic biology and environmental biotechnology, we believe that our work is not only an enterprise for tackling ARG problems but also a potential solution for managing undesired genetic materials in general in the future.ImportanceAntibiotic resistance has been causing severe health problems and leading to millions of deaths in recent years. Environmental processes, especially the wastewater treatment sector, are important to barrier the spread of antibiotic resistance from the pharmaceutical industry, hospitals, or civil sewage. However, they have been identified as the source of antibiotic resistance at the same time, as antibiotic resistance with its main cause antibiotic resistance genes (ARGs) may be required and accumulate in the biological treatment units, leading to the dissemination of ARGs. Here, we transplanted the CRISPR-Cas system, an immune system via programmable DNA cleavage, to environmental biotechnology for tackling the antibiotic resistance dilemma thereof, and we propose a new sector in environmental processes specialized in ARG removal with a reactor inhabiting the CRISPR-Cas system per se. Our study provides a new angle to resolve public health issues via the implementation of synthetic biology at the process level.
Epithelial monolayer development and tight junction assembly on nanopillar arrays
Authors: Yeste Jose , Illa Xavi , Shashikanth Nitesh , Guimerà-Brunet Anton , Villa Rosa , Turner Jerrold R 
Published: March 2022

ABSTRACTNanostructured materials provide an outstanding opportunity to both stimulate and measure cellular processes. In the context of tight junctions, it was previously reported that transient application of a nanotopographic surface over the apical brush border membrane of epithelial monolayers triggers redistribution of ZO-1, claudins, and F-actin that increases paracellular macromolecular flux. In excitable tissues, nanomaterials have been used to apply and measure electrical signals, such action potentials. As a first step towards translating these technologies for use in analysis of epithelial function, we sought to culture monolayers composed of transporting epithelia over nanopillar arrays without perturbing cellular structure or function. Madin-Darby Canine kidney I (MDCK I) cells were cultured on collagen-coated silicon chips with ∼1 μm diameter nanopillar arrays. Fluorescence and scanning electron microscopy were used to assess the impact of height on nanopillar-epithelial interactions. Monolayers formed over and were largely unaffected by short nanopillars. These nanopillars were located beneath basal epithelial surfaces and were not preferentially located within lateral intercellular spaces or beneath ZO-1-containing junctions. In contrast, tall nanopillars that exceeded cell height disrupted MDCK I monolayer growth. Cells interacted with, encircled, and extended cytoplasm over the top of tall nanopillars, and dense ZO-1 and F-actin accumulations occasionally surrounded apical membranes adjacent to nanopillars. Finally, when grown over arrays composed of nanopillars 1 – 2 μm shorter than cells, MDCK I frequently grew between nanopillars. As a result, nanopillars were more commonly present within lateral intercellular spaces beneath junctions. Apical complex structure was intact, as assessed by fluorescence microscopy of ZO-1, occludin, claudin-2, F-actin, and E-cadherin. Apical microvilli were also unaffected. We therefore show that conditions can be defined to allow growth of mature, correctly assembled epithelial monolayers with nanopillars localized to lateral intercellular spaces. This sets the stage for application of nanotechnologies for perturbation and analysis of epithelial biology.
Stretching of long double-stranded DNA and RNA described by the same model
Authors: Afanasyev Alexander Y. , Onufriev Alexey V. 
Published: March 2022

AbstractWe propose a bead-spring model that accurately reproduces a variety of experimental force-extension curves of long double-stranded DNA and RNA, including torsionally constrained and unconstrained DNA, and negatively supercoiled DNA. A key feature of the model is a specific non-convex energy function of the spring. We provide an algorithm for obtaining five required parameters of the model from experimental force-extension curves. In the plateau region of the force-extension curves, our molecular dynamics simulations show that the polymer separates into a mix of weakly and strongly stretched states without forming macroscopically distinct phases.
The characterization of multiple novel paramyxovirus species highlights the diverse nature of the subfamily Orthoparamyxovirinae
Authors: Vanmechelen Bert , Meurs Sien , Horemans Marie , Loosen Arne , Maes Tibe Joly , Laenen Lies , Vergote Valentijn , Koundouno Fara Raymond , Magassouba N’faly , Konde Mandy Kader , Condé Ibrahima Sory , Carroll Miles W. , Maes Piet 
Published: March 2022

AbstractThe subfamily Orthoparamyxovirinae is a group of single-stranded, negative-sense RNA viruses that contains many human, animal and zoonotic pathogens. While there are currently only 34 recognized member species in this subfamily, recent research has revealed that much of its diversity remains to be characterized. Using a newly developed nested PCR-based screening assay, we report here the discovery of fifteen orthoparamyxoviruses in rodents and shrews from Belgium and Guinea, thirteen of which are believed to represent new species. Using nanopore sequencing, complete genomes could be determined for almost all of these viruses, enabling a detailed evaluation of their genome characteristics. While most viruses are thought to belong to the rapidly expanding genus Jeilongvirus, we also identify novel members of the genera Narmovirus, Henipavirus and Morbillivirus. Together with other recently discovered orthoparamyxoviruses, both the henipaviruses and the morbillivirus discovered here appear to form distinct rodent-/shrew-borne clades within their respective genera, clustering separately from all currently classified member species. In the case of the henipaviruses, a comparison of the different members of this clade revealed the presence of a secondary conserved open reading frame, encoding for a transmembrane protein, within the F gene, the biological relevance of which remains to be established. While the characteristics of the viruses described here shed further light on the complex evolutionary origin of paramyxoviruses, they also illustrate that the diversity of this group of viruses in terms of genome organization appears to be much larger than previously assumed.Data availabilityThe genome sequences generated in this study have been submitted to GenBank (accession numbers OK623353-OK623368).
IPMK modulates insulin-mediated suppression of hepatic glucose production
Authors: Jung Ik-Rak , Anokye-Danso Frederick , Jin Sunghee , Ahima Rexford S. , Kim Sangwon F. 
Published: March 2022

AbstractHepatic glucose production is crucial for the maintenance of normal glucose homeostasis. Although hepatic insulin resistance contributes to excessive glucose production, its mechanism is not well understood. Here, we show that inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate biosynthesis, plays a role in regulating hepatic insulin signaling and gluconeogenesis both in vitro and in vivo.IPMK-deficient hepatocytes exhibit decreased insulin-induced activation of Akt-FoxO1 signaling. The expression of mRNA levels of phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose 6-phosphatase (G6pc), key enzymes mediating gluconeogenesis, are increased in IPMK-deficient hepatocytes compared to wild type (WT) hepatocytes. Importantly, re-expressing IPMK restores insulin sensitivity and alleviates glucose production in IPMK-deficient hepatocytes. Moreover, hepatocyte-specific IPMK deletion exacerbates hyperglycemia and insulin sensitivity in mice fed a high-fat diet (HFD), accompanied by an increase in hepatic glucose production during pyruvate tolerance test and reduction in Akt phosphorylation in IPMK deficient liver. Our results demonstrate that IPMK mediates insulin signaling and gluconeogenesis and may be potentially targeted for treatment of diabetes.HighlightsIPMK expression is reduced in livers of HFD-fed mice.Hepatocyte-specific deletion of IPMK in mice aggravated HFD-induced insulin resistance.Loss of IPMK decreased insulin-induced activation of Akt-FoxO1 signaling, leading to the increase of glucose production in hepatocytes.
Small non-coding RNA landscape of extracellular vesicles from a post-traumatic model of equine osteoarthritis
Authors: Anderson James R , Jacobsen Stine , Walters Marie , Bundgaard Louise , Diendorfer Andreas , Hackl Matthias , Clarke Emily J , James Victoria , Peffers Mandy J 
Published: March 2022

AbstractExtracellular vesicles comprise an as yet inadequately investigated intercellular communication pathway in the field of early osteoarthritis. We hypothesised that small non-coding RNA expression pattern in synovial fluid and plasma would change during progression of experimental osteoarthritis. In this study, we used small RNA sequencing to provide a comprehensive overview of the temporal expression profiles of small non-coding transcripts carried by EVs derived from plasma and synovial fluid for the first time in a post-traumatic model of equine osteoarthritis. Additionally, we characterised synovial fluid and plasma-derived extracellular vesicles with respect to quantity, size, and surface markers. The differential expression of seven microRNAs in plasma and synovial fluid-derived extracellular vesicles; miR-451, miR-25, miR-215, miR-92a, miR-let-7c, miR-486-5p, miR-23a and four snoRNAs; U3, snord15, snord46, snord58 represent potential biomarkers for early OA. Bioinformatics analysis of the differentially expressed microRNAs in synovial fluid highlighted that in early OA these related to the inhibition of cell cycle, cell cycle progression, DNA damage and cell proliferation but increased cell viability, and differentiation of stem cells. Plasma and synovial fluid-derived extracellular vesicle small non-coding signatures have been established for the first time in a temporal model of osteoarthritis. These could serve as novel biomarkers for the evaluation of osteoarthritis progression or act as potential therapeutic targets.
Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair
Authors: Barr Justinn , Gentile Maria Elena , Lee Sunyoung , Kotas Maya E. , de Mello Costa Maria Fernanda , Holcomb Nicolas P. , Jaquish Abigail , Palashikar Gargi , Matsumoto Ichiro , Margolskee Robert , Cohen Noam A. , Sun Xin , Vaughan Andrew E. 
Published: March 2022

AbstractWhile the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4Rα signaling are required to drive tuft cell development in dysplastic/injured lungs. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.