bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel drivers of virulence inClostridioides difficileidentified via context-specific metabolic network analysis
Authors: Jenior Matthew L , Leslie Jhansi L , Powers Deborah A , Garrett Elizabeth M , Walker Kimberly A , Dickenson Mary E , Petri William A , Tamayo Rita , Papin Jason A 
Published: November 2020

AbstractThe pathogenClostridioides difficilecauses toxin-mediated diarrhea and is the leading cause of hospital-acquired infection in the US. Due to growing antibiotic resistance and recurrent infection, targetingC. difficilemetabolism presents a new approach to combat this infection. Genome-scale metabolic network reconstructions (GENREs) have been used to identify therapeutic targets and uncover properties that determine cellular behaviors. Thus, we constructedC. difficileGENREs for a hyper-virulent isolate (str. R20291) and a historic strain (str. 630), validating both within vitroandin vivodatasets. Growth simulations revealed significant correlations with measured carbon source usage (PPV ≥ 92.7%), and single-gene deletion analysis showed >89.0% accuracy. Next, we utilized each GENRE to identify metabolic drivers of both sporulation and biofilm formation. Through contextualization of each model using transcriptomes generated fromin vitroand infection conditions, we discovered reliance on the Pentose Phosphate Pathway as well as increased usage of cytidine and N-acetylneuraminate when virulence expression is reduced, which was subsequently supported experimentally. Our results highlight the ability of GENREs to identify novel metabolite signals in bacterial pathogenesis.ImportanceClostridioides difficileis a Gram-positive, sporulating anaerobe that has become the leading cause of hospital-acquired infections. Numerous studies have demonstrated the importance of specific metabolic pathways in aspects ofC. difficilepathophysiology, from initial colonization to regulation of virulence factors. In the past, genome-scale metabolic network reconstruction (GENRE) analysis of bacteria has enabled systematic investigation of the genetic and metabolic properties that contribute to downstream virulence phenotypes. With this in mind, we generated and extensively curatedC. difficileGENREs for both a well-studied laboratory strain (str. 630) as well as a more recently characterized hyper-virulent isolate (str. R20291).In silicovalidation of both GENREs revealed high degrees of agreement with experimental gene essentiality and carbon source utilization datasets. Subsequent exploration of context-specific metabolism during bothin vitrogrowth and infection revealed consistent patterns of metabolism which corresponded with experimentally measured increases in virulence factor expression. Our results support that differentialC. difficilevirulence is associated with distinct metabolic programs related use of carbon sources and provides a platform for identification of novel therapeutic targets.
Inherent protection of bacteria from beta-lactam antibiotics by wet-dry cycles with microscopic surface wetness
Authors: Beizman-Magen Yana , Grinberg Maor , Orevi Tomer , Kashtan Nadav 
Published: November 2020

AbstractA large portion of bacterial life occurs on surfaces that are not constantly saturated with water and experience recurrent wet-dry cycles. While soil, plant leaves and roots, and many indoor surfaces may appear dry when not saturated with water, they are in fact often covered by thin liquid films and microdroplets, invisible to the naked eye, known as microscopic surface wetness (MSW). Such MSW, resulting from the condensation of water vapor to hygroscopic salts, is ubiquitous yet largely underexplored. A wide variety of antibiotics are abundant in environments where MSW occurs, yet little is known about bacterial response to antibiotics in wet-dry cycles and under MSW conditions. UsingE. colias a model organism, we show, through a combination of experiments and computational modeling, that bacteria are considerably more protected from beta-lactams under wet-dry cycles with MSW phases, than they are under constantly wet conditions. This is due to the combined effect of several mechanisms, including tolerance triggered by inherent properties of MSW, i.e., high salt concentrations and slow cell growth, and the deactivation of antibiotics due to physicochemical properties of MSW. Remarkably, we also find evidence for a cross-protection effect, where addition of lethal doses of antibiotic before drying significantly increases cells’ survival under MSW. As wet-dry cycles with MSW and beta-lactams, as well as other antibiotics, are common in vast terrestrial microbial habitats, our findings are expected to have significant implications for how we understand antibiotic response, population dynamics, and interspecies interactions in these globally important microbial ecosystems.
TiPS: rapidly simulating trajectories and phylogenies from compartmental models
Authors: Danesh Gonché , Saulnier Emma , Gascuel Olivier , Choisy Marc , Alizon Samuel 
Published: November 2020

AbstractWe introduceTiPS, an R package to generate trajectories and phylogenetic trees associated with a compartmental model. Trajectories are simulated using Gillespie’s exact or approximate stochastic simulation algorithm, or a newly-proposed mixed version of the two. Phylogenetic trees are simulated from a trajectory under a backwards-in-time approach (i.e. coalescent).TiPSis based on theRcpppackage, allowing to combine the flexibility of R for model definition and the speed of C++ for simulations execution. The model is defined in R with a set of reactions, which allow capturing heterogeneity in life cycles or any sort of population structure.TiPSconverts the model into C++ code and compiles it into a simulator that is interfaced in Rviaa function. Furthermore, the package allows defining time periods in which the model’s parameters can take different values. This package is particularly well suited for population genetics and phylodynamics studies that need to generate a large number of phylogenies used for population dynamics studies. This package is available on the CRAN athttps://cran.r-project.org/package=TiPS.
Glymphatic function in the gyrencephalic brain
Authors: Bèchet Nicholas Burdon , Shanbhag Nagesh C. , Lundgaard Iben 
Published: November 2020

ABSTRACTIdentification of the perivascular compartment as the point of exchange between cerebrospinal fluid (CSF) and interstitial fluid mediating solute clearance in the brain, named the glymphatic system, has emerged as an important clearance pathway for neurotoxic peptides such as amyloid-beta. However, the foundational science of the glymphatic system is based on rodent studies. Here we investigated whether the glymphatic system exists in a large mammal with a highly gyrified brain. CSF penetration into the brain via perivascular pathways, a hallmark of glymphatic function, was seen throughout the gyrencephalic cortex and subcortical structures, validating the conservation of the glymphatic system in a large mammal. Macroscopic CSF tracer distribution followed the sulci and fissures showing that the gyri enhance CSF dispersion. Three-dimensional renditions from light sheet microscopy showed that CSF influx through perivascular spaces was 4-fold more extensive in the pig brain than in mice. This demonstrates the existence of an advanced solute transport system in the gyrencephalic brain that could be utilised therapeutically for enhancing waste clearance.
Beneficent and maleficent effects of cations on bufadienolide binding to Na+,K+-ATPase
Authors: Ladefoged Lucy K. , Schiøtt Birgit , Fedosova Natalya U. 
Published: November 2020

AbstractKinetic properties and crystal structures of the Na+,K+-ATPase in complex with cardiotonic steroids (CTS) revealed significant differences between CTS subfamilies (Laursen et al., 2015): beneficial effects of K+on bufadienolide binding strongly contrasted with K+/cardenolide antagonism. To solve this riddle we applied docking and molecular dynamics simulations of the complexes involving Na+,K+-ATPase, bufadienolides (bufalin, cinobufagin), and ions (K+, Na+, Mg2+). The results revealed that bufadienolide binding is affected by i) electrostatic attraction of the lactone ring by a cation, and ii) the ability of a cation to stabilize and “shape” the site constituted by transmembrane helices of the α-subunit (αM1-6). The latter effect was due to varying coordination patterns involving amino acid residues from helix bundles αM1-4 and αM5-10. Substituents on the steroid core of a bufadienolide add to and modify the cation effects. The above rationale is fully consistent with the ion effects on the kinetics of Na+,K+-ATPase/bufadienolide interactions.
Effects of sea ice and wind speed on Phytoplankton spring bloom in Central and Southern Baltic Sea
Authors: Pärn Ove , Lessin Gennadi , Stips Adolf 
Published: November 2020

AbstractIn this study, the effects of sea ice and wind speed on the timing and composition of phytoplankton spring bloom in the central and southern Baltic Sea are investigated by a hydrodynamic–biogeochemical model and observational data. The modelling experiment compared the results of a reference run in the presence of sea ice with those of a run in the absence of sea ice, which confirmed that ecological conditions differed significantly for both the scenarios. It has been found that diatoms dominate the phytoplankton biomass in the absence of sea ice, whereas dinoflagellates dominate the biomass in the presence of thin sea ice. The study concludes that under moderate ice conditions (representing the last few decades), dinoflagellates dominate the spring bloom phytoplankton biomass in the Baltic Sea, whereas diatoms will be dominant in the future as a result of climate change i.e. in the absence of sea ice..
Soil microbial community responses to short-term nitrogen addition in China’s Horqin Sandy Land
Authors: Yayi Niu , Yulong Duan , Yuqiang Li , Xuyang Wang , Yun Chen , Lilong Wang 
Published: November 2020

AbstractAnthropogenic nitrogen (N) addition has increased soil nutrient availability, thereby affecting ecosystem processes and functions in N-limited ecosystems. Long-term N addition decreases plant biodiversity, but the effects of short-term N addition on soil microbial community is poorly understood. The present study examined the impacts of short-term N addition (NH4NO3) on these factors in a sandy grassland and semi-fixed sandy land in the Horqin Sandy Land. We measured the responses of soil microbial biomass C and N; on soil β-1,4-glucosidase (BG) and β-1,4-N-acetylglucosaminidase (NAG) activity; and soil microflora characteristics to N additions gradient with 0 (control), 5 (N5), 10 (N10), and 15 (N15) g N m−2yr−1. The soil microbial biomass indices, NAG activity, and soil microflora characteristics did not differ significantly among the N levels, and there was no difference at the two sites. The competition for N between plants and soil microbes was not eliminated by short-term N addition due to the low soil nutrient and moisture contents, and the relationships among the original soil microbes did not change. However, N addition increased BG activity in the N5 and N10 additions in the sandy grassland, and in the N5, N10, and N15 additions in the semi-fixed sandy land. This may be due to increased accumulation and fixation of plant litter into soils in response to N addition, leading to increased microbial demand for a C source and increased soil BG activity. Future research should explore the relationships between soil microbial community and N addition at the two sites.
Target-Decoy MineR for determining the biological relevance of variables in noisy data sets
Authors: Ovando-Vázquez Cesaré , Cázarez-García Daniel , Winkler Robert 
Published: November 2020

AbstractMachine learning algorithms excavate important variables from biologicalbig data. However, deciding on the biological relevance of identified variables is challenging. The addition of artificial noise, ‘decoy’ variables, to raw data, ‘target’ variables, enables calculating a false-positive rate (FPR) and a biological relevance probability (BRp) for each variable rank. These scores allow the setting of a cut-off for informative variables can be defined, depending on the required sensitivity/ specificity of a scientific question. We demonstrate the function of theTarget-Decoy MineR(TDM) with synthetic data and with experimental metabolomics results. The Target-Decoy MineR is suitable for different types of quantitative data in tabular format. An implementation of the algorithm in R is freely available fromhttps://bitbucket.org/cesaremov/targetdecoy_mining/.
Novel proteostasis reporter mouse reveals different effects of cytoplasmic and nuclear aggregates on protein quality control in neurons
Authors: Blumenstock Sonja , Schulz-Trieglaff Elena Katharina , Bolender Anna-Lena , Voelkl Kerstin , Lapios Paul , Lindner Jana , Hipp Mark S. , Hartl F. Ulrich , Klein Rüdiger , Dudanova Irina 
Published: November 2020

AbstractThe cellular protein quality control machinery is important for preventing protein misfolding and aggregation, and decline in protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how proteostasis capacity of neurons changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice forin vivoanalysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc), a conformationally unstable protein that requires chaperones for proper folding and sensitively reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked impairment in proteostasis in tauopathy mice, but not in Huntington’s disease mice. Mechanistic investigations in primary neuronal cultures demonstrate that cytoplasmic, but not nuclear, aggregates cause defects of cellular protein quality control. Thus, the Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.
Theta rhythmicity governs the timing of behavioral and hippocampal responses in humans specifically during memory-dependent tasks
Authors: Wal Marije ter , Domingo Juan Linde , Lifanov Julia , Roux Frederic , Kolibius Luca , Gollwitzer Stephanie , Lang Johannes , Hamer Hajo , Rollings David , Sawlani Vijay , Chelvarajah Ramesh , Staresina Bernhard , Hanslmayr Simon , Wimber Maria 
Published: November 2020

1.SummaryMemory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding or retrieval of cue-object associative memories. We found no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz), while responses from later forgotten trials do not lock to the behavioral oscillation. Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but only for correctly remembered trials, providing a mechanistic underpinning for the theta oscillations found in behavioral responses.
Oligodendrocyte secreted factors shape hippocampal GABAergic neuron transcriptome and physiology
Authors: Mazuir Elisa , Richevaux Louis , Nassar Merie , Robil Noémie , de la Grange Pierre , Lubetzki Catherine , Fricker Desdemona , Sol-Foulon Nathalie 
Published: November 2020

ABSTRACTOligodendrocytes form myelin for central nervous system axons and release factors which signal to neurons during myelination. Here, we ask how oligodendroglial factors influence hippocampal GABAergic neuron physiology. In mixed hippocampal cultures GABAergic neurons fired action potentials of short duration and received high frequencies of excitatory synaptic events. In purified neuronal cultures without glial cells, GABAergic neuron excitability increased and the frequency of synaptic events decreased. These effects were largely reversed by adding oligodendrocyte conditioned medium. We compared the transcriptomic signature with the electrophysiological phenotype of single neurons in these three culture conditions. Genes expressed by single pyramidal or GABAergic neurons largely conformed to expected cell-type specific patterns. Multiple genes of GABAergic neurons were significantly downregulated by the transition from mixed cultures containing glial cells to purified neuronal cultures. Levels of these genes were restored by the addition of oligodendrocyte conditioned medium to purified cultures. Clustering genes with similar changes in expression between different culture conditions revealed processes affected by oligodendroglial factors. Enriched genes are linked to roles in synapse assembly, action potential generation and transmembrane ion transport, including of zinc. These results provide new insight into the molecular targets by which oligodendrocytes influence neuron excitability and synaptic function.
Human antigen-specific memory natural killer cell responses develop against HIV-1 and influenza virus and are dependent on MHC-E restriction
Authors: Jost Stephanie , Lucar Olivier , Yoder Taylor , Kroll Kyle , Sugawara Sho , Smith Scott , Jones Rhianna , Tweet George , Werner Alexandra , Tomezsko Phillip J. , Dugan Haley L. , Ghofrani Joshua , Altfeld Marcus , Grundhoff Adam , Muller-Trutwin Michaela , Goepfert Paul , Reeves R. Keith 
Published: November 2020

ABSTRACTFor over a decade, multiple studies have disputed the notion of natural killer (NK) cells as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including two critical global health priorities – HIV and influenza. However, the mechanisms underlying antigen specificity remain unknown. Herein, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism firmly dependent on the activating CD94/NKG2C receptor and its ligand HLA-E, and confirm these findings by three rigorous and novel assays. We validated the permanent acquisition of antigen-specificity by individual memory NK cells by single-cell cloning. We identified biomarkers of antigen-specific NK cell memory through RNA-Seq transcriptomic fingerprints and complex immunophenotyping by 30-parameter flow cytometry showing elevated expression of KLRG1, α4β7 and NKG2C. Finally, we show individual HLA-E-restricted peptides that may constitute the dominant response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms behind formation of antigen-specific memory NK cells, and suggest they could be targeted for future vaccines, cure strategies, or other therapeutic interventions.
Evolution of the genetic architecture of local adaptations under genetic rescue is determined by mutational load and polygenicity
Authors: Zhang Yulin , Stern Aaron J. , Nielsen Rasmus 
Published: November 2020

AbstractInbred populations often suffer from heightened mutational load and decreased fitness due to lower efficiency of purifying selection at small effective population size. Genetic rescue (GR) is a tool that is studied and deployed with the aim of increasing fitness of such inbred populations. The success of GR is known to depend on certain factors that may vary between different populations, such as their demographic history and distribution of dominance effects of mutations. While we understand the effects of these factors on the evolution of overall ancestry in the inbred population after GR, it is less clear what the effect is on local adaptations and their genetic architecture. To this end, we conduct a population genetic simulation study evaluating the effect of several different factors on the efficacy of GR including trait complexity (Mendelian vs. polygenic), dominance effects, and demographic history. We find that the effect on local adaptations depends highly on the mutational load at the time of GR, which is shaped dynamically by interactions between demographic history and dominance effects of deleterious variation. While local adaptations are generally restored post-GR in the long run, in the short term they are often compromised in the process of purging deleterious variation. We also show that while local adaptations are almost always fully restored, the degree to which ancestral genetic variation comprising the trait is replaced by donor variation can vary drastically, and is especially high for complex traits. Our results provide considerations for practical GR and its effects on trait evolution.
Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan
Authors: Kaya Alaattin , Phua Cheryl Zi Jin , Lee Mitchell , Wang Lu , Tyshkovskiy Alexander , Ma Siming , Barre Benjamin , Liu Weiqiang , Harrison Benjamin R. , Zhao Xiaqing , Zhou Xuming , Wasko Brian M. , Bammler Theo K. , Promislow Daniel E. , Kaeberlein Matt , Gladyshev Vadim N. 
Published: November 2020

AbstractTo understand the genetic basis and selective forces acting on longevity, it is useful to examine lifespan variation among closely related species, or ecologically diverse isolates of the same species, within a controlled environment. In particular, this approach may lead to understanding mechanisms underlying natural variation in lifespan. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered a wide diversity of replicative lifespan. Phylogenetic analyses pointed to genes and environmental factors that strongly interact to modulate the observed aging patterns. We then identified genetic networks causally associated with natural variation in replicative lifespan across wild yeast isolates, as well as genes, metabolites and pathways, many of which have never been associated with yeast lifespan in laboratory settings. In addition, a combined analysis of lifespan-associated metabolic and transcriptomic changes revealed unique adaptations to interconnected amino acid biosynthesis, glutamate metabolism and mitochondrial function in long-lived strains. Overall, our multi-omic and lifespan analyses across diverse isolates of the same species shows how gene-environment interactions shape cellular processes involved in phenotypic variation such as lifespan.