bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome recombination-mediated tRNA up-regulation conducts general antibiotic resistance of bacteria at early stage
Authors: Fang Huiying , Zeng Guandi , Zhao Jing , Zheng Tingkai , Xu Lina , Gu Wei , Liu Yutong , Zhang Jinning , Sun Xuesong , Zhang Gong 
Published: January 2021

AbstractBacterial antibiotic resistance sets a great challenge to human health. It seems that the bacteria can spontaneously evolve resistance against any antibiotic within short time without the horizontal transfer of heterologous genes and before accumulating drug-resistant mutations. We have shown that the tRNA-mediated translational regulation counteracts the reactive oxygen species in bacteria. In this study, we demonstrated that isolated and subculturedEscherichia colielevated its tRNAs under antibiotic stress to rapidly provide antibiotic resistance, especially at the early stage, before upregulating the efflux pump and evolving resistance mutations. The DNA recombination system repaired the antibiotic-induced DNA breakage in the genome, causing numerous structural variations. These structural variations are overrepresented near the tRNA genes, which indicated the cause of tRNA up-regulation. The strains knocking out the recombination system could not up-regulate tRNAs, and coincidently, they could hardly evolve antibiotic resistance in multiple antibiotics, respectively. With these results, we proposed a multi-stage model of bacterial antibiotic resistance in an isolated scenario: the early stage (recombination – tRNA up-regulation – translational regulation); the medium stage (up-regulation of efflux pump); the late stage (resistance mutations). These results also indicated that the bacterial DNA recombination system and tRNA could be targeted to retard the bacterial spontaneous drug resistance.
Alcohol consumption is associated with structural changes in various organ systems: A population-based study in UK Biobank
Authors: Evangelou Evangelos , Suzuki Hideaki , Bai Wenjia , Pazoki Raha , Gao He , Matthews Paul M , Elliott Paul 
Published: January 2021

AbstractExcessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample. We assessed global effects of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta and liver of UK-Biobank participants who reported drinking alcohol. We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (–1.7×10−3±0.76×10−3per doubling of alcohol consumption,P=3.0×10−14). Alcohol consumption also was associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption. Our results imply that there is not a “safe threshold” below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited.
Coupled myovascular expansion directs cardiac growth and regeneration
Authors: DeBenedittis Paige , Karpurapu Anish , Henry Albert , Thomas Michael C. , McCord Timothy J. , Brezitski Kyla , Prasad Anil , Kobayashi Yoshihiko , Shah Svati H. , Kontos Christopher D. , Tata Purushothama Rao , Lumbers R. Thomas , Karra Ravi 
Published: January 2021

ABSTRACTBackgroundHeart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled.Methods and ResultsWe show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion ofVegfr2from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encodingVegfaenhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting thatVegfacan stimulate human cardiac growth.ConclusionsOur work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.
APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer
Authors: Isozaki Hideko , Abbasi Ammal , Nikpour Naveed , Langenbucher Adam , Su Wenjia , Stanzione Marcello , Cabanos Heidie Frisco , Siddiqui Faria M. , Phan Nicole , Jalili Pégah , Oh Sunwoo , Timonina Daria , Bilton Samantha , Gomez-Caraballo Maria , Archibald Hannah L. , Nangia Varuna , Dionne Kristin , Riley Amanda , Lawlor Matthew , Banwait Mandeep Kaur , Cobb Rosemary G. , Zou Lee , Dyson Nicholas J. , Ott Christopher J. , Benes Cyril , Getz Gad , Chan Chang S. , Shaw Alice T. , Lin Jessica J. , Sequist Lecia V. , Piotrowska Zofia , Engelman Jeffrey A. , Lee Jake June-Koo , Maruvka Yosef , Buisson Rémi , Lawrence Michael S. , Hata Aaron N. 
Published: January 2021

AbstractAcquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1‒6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.
Association between land use, land cover, plant genera, and pollinator abundance in mixed-use landscapes
Authors: Diengdoh Vishesh L. , Brook Barry W. , Hunt Mark , Ondei Stefania 
Published: January 2021

AbstractPollinators are globally threatened by land-use change, but its effect varies depending on the taxa and the intensity of habitat degradation. However, pollinator-landscape studies typically focus on regions of intensive human activities and on a few focal species. Evaluating pollinator responses in landscapes with moderate land-use changes and on multiple pollinator groups would therefore fill an important knowledge gap. This study aims to determine the predictive capacity and effect of habitat characteristics on the relative abundance of multiple pollinator groups in mixed-use landscapes. To do this, we collected field data on the relative abundance of nectivorous birds, bees, beetles, and butterflies across the Tasman Peninsula (Tasmania, Australia). We then applied Random Forests to resolve the effects of land use (protected areas, plantation, and pasture), land cover at different radii (100 m and 2000 m), and plant genera on pollinator abundance. Overall, land cover and plant genera were more important predictors of pollinator abundance than land use. And the effect of land use, land cover, and plant genera varied depending on the pollinating group. Pollinator groups were associated with a range of plant genera, with the native generaAcacia, Leptospermum, Leucopogon, Melaleuca, Pomaderris, andPultenaeabeing among the most important predictors. Our results highlight that one size does not fit all—that is pollinator response to different landscape characteristics vary, emphasise the importance of considering multiple habitat factors to manage and support a dynamic pollinator community, and demonstrates how land management can be informed using predictive modelling.
Ocular elongation and retraction in foveated reptiles
Authors: Rasys Ashley M. , Pau Shana H. , Irwin Katherine E. , Luo Sherry , Trainor Paul A. , Menke Douglas B. , Lauderdale James D. 
Published: January 2021

AbstractBackgroundPronounced asymmetric changes in ocular globe size during eye development have been observed in a number of species ranging from humans to lizards. In contrast, largely symmetric changes in globe size have been described for other species like rodents. We propose that asymmetric changes in the three-dimensional structure of the developing eye correlate with the types of retinal remodeling needed to produce areas of high photoreceptor density. To test this idea, we systematically examined three-dimensional aspects of globe size as a function of eye development in the bifoveated brown anole,Anolis sagrei.ResultsDuring embryonic development, the anole eye undergoes dynamic changes in ocular shape. Initially spherical, the eye elongates in the presumptive foveal regions of the retina and then proceeds through a period of retraction that returns the eye to its spherical shape. During this period of retraction, pit formation and photoreceptor cell packing are observed. We found a similar pattern of elongation and retraction associated with the single fovea of the veiled chameleon,Chamaeleo calyptratus.ConclusionsThese results, together with those reported for other foveated species, support the idea that areas of high photoreceptor packing occur in regions where the ocular globe asymmetrically elongates and retracts during development.Key FindingsThe eyes of the brown anole,Anolis sagrei, and veiled chameleon,Chamaeleo calyptratusundergo dynamic asymmetrical changes in ocular shape during development.In both species, asymmetric elongation and retraction of the ocular globe is associated with fovea morphogenesis.Pit formation and photoreceptor cell packing in the foveal area occur when the corresponding region of the ocular globe is retracting relative to adjacent regions.
LAM – an image analysis method for regionally defined organ-wide cellular phenotyping of theDrosophilamidgut
Authors: Viitanen Arto , Gullmets Josef , Morikka Jack , Katajisto Pekka , Mattila Jaakko , Hietakangas Ville 
Published: January 2021

ABSTRACTIntestine is divided into functionally distinct regions along the anteroposterior (A/P) axis. How the regional identity influences the function of intestinal stem cells (ISCs) and their offspring remain largely unresolved. We introduce an imaging-based method, ‘Linear Analysis of Midgut’ (LAM), which allows quantitative regionally defined cellular phenotyping of the wholeDrosophilamidgut. LAM transforms image-derived cellular data from three-dimensional midguts into a linearized representation, binning it into segments along the A/P axis. Through automated multi-variate determination of regional borders, LAM allows mapping and comparing cellular features and frequencies with subregional resolution. Through the use of LAM, we quantify the distributions of ISCs, enteroblasts and enteroendocrine cells in a steady state midgut, and reveal unprecedented regional heterogeneity in the ISC response to aDrosophilamodel of colitis. Taken together, LAM is a powerful tool for organ-wide quantitative analysis of the regional heterogeneity of midgut cells.Graphical abstract
Rab11a mediates cell-cell spread and reassortment of influenza A virus genomes via tunneling nanotubes
Authors: Ganti Ketaki , Han Julianna , Manicassamy Balaji , Lowen Anice C. 
Published: January 2021

AbstractInfluenza A virus (IAV) genomes comprise eight negative strand RNAs packaged into virions in the form of viral ribonucleoproteins (vRNPs). Rab11a plays a crucial role in the transport of vRNPs from the nucleus to the plasma membrane via microtubules, allowing assembly and virus production. Here, we identify a novel function for Rab11a in the inter-cellular transport of IAV vRNPs using tunneling nanotubes (TNTs) as molecular highways. TNTs are F-Actin rich tubules that link the cytoplasm of nearby cells. In IAV-infected cells, Rab11a was visualized together with vRNPs in these actin-rich intercellular connections. To better examine viral spread via TNTs, we devised an infection system in which conventional, virion-mediated, spread was not possible. Namely, we generated HA-deficient reporter viruses which are unable to produce progeny virions but whose genomes can be replicated and trafficked. In this system, vRNP transfer to neighboring cells was observed and this transfer was found to be dependent on both actin and Rab11a. Generation of infectious virus via TNT transfer was confirmed using donor cells infected with HA-deficient virus and recipient cells stably expressing HA protein. Mixing donor cells infected with genetically distinct IAVs furthermore revealed the potential for Rab11a and TNTs to serve as a conduit for genome mixing and reassortment in IAV infections. These data therefore reveal a novel role for Rab11a in the IAV life cycle, which could have significant implications for within-host spread, genome reassortment and immune evasion.Author SummaryInfluenza A viruses infect epithelial cells of the upper and lower respiratory tract in humans. Infection is propagated by the generation of viral particles from infected cells, which disseminate within the tissue. Disseminating particles can encounter obstacles in the extracellular environment, including mucus, ciliary movement, antibody neutralization and uptake by phagocytic immune cells. An alternative mode of spread, which avoids these hazards, involves direct transport of viral components between cells. This cell-cell spread of infection is not a well understood process. In this study we demonstrate that the host factor Rab11a mediates the transport of viral genomes in the cell-cell spread of infection. Rab11a is already known to play a pro-viral role in the transport of viral genomes to the plasma membrane for assembly into virus particles. Here, we see that this same transport mechanism is co-opted for direct cell-cell spread through cellular connections called tunneling nanotubes. We show that complexes of Rab11a and viral components can be trafficked across tunneling nanotubes, transmitting infection without the formation of virus particles. Importantly, this route of spread often seeds viral genomes from multiple donor cells into recipient cells, which in turn increases viral genetic diversity.
Automatic and unbiased segmentation and quantification of myofibers in skeletal muscle
Authors: Waisman Ariel , Norris Alessandra , Costa Martín Elías , Kopinke Daniel 
Published: January 2021

ABSTRACTSkeletal muscle has the remarkable ability to regenerate. However, with age and disease muscle strength and function decline. Myofiber size, which is affected by injury and disease, is a critical measurement to assess muscle health. Here, we test and apply Cellpose, a recently developed deep learning algorithm, to automatically segment myofibers within murine skeletal muscle. We first show that tissue fixation is necessary to preserve cellular structures such as primary cilia, small cellular antennae, and adipocyte lipid droplets. However, fixation generates heterogeneous myofiber labeling, which impedes intensity-based segmentation. We demonstrate that Cellpose efficiently delineates thousands of individual myofibers outlined by a variety of markers, even within fixed tissue with highly uneven myofiber staining. We created a novel ImageJ plugin (LabelsToRois) that allows processing multiple Cellpose segmentation images in batch. The plugin also contains a semi-automatic erosion function to correct for the area bias introduced by the different stainings, identifying myofibers as accurately as human experts. We successfully applied our segmentation pipeline to uncover myofiber size differences between two different muscle injury models, cardiotoxin and glycerol. Thus, Cellpose combined with LabelsToRois allows for fast, unbiased, and reproducible myofiber quantification for a variety of staining and fixation conditions.
Fine-scale changes in speed and altitude suggest protean movements in homing pigeon flights
Authors: Garde Baptiste , Wilson Rory P. , Lempidakis Emmanouil , Börger Luca , Portugal Steven J. , Hedenström Anders , Dell’Omo Giacomo , Quetting Michael , Wikelski Martin , Shepard Emily L. C. 
Published: January 2021

AbstractThe flight speeds that animals should adopt to minimise energy expenditure in different scenarios can be predicted by the curve of power against speed. However, relatively few studies have examined how animals respond to the landscape below them, which could affect speed through modifications in climb rate and perceived predation risk. We equipped homing pigeons(Columba livia)with high frequency loggers to examine how flight speed varies in relation to topography and land cover, predicting that these parameters may have a substantial impact on flight speed and hence cost. Pigeons showed mixed evidence for an energy saving strategy, as they minimised climb rates by starting their ascent ahead of hills, but selected rapid speeds in their ascents. Birds did not modify their speed substantially in relation to land cover, but higher speeds were observed during descending flight, highlighting the importance to consider the rate of change in altitude before estimating power use from speed. Finally, we document an unexpected variability in speed and altitude over fine scales; a source of substantial inefficiency. We suggest this may a form of protean behaviour adopted to reduce predation risk when flocking is not an option, and that such a strategy could be widespread.
Upregulation of eIF4E, but not other translation initiation factors, in dendritic spines during memory consolidation
Authors: Gindina Sofya , Botsford Benjamin , Cowansage Kiriana , LeDoux Joseph , Klann Eric , Hoeffer Charles , Ostroff Linnaea 
Published: January 2021

AbstractLocal translation can provide a rapid, spatially targeted supply of new proteins in distal dendrites to support synaptic changes that underlie learning. Learning and memory are especially sensitive to manipulations of translational control mechanisms, particularly those that target the initiation step, and translation initiation at synapses could be a means of maintaining synapse specificity during plasticity. Initiation predominantly occurs via recruitment of ribosomes to the 5’ mRNA cap by complexes of eukaryotic initiation factors (eIFs), and the interaction between eIF4E and eIF4G1 is a particularly important target of translational control pathways. Pharmacological inhibition of eIF4E-eIF4G1 binding impairs consolidation of memory for aversive Pavlovian conditioning as well as the accompanying increase in polyribosomes in the heads of dendritic spines in the lateral amygdala (LA). This is consistent with a role for initiation at synapses in memory formation, but whether eIFs are even present near synapses is unknown. To determine whether dendritic spines contain eIFs and whether eIF distribution is affected by learning, we combined immunolabeling with serial section transmission electron microscopy (ssTEM) volume reconstructions of LA dendrites after Pavlovian conditioning. Labeling for eIF4E, eIF4G1, and eIF2α – another key target of regulation – occurred in roughly half of dendritic spines, but learning effects were only found for eIF4E, which was upregulated in the heads of dendritic spines. Our results support the possibility of regulated translation initiation as a means of synapse-specific protein targeting during learning and are consistent with the model of eIF4E availability as a central point of control.
Human neuronal networks on micro-electrode arrays are a highly robust tool to study disease-specific genotype-phenotype correlationsin vitro
Authors: Mossink B. , Verboven A.H.A. , van Hugte E.J.H. , Gunnewiek T.M. Klein , Parodi G. , Linda K. , Schoenmaker C. , Kleefstra T. , Kozicz T. , van Bokhoven H. , Schubert D. , Kasri N. Nadif , Frega M. 
Published: January 2021

AbstractMicro-electrode arrays (MEAs) are increasingly used to characterize neuronal network activity of human induced pluripotent stem-cell (hiPSC)-derived neurons. Despite their gain in popularity, MEA recordings from hiPSC-derived neuronal networks are not always used to their full potential in respect to experimental design, execution and data analysis. Therefore, we benchmarked the robustness and sensitivity of MEA-derived neuronal activity patterns derived from ten healthy individual control lines. We provide recommendations on experimental design and analysis to achieve standardization. With such standardization, MEAs can be used as a reliable platform to distinguish (disease-specific) network phenotypes. In conclusion, we show that MEAs are a powerful and robust tool to uncover functional neuronal network phenotypes from hiPSC-derived neuronal networks, and provide an important resource to advance the hiPSC field towards the use of MEAs for disease-phenotyping and drug discovery.
AdipoAtlas: A Reference Lipidome for Human White Adipose Tissue
Authors: Lange Mike , Angelidou Georgia , Ni Zhixu , Criscuolo Angela , Schiller Jürgen , Blüher Matthias , Fedorova Maria 
Published: January 2021

SummaryObesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of metabolic disorders. Remodelling of WAT lipidome in obesity and associated comorbidities can explain disease etiology and provide valuable diagnostic and prognostic markers. To support understanding of WAT lipidome remodelling at the molecular level, we performed in-depth lipidomics profiling of human subcutaneous and visceral WAT of lean and obese individuals. Tissue-tailored preanalytical and analytical workflows allowed accurate identification and semi-absolute quantification of 1636 and 737 lipid molecular species, respectively, and summarized here in a form of human WAT reference lipidome. Deep lipidomic profiling allowed to identify main lipid (sub)classes undergoing depot/phenotype specific remodelling. Furthermore, previously unanticipated diversity of WAT ceramides was uncovered. AdipoAtlas reference lipidome will serve as a data-rich resource for the development of WAT-specific high-throughput methods and as a scaffold for systems medicine data integration.