bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combining Stem Cell Rejuvenation and Senescence Targeting to Synergistically Extend Lifespan
Authors: Kaur Prameet , Otgonbaatar Agimaa , Ramamoorthy Anupriya , Zhen Chua Ellora Hui , Harmston Nathan , Gruber Jan , Tolwinski Nicholas S. 
Published: May 2022

ABSTRACTWhy biological age is a major risk factor for many of the most important human diseases remains mysterious. We know that as organisms age, stem cell pools are exhausted while senescent cells progressively accumulate. Independently, induction of pluripotency via expression of Yamanaka factors (Oct4, Klf4, Sox2, c-Myc; OKSM) and clearance of senescent cells have each been shown to ameliorate cellular and physiological aspects of aging, suggesting that both processes are drivers of organismal aging. However, stem cell exhaustion and cellular senescence likely interact in the etiology and progression of age-dependent diseases because both undermine tissue and organ homeostasis in different if not complementary ways. Here, we combine transient cellular reprogramming (stem cell rejuvenation) with targeted removal of senescent cells to test the hypothesis that simultaneously targeting both cell-fate based aging mechanisms will maximize life and health span benefits. We show that these interventions protect the intestinal stem cell pool, lower inflammation, activate pro-stem cell signaling pathways, and synergistically improve health and lifespan. Our findings suggest that a combination therapy, simultaneously replacing lost stem cells and removing senescent cells, shows synergistic potential for anti-aging treatments. Our finding that transient expression of both is the most effective suggests that drug-based treatments in non-genetically tractable organisms will likely be the most translatable.
Explosive seed dispersal depends on SPL7 to ensure sufficient copper for localized lignin deposition via laccases
Authors: Pérez-Antón Miguel , Schneider Ilsa , Kroll Patrizia , Hofhuis Hugo , Metzger Sabine , Pauly Markus , Hay Angela 
Published: May 2022

AbstractExploding seed pods evolved in the Arabidopsis relative, Cardamine hirsuta, via morphomechanical innovations that allow the storage and rapid release of elastic energy. Asymmetric lignin deposition within endocarpb cell walls is one such innovation that is required for explosive seed dispersal and evolved in association with the trait. However, the genetic control of this novel lignin pattern is unknown. Here, we identify three lignin-polymerizing laccases, LAC4, 11 and 17, that precisely co-localize with, and are redundantly required for, asymmetric lignification of endocarpb cells. By screening for C. hirsuta mutants with less lignified fruit valves, we found that loss of function of the transcription factor gene SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 7 (SPL7) caused a reduction in endocarpb cell wall lignification and a consequent reduction in seed dispersal range. SPL7 is a conserved regulator of copper homeostasis and is both necessary and sufficient for copper to accumulate in the fruit. Laccases are copper-requiring enzymes. We discovered that laccase activity in endocarpb cell walls depends on the SPL7 pathway to acclimate to copper deficiency and provide sufficient copper for lignin polymerization. Hence, SPL7 links mineral nutrition to efficient dispersal of the next generation.
Optimal burstiness in populations of spiking neurons facilitates decoding of decreases in tonic firing
Authors: Durian Sylvia C. L. , Agrios Mark , Schwartz Gregory W. 
Published: May 2022

AbstractA stimulus can be encoded in a population of spiking neurons through any change in the statistics of the joint spike pattern, yet we commonly summarize single-trial population activity by the summed spike rate across cells: the population peri-stimulus time histogram (pPSTH). For neurons with low baseline spike rate that encode a stimulus with a rate increase, this simplified representation works well, but for populations with high baseline rates and heterogeneous response patterns, the pPSTH has limited utility in capturing the neural representation of the stimulus. We simulated populations of spiking neurons that varied in size, baseline rate, burst statistics, and correlation, and we measured how these populations represent decreases (gaps) in spike rate. We introduce a different representation of the population spike pattern which we call an “information train,” and we show that it is more flexible and robust than the pPSTH in capturing stimulus information across different types of neuronal populations. In particular, we use this tool to study populations with varying levels of burstiness in their spiking statistics. We find that there is an optimal level of burstiness for gap detection that is robust to several other parameters of the population. Next, we consider this theoretical result in the context of experimental data from different types of retinal ganglion cells and determine that the baseline spike statistics of a particular, recently identified type support nearly optimal detection of both the onset and strength of a contrast step.
Integrative assessment of the transcriptome and virome of the poultry red mite Dermanyssus gallinae
Authors: Ribeiro José M , Hartmann David , Bartošová-Sojková Pavla , Debat Humberto , Moos Martin , Šimek Petr , Fara Jiří , Palus Martin , Kučera Matěj , Hajdušek Ondřej , Sojka Daniel , Kopáček Petr , Perner Jan 
Published: May 2022

AbstractDermanyssus gallinae is a blood-feeding mite that parasitises on wild birds and farmed poultry. The D. gallinae mite has a short life cycle of fewer than two weeks from the egg to an egg-laying female. The remarkably swift processing of blood, together with the capacity to blood-feed in most developmental stages, makes this mite a highly debilitating pest. We have constructed developmental stage-specific transcriptomes, through Illumina RNA-seq, to mine the repertoire of protein-encoding mRNA transcripts, products of which participate in key processes that ensure the success of blood digestion, rapid ontogeny, and immunity. As a result of high reproductive capacity, the prevalence of D. gallinae in egg-producing poultry farms globally causes significant economic losses. Acaricides that are used to limit the reproduction of D. gallinae mites target cys-loop ion channels, which are widely shared across the phylogeny of invertebrates. To catalogue a comprehensive list of potential invertebrate-specific ion channels, we have constructed and analysed an additional RNA-seq library of D. gallinae micro-dissected midguts, a tissue with direct exposure to host blood and potential anti-parasitics. We phylogenetically defined groups of cys-loop proteins and probed their sensitivity to selected acaricides. Ultimately, we have catalogued all assembled transcripts and their expression values in a hyper-linked excel sheet with available sequences of individual contigs. The transcriptomic data were complemented by mass-spectrometry (MS)-based metabolite identification and by viability assays using selected inhibitors applied either by microinjection or through artificial membrane feeding. Additionally, we have described the RNA-virome of D. gallinae and identified a novel virus dubbed Red Mite Quaranjavirus 1.
Multiple routes of adaptation to high levels of CIN and aneuploidy in budding yeast
Authors: Clarke Matthew N. , Marsoner Theodor , Alonso Y Adell Manuel , Ravichandran Madhwesh C. , Campbell Christopher S. 
Published: May 2022

AbstractBoth an increased frequency of chromosome missegregation (chromosomal instability) and the presence of an abnormal complement of chromosomes (aneuploidy) are hallmarks of cancer. Paradoxically, both chromosomal instability and aneuploidy are also associated with substantial decreases in cellular fitness. To better understand how cells are able to adapt to high levels of chromosomal instability, we previously examined yeast cells that were deleted of the gene BIR1, a member of the chromosomal passenger complex (CPC). The CPC is an essential regulator of chromosome segregation fidelity. We found bir1Δ cells quickly adapted by acquiring specific combinations of beneficial aneuploidies. However, targeted mutations of specific genes were notably absent in the short term. In this study, we monitored these yeast strains for longer periods of time to determine how cells adapt to high levels of both CIN and aneuploidy in the long term. We identify suppressor mutations that mitigate the chromosome missegregation phenotype. The mutated proteins fall into four main categories: outer kinetochore subunits, members of the SCFCdc4 complex, the mitotic kinase Mps1, and a member of the CPC itself. These mutants function in two distinct ways, as mutations in the outer kinetochore suppress Bir1 deletion indirectly by destabilizing connections between the chromosomes and the mitotic spindle, whereas the other three categories of mutations affect the CPC directly. As a consequence of the accumulation of suppressor point mutations, overall levels of aneuploidy decreased. These experiments demonstrate a timeline of adaptation to high rates of CIN wherein cells first acquire specific aneuploidies that suppress the CIN phenotype, next develop point mutations that more specifically target the source of CIN, and finally reduce the level of aneuploidy to relieve the fitness burden placed by aneuploidy on the cell.
Fluid extraction from the left-right organizer uncovers mechanical properties needed for symmetry breaking
Authors: Sampaio Pedro , Pestana Sara , Guerrero Adán , Telley Ivo A. , Smith David. J. , Lopes Susana S. 
Published: May 2022

AbstractHumans and other vertebrates define body axis left-right asymmetry in the early stages of embryo development (Shiratori and Hamada, 2006). The mechanism behind left-right establishment is not fully understood (Mizuno et al., 2020; Maerker et al., 2021; Minegishi et al., 2021). Symmetry breaking occurs in a dedicated organ called the left-right organizer (LRO) and involves motile cilia generating fluid-flow therein. However, it has been a matter of debate whether the process of symmetry breaking relies on a chemosensory or a mechanosensory mechanism (Shinohara et al., 2012). Novel tailored manipulations for LRO fluid extraction in living zebrafish embryos allowed us to pinpoint a decisive developmental period for breaking left-right symmetry during development. The shortest critical time-window was narrowed to one hour and characterized by a mild counterclockwise flow. The experimental challenge consisted in emptying the LRO of its fluid, abrogating simultaneously flow force and chemical determinants. Our findings revealed an unprecedented recovery capacity of the embryo to re-fil and re-circulate new LRO fluid. The embryos that later developed laterality problems were found to be those that had lower anterior angular velocity and thus less anterior-posterior heterogeneity. Aiming to test if this led to differential endocytosis of any molecular determinant, we replaced the LRO fluid by a physiological buffer. Despite some transitory flow homogenization, laterality defects were absent unless viscosity was altered demonstrating that symmetry breaking does not depend on the nature of the fluid content but rather relies on fluid mechanics. Altogether, we conclude that mechanosensing is the likely mechanism to govern left-right early establishment.
Improved assessments of milk microbiota composition via sample preparation and DNA extraction methods
Authors: Xue Zhengyao , Marco Maria L. 
Published: May 2022

AbstractAlthough bacterial detection by 16S rRNA gene amplicon DNA sequencing is now a widely-applied technique, standardized methods for sample preparation and DNA extraction are needed to ensure accuracy, reproducibility, and scalability for automation. To develop these methods for bovine milk, we assembled a bacterial cell mock community (BCMC) containing bacterial species commonly found in milk. Variations to the following methods were examined: BCMC enumeration method (colony enumeration or microscopy), sample volume (200 μl to 30 ml), sample storage condition (frozen in PBS or 25% glycerol or exposure to freeze-thaw cycles), cell lysis method (bead-beating, vortex, enzymatic), and DNA extraction procedure (MagMAX Total, MagMAX CORE, and MagMAX Ultra 2.0, with and without either Proteinase K or RNase A). Cell enumeration by microscopy was shown to be more accurate for quantification of the BCMC contents. We found that least 10 mL (≥ 104 cells in high quality milk) is needed for reproducible bacterial detection by 16S rRNA gene amplicon DNA sequencing, whereas variations in storage conditions caused minor differences in the BCMC. For DNA extraction and purification, a mild lysis step (bead-beating for 10 s at 4 m/s or vortexing at 1800 rpm for 10 s) paired with the MagMAX Total kit and Proteinase K digestion provided the most accurate representation of the BCMC. These approaches were confirmed to provide similar results in commercial milk samples. Overall, variations in cell lysis methods conferred the greatest changes to milk microbiota composition and therefore should be optimized for sample type.
Glucagon-Like Peptide-1 Receptor Activation Stimulates PKA-Mediated Phosphorylation of Raptor and this Contributes to the Weight Loss Effect of Liraglutide
Authors: Le Thao D. V. , Liu Dianxin , Besing Gai-Linn K. , Raghavan Ritika , Ellis Blair J. , Ceddia Ryan P. , Collins Sheila , Ayala Julio E. 
Published: May 2022

AbstractThe canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser791following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser791and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide. We measured phosphorylation of the mTORC1 signaling target ribosomal protein S6 in Chinese Hamster Ovary cells expressing GLP-1R (CHO-Glp1r) treated with liraglutide in combination with PKA inhibitors. We also assessed liraglutide-mediated phosphorylation of the PKA substrate RRXS*/T* motif in CHO-Glp1r cells expressing Myc-tagged wild-type (WT) Raptor or a PKA-resistant (Ser791Ala) Raptor mutant. Finally, we measured the body weight response to liraglutide in WT mice and mice with a targeted knock-in of PKA-resistant Ser791Ala Raptor. Liraglutide increased phosphorylation of S6 and the PKA motif in WT Raptor in a PKA-dependent manner but failed to stimulate phosphorylation of the PKA motif in Ser791Ala Raptor in CHO-Glp1r cells. Lean Ser791Ala Raptor knock-in mice were resistant to liraglutide-induced weight loss but not setmelanotide-induced (melanocortin-4 receptor-dependent) weight loss. Diet-induced obese Ser791Ala Raptor knock-in mice were not resistant to liraglutide-induced weight loss; however, there was weight-dependent variation such that there was a tendency for obese Ser791Ala Raptor knock-in mice of lower relative body weight to be resistant to liraglutide-induced weight loss compared to weight-matched controls. Together, these findings suggest that PKA-mediated phosphorylation of Raptor at Ser791contributes to liraglutide-induced weight loss.
How does data structure impact cell-cell similarity? Evaluating the influence of structural properties on proximity metric performance in single cell RNA-seq data
Authors: Watson Ebony Rose , Mora Ariane , Fard Atefeh Taherian , Mar Jessica Cara 
Published: May 2022

AbstractAccurately identifying cell populations is paramount to the quality of downstream analyses and overall interpretations of single-cell RNA-seq (scRNA-seq) datasets but remains a challenge. The quality of single-cell clustering depends on the proximity metric used to generate cell-to-cell distances. Accordingly, proximity metrics have been benchmarked for scRNA-seq clustering, typically with results averaged across datasets to identify a highest performing metric. However, the ‘best-performing’ metric varies between studies, with the performance differing significantly between datasets. This suggests that the unique structural properties of a scRNA-seq dataset, specific to the biological system under study, has a substantial impact on proximity metric performance. Previous benchmarking studies have omitted to factor the structural properties into their evaluations. To address this gap, we developed a framework for the in-depth evaluation of the performance of 17 proximity metrics with respect to core structural properties of scRNA-seq data, including sparsity, dimensionality, cell population distribution and rarity. We find that clustering performance can be improved substantially by the selection of an appropriate proximity metric and neighbourhood size for the structural properties of a dataset, in addition to performing suitable pre-processing and dimensionality reduction. Furthermore, popular metrics such as Euclidean and Manhattan distance performed poorly in comparison to several lessor applied metrics, suggesting the default metric for many scRNA-seq methods should be re-evaluated. Our findings highlight the critical nature of tailoring scRNA-seq analyses pipelines to the system under study and provide practical guidance for researchers looking to optimise cell similarity search for the structural properties of their own data.
Metatranscriptomic comparison of viromes in endemic and introduced passerines in New Zealand
Authors: French Rebecca K. , Filion Antoine , Niebuhr Chris N. , Holmes Edward C. 
Published: May 2022

AbstractNew Zealand has many endemic passerine birds vulnerable to emerging infectious diseases. Yet little is known about viruses in passerines, and in some countries, including New Zealand, the virome of wild passerines has received little research attention. Using metatranscriptomic sequencing we characterised the virome of New Zealand endemic and introduced species of passerine. Accordingly, we identified 34 possible avian viruses from cloacal swabs of 12 endemic and introduced bird species not showing signs of disease. These included a novel siadenovirus, iltovirus and avastrovirus in the Eurasian blackbird (Turdus merula, an introduced species), song thrush (Turdus philomelos, introduced) and silvereye (Zosterops lateralis, introduced), respectively. This is the first time novel viruses from these genera have been identified in New Zealand, likely reflecting prior undersampling. It also represents the first identification of an iltovirus and siadenovirus in blackbirds and thrushes globally. These three viruses were found only in introduced species and may pose a risk to endemic species if they were to jump species boundaries, particularly the iltoviruses and siadenoviruses that have a prior history of disease associations. Further virus study and surveillance is needed in New Zealand avifauna, particularly inTurduspopulations and endemic species.
A within-host model of SARS-CoV-2 infection
Authors: Carruthers Jonathan , Xu Jingsi , Finnie Thomas , Hall Ian 
Published: May 2022

AbstractWithin-host models have been used to successfully describe the dynamics of multiple viral infections, however, the dynamics of SARS-CoV-2 virus infection remain poorly understood. A greater understanding of how the virus interacts with the host can contribute to more realistic epidemiological models and help evaluate the effect of antiviral therapies and vaccines. Here, we present a within-host model to describe SARS-CoV-2 viral dynamics in the upper respiratory tract of individuals enrolled in the UK COVID-19 Human Challenge Study. Using this model, we investigate the viral dynamics and provide timescales of infection that independently verify key epidemiological parameters important in the management of an epidemic. In particular, we estimate that an infected individual is first capable of transmitting the virus after approximately 2.1 days, remains infectious for a further 8.3 days, but can continue to test positive using a PCR test for up to 27 days.
Crop management shapes the diversity and activity of DNA and RNA viruses in the rhizosphere
Authors: Muscatt George , Hilton Sally , Raguideau Sebastien , Teakle Graham , Lidbury Ian D. E. A. , Wellington Elizabeth M. H. , Quince Christopher , Millard Andrew , Bending Gary D. , Jameson Eleanor 
Published: May 2022

AbstractBackgroundThe rhizosphere is a hotspot for microbial activity and contributes to ecosystem services including plant health and biogeochemical cycling. The activity of microbial viruses, and their influence on plant-microbe interactions in the rhizosphere, remains undetermined. Given the impact of viruses on the ecology and evolution of their host communities, determining how soil viruses influence microbiome dynamics is crucial to build a holistic understanding of rhizosphere functions.ResultsHere, we aimed to investigate the influence of crop management on the composition and activity of bulk soil, rhizosphere soil, and root viral communities. We combined viromics, metagenomics, and metatranscriptomics on soil samples collected from a 3-year crop rotation field trial of oilseed rape (Brassica napus L.). By recovering 1,059 dsDNA viral populations and 16,541 ssRNA bacteriophage populations, we expanded the number of underexplored Leviviricetes genomes by > 5 times. Through detection of viral activity in metatranscriptomes, we uncovered evidence of “Kill-the-Winner” dynamics, implicating soil bacteriophages in driving bacterial community succession. Moreover, we found the activity of viruses increased with proximity to crop roots and identified that soil viruses may influence plant-microbe interactions through the reprogramming of bacterial host metabolism. We have provided the first evidence of crop rotation-driven impacts on soil microbial communities extending to viruses. To this aim, we present the novel principal of “viral priming”, which describes how the consecutive growth of the same crop species primes viral activity in the rhizosphere through local adaptation.ConclusionsOverall, we reveal unprecedented spatial and temporal diversity in viral community composition and activity across root, rhizosphere soil and bulk soil compartments. Our work demonstrates that the roles of soil viruses need greater consideration to exploit the rhizosphere microbiome for food security, food safety, and environmental sustainability.