bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural studies reveal that endosomal cations promote formation of infectious CVA9 A particles, facilitating RNA and VP4 release
Authors: Domanska Aušra , Plavec Zlatka , Ruokolainen Visa , Löflund Benita , Marjomäki Varpu , Butcher Sarah J 
Published: September 2022

AbstractCoxsackievirus A9, an enterovirus, is a common cause of paediatric aseptic meningitis and neonatal sepsis. During cell entry, enterovirus capsids undergo conformational changes leading to expansion, formation of large pores, externalization of VP1 N-termini and loss of the lipid factor from VP1. Factors such as receptor binding, heat, and acidic pH can trigger capsid expansion in some enteroviruses. Here we show that fatty-acid free bovine serum albumin or neutral endosomal ionic conditions can independently prime CVA9 for expansion and genome release. Our results show that CVA9 treatment with albumin or endosomal ions generates a heterogeneous population of virions, which could be physically separated by asymmetric flow field flow fractionation and computationally by cryo-EM and image processing. We report cryo-EM structures of CVA9 A-particles obtained by albumin or endosomal ion treatment and a control non-expanded virion to 3.5, 3.3 and 2.9 Å resolutions, respectively. Where albumin promotes stabile expanded virions, the endosomal ionic concentrations induce unstable CVA9 virions which easily disintegrate losing their genome. Loss of most of the VP4 molecules and exposure of negatively-charged amino acid residues in the capsid’s interior after expansion, create a repulsive viral RNA-capsid interface, aiding genome release.ImportanceCoxsackievirus A9 (CVA9) is a common cause of meningitis and neonatal sepsis. The triggers and mode of action of RNA release into the cell unusually do not require receptor interaction. Rather, a slow process in the endosome, independent of low pH is required. Here, we show by biophysical separation, cryogenic electron microscopy and image reconstruction that albumin and buffers mimicking the endosomal ion composition can separately and together expand and prime CVA9 for uncoating. Furthermore, we show in these expanded particles that VP4 is present at only ~10% of the occupancy found in the virion, VP1 is externalised and the genome is repelled by the negatively-charged, repulsive inner surface of the capsid that occurs due to the expansion. Thus, we can now link observations from cell biology of infection with the physical processes that occur in the capsid to promote genome uncoating.
Head and Neck Cancer-derived small extracellular vesicles sensitize TRPV1+ neurons to mediate cancer pain
Authors: Inyang Kufreobong E. , Evans Christine M. , Heussner Matthew , Petroff Margaret , Reimers Mark , Vermeer Paola D. , Tykocki Nathan , Folger Joseph K. , Laumet Geoffroy 
Published: September 2022

SummarySevere pain is often experienced by patients with head and neck cancer and is associated with a poor prognosis. Despite its frequency and severity, current treatments fail to adequately control cancer-associated pain, because of our lack of mechanistic understanding. Cancer-derived small extracellular vesicles (Cancer-sEVs) are well- positioned to function as mediators of communication between cancer cells and neurons. Inhibition of Cancer-sEV release attenuated pain in tumor-bearing mice. Injection of purified Cancer-sEVs is sufficient to induce pain hypersensitivity in naïve mice. Cancer-sEVs triggered calcium influx in nociceptors and inhibition or ablation of nociceptors protect against cancer pain. Interrogation of published sequencing data of human sensory neurons exposed to human Cancer-sEVs suggested a stimulation of protein translation in neurons. Induction of translation by Cancer-sEVs was validated in our mouse model and its inhibition alleviated cancer pain in mice. These findings define a role of Cancer-sEVs in cancer pain and identify several druggable targets.Graphical abstract
Cystathionine gamma lyase overexpression enhances neovascularization through NAD-dependent mechanisms
Authors: Kiesworo Kevin , MacArthur Michael R , Kip Peter , Agius Thomas , Macabrey Diane , Lambelet Martine , Hamard Lauriane , Ozaki C.-Keith , Mitchell James R , Déglise Sebastian , Mitchell Sarah J , Allagnat Florent , Longchamp Alban 
Published: September 2022

ABSTRACTObjectiveHydrogen sulfide (H2S) is a proangiogenic gas produced primarily by the transsulfuration enzyme cystathionine-gamma-lyase (CGL). CGL-dependant H2S production is required for neovasculariation in models of peripheral arterial disease. However, the benefits of increasing endogenous CGL and its mechanism of action have yet to be elucidated.Methods10 weeks old male whole-body CGL overexpressing mice (CGLTg) and wild type littermates (C57BL/6J) were subjected to the hindlimb ischemia model. Functional recovery was assessed through treadmill exercise endurance testing, while ischemic leg perfusion recovery was measured by laser Doppler perfusion imaging and tissue immunohistochemistry. To examine angiogenic potential, aortic ring sprouting assay and post-natal mouse retinal vasculature development studies were performed. Lastly, comparative metabolomics, NAD+/NADH analysis, and quantitative real-time PCR were performed on WT and CGLTg gastrocnemius muscles.ResultsThe restoration of blood flow upon femoral ligation occurred more rapidly in CGLTg mice. CGLTg mice were able to run further and for longer compared to WT mice. In ischemic gastrocnemius, capillary density was increased in mice overexpressing CGL. Endothelial cell sprouting was increased in aorta isolated from CGLTg mice, especially when cultured in VEGF-only media. Metabolomics analysis demonstrated an increased presence of niacinamide, a precursor of nicotinamide adenine dinucleotide (NAD+/ NADH) in the muscle of CGLTg mice. Finally, CGL overexpression and NMN supplementation improved endothelial cell migration in vitro.ConclusionsTaken together, our results demonstrate that CGL overexpression improves the neovascularization of skeletal muscle upon hindlimb ischemia. These effects are mediated by changes in the NAD pathway, which improves endothelial cell migration.
Bayesian optimization for demographic inference
Authors: Noskova Ekaterina , Borovitskiy Viacheslav 
Published: September 2022

AbstractMotivationInference of demographic histories of species and populations is one of the central problems in population genetics. It is usually stated as an optimization problem: find a model’s parameters that maximize a certain log-likelihood. This log-likelihood is often expensive to evaluate in terms of time and hardware resources, critically more so for larger population counts. Although genetic algorithm based solution have proven efficient for demographic inference in the past, it struggles to deal with log-likelihoods in the setting of more than three populations. Different tools are therefore needed to handle such scenarios.ResultsWe introduce a new specialized optimization pipeline for demographic inference with time-consuming log-likelihood evaluations. It is based on Bayesian optimization, a prominent technique for optimizing expensive black box functions. Comparing to the existing widely used genetic algorithm solution, we demonstrate new pipeline’s superiority in time limited conditions for demographic inference with four and five populations when using log-likelihoods provided by the moments tool. Moreover, we expect this behavior to generalize just as well to other expensive-to-evaluate log-likelihood functions in the field.AvailabilityThe proposed method was implemented as part of the GADMA software framework and is freely and openly available on GitHub: https://github.com/ctlab/GADMA.Contactekaterina.e.noskova@gmail.com, viacheslav.borovitskiy@gmail.comSupplementary informationSupplementary materials are available as a separate document.
Reactive astrocyte derived extracellular vesicles promote functional repair post stroke
Authors: Xin Shangjing , Zhang Lucy , Phan Nhi V. , Carmichael S. Thomas , Segura Tatiana 
Published: September 2022

AbstractReactive astrocytes are both neurotoxic and pro-regenerative. Their reparative roles after injury have been demonstrated, but how they play a contributing role to regeneration remains question. Here, we investigate the use of astrocytic extracellular vesicles from primary astrocytes cultured in reactive conditions in promoting repair after ischemic stroke. Our studies show that extracellular vesicles derived from reactive astrocytes that co-express a significant number of reactive genes (155 upregulated including log2 of 9.61 forLcn2) and axonal outgrowth genes (59 upregulated including log2 of 3.49Ntn1) are necessary for improved regenerative outcomes, including axonal infiltration, vascularization, and improved behavioral recovery. Proteomic analysis of the extracellular vesicles show that astrocytes enrich pro-reparative proteins in extracellular vesicles with only 30 proteins relating to inflammatory or complement pathways loaded out of a total of 1073 proteins. Further, we show that the use of a biomaterial scaffold is necessary for the improved regeneration observed from reactive astrocyte extracellular vesicles. These studies show that reactive astrocytes use extracellular vesicles enriched with pro-repair proteins to promote recovery after injury.
Transcriptomic analysis of seed development in Paysonia auriculata (Brassicaceae) identifies genes involved in hydroxy fatty acid biosynthesis and seed maturation
Authors: Hu Hao , Swift Armond , Mauro-Herrera Margarita , Borrone James , Borja Guadalupe , Doust Andrew N. 
Published: September 2022

AbstractPaysonia auriculata (Brassicaceae) produces multiple hydroxy fatty acids as major components of the seed oil. We tracked the changes in seed oil composition and gene expression during development, starting 14 days after flowers had been pollinated. Seed oil changes showed initially higher levels of saturated and unsaturated fatty acids (FAs) but little accumulation of hydroxy fatty acids (HFAs). Starting 21 days after pollination (DAP) HFA content sharply increased, and reached almost 30% at 28 DAP. Total seed oil also increased from a low of approximately 2% at 14 DAP to a high of approximately 20% by 42 DAP. We identified almost all of the fatty acid synthesis and modification genes that are known from Arabidopsis, and, in addition, a strong candidate for the hydroxylase gene that mediates the hydroxylation of fatty acids to produce valuable hydroxy fatty acids (HFAs) in this species. The gene expression network revealed is very similar to that of the emerging oil crop, Physaria fendleri, in the sister genus to Paysonia. Phylogenetic analyses indicate the hydroxylase enzyme, FAH12, evolved only once in Paysonia and Physaria, and that the enzyme is closely related to FAD2 enzymes. Phylogenetic analyses of FAD2 and FAH12 in the Brassicaceae and outgroup genera suggest that the branch leading to the hydroxylase clade of Paysonia and Physaria is under relaxed selection, compared with the strong purifying selection found across the FAD2 lineages.
Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats
Authors: Hardy Delphine , Buhler Emmanuelle , Suchkov Dmitrii , Vinck Antonin , Fortoul Aurélien , Watrin Françoise , Represa Alfonso , Minlebaev Marat , Manent Jean-Bernard 
Published: September 2022

AbstractMalformations of cortical development represent a major cause of epilepsy in childhood. However, the pathological substrate and dynamic changes leading to the development and progression of epilepsy remain unclear. Here, we characterized an etiology-relevant rat model of subcortical band heterotopia (SBH), a diffuse type of cortical malformation associated with drug-resistant seizures in humans. We used longitudinal electrographic recordings to monitor the age-dependent evolution of epileptiform discharges during the course of epileptogenesis in this model. We found both quantitative and qualitative age-related changes in seizures properties and patterns, accompanying a gradual progression towards a fully developed seizure pattern seen in adulthood. We also dissected the relative contribution of the band heterotopia and the overlying cortex to the development and age-dependent progression of epilepsy using timed and spatially targeted manipulation of neuronal excitability. We found that an early suppression of neuronal excitability in SBH slows down epileptogenesis in juvenile rats, whereas epileptogenesis is paradoxically exacerbated when excitability is suppressed in the overlying cortex. However, in rats with active epilepsy, similar manipulations of excitability have no effect on chronic spontaneous seizures. Together, our data support the notion that complex developmental alterations occurring in both the SBH and the overlying cortex concur to creating pathogenic circuits prone to generate seizures. Our study also suggests that early and targeted interventions could potentially influence the course of these altered developmental trajectories, and favorably modify epileptogenesis in malformations of cortical development.Abstract Figure
Cross-tissue multiomics studies reveal gut-brain interactions mediating the effect of Akkermansia muciniphila in counteracting fructose-induced obesity
Authors: Ha Sung Min , Ahn In-Sook , Kowal-safron Thomas , Yoon Justin , Diamante Graciel , Cely Ingrid , Zhang Guanglin , Wang Susana , Yang Xia 
Published: September 2022

SummaryThe gut bacterium Akkermansia muciniphila (A. muciniphila) has been implicated in anti-obesity effects, but a systems level understanding of the molecular mechanisms is lacking. We carried out multiomics studies to investigate the molecular cascades mediating the anti-obesity effect of A. muciniphila in a fructose-induced obesity mouse model. We found that A. muciniphila colonization triggered significant shifts in gut microbiota composition, gut and plasma metabolites, and gene expression in hypothalamic neurons. Multiomics integration and network analysis prioritized the metabolite oleoyl-ethanolamide (OEA) in the gut and circulation as a regulator of gut-brain interactions that underlie the A. muciniphila anti-obesity effect. Oral administration of OEA counteracted the fructose-induced obesity through the regulation of hypothalamic anorexigenic neuropeptides such as oxytocin and arginine vasopressin. Our multiomics investigation and experimental validation elucidates the molecular regulators and pathways involved in the communication between A. muciniphila in the gut and hypothalamic neurons that counter fructose-induced obesity.
No evidence for associations between brood size, gut microbiome diversity and survival in great tit (Parus major) nestlings
Authors: Liukkonen M. , Hukkanen M. , Cossin-Sevrin N. , Stier A. , Vesterinen E. , Grond K. , Ruuskanen S. 
Published: September 2022

ABSTRACTBackgroundThe gut microbiome forms at an early stage, yet data on the environmental factors influencing the development of wild avian microbiomes is limited. As the gut microbiome is a vital part of organismal health, it is important to understand how it may connect to host performance. The early studies with wild gut microbiome have shown that the rearing environment may be of importance in gut microbiome formation, yet the results vary across taxa, and the effects of specific environmental factors have not been characterized. Here, wild great tit (Parus major) broods were manipulated to either reduce or enlarge the original brood soon after hatching. We investigated if brood size was associated with nestling bacterial gut microbiome, and whether gut microbiome diversity predicted survival. Fecal samples were collected at mid-nestling stage and sequenced with the 16S rRNA gene amplicon sequencing, and nestling growth and survival were measured.ResultsGut microbiome diversity showed high variation between individuals, but this variation was not significantly explained by brood size or body mass. Additionally, we did not find a significant effect of brood size on body mass or gut microbiome composition. We also demonstrated that early handling had no impact on nestling performance or gut microbiome. Furthermore, we found no significant association between gut microbiome diversity and short-term (survival to fledging) or mid-term (apparent juvenile) survival.ConclusionsWe found no clear association between early-life environment, offspring condition and gut microbiome. This suggests that brood size is not a significantly contributing factor to great tit nestling condition, and that other environmental and genetic factors may be more strongly linked to offspring condition and gut microbiome. Future studies should expand into other early-life environmental factors e.g., diet composition and quality, and parental influences.
A three-strain synthetic community model whose rapid response to antagonism allows the study of higher-order dynamics and emergent properties in minutes
Authors: Aguilar-Salinas Bernardo , Olmedo-Álvarez Gabriela 
Published: September 2022

ABSTRACTA fundamental question in the assembly of microbial communities is how complex systems arise from a few components. Synthetic communities allow addressing the dynamics and mechanisms of complex microbial interactions. Most studies on microbial interactions are done in lapses of hours and even days, but microbes must be able to sense danger in seconds. We assembled a three-strain synthetic community from the phylum Bacillota that, based on previously evaluated paired interactions, appear to have different ecological roles: resistant (R), antagonists (A), and sensitive (S). The BARS synthetic community (Bacillota A + S + R) reproduces features of complex communities and exhibits higher-order interaction dynamics. The majority of the S strain population, Sutclifiella horikoshii 20a, dies within 5 min in a paired interaction with A strain, Bacillus pumilus 145. An emergent property appears upon adding the third interactor, as antagonism of strain A over S is not observed in the presence of the R strain, Bacillus cereus 111. After the first five min a change of state of the cells is observed, as the surviving population of the S strain seemed to have acquired tolerance to A. In summary, our model allows the study of the assembly dynamics of a three-species community and to evaluate the immediate outcome within a 30 min frame. The BARS has features of a complex system where the paired interactions do not predict the community dynamics. The model is amenable to mechanistic dissection and to modeling how the parts integrate to achieve collective properties.1IMPORTANCEMicrobial communities are of utmost importance, given their roles in health, agriculture, and all biogeochemical cycles on Earth. Synthetic ecology studies communities by reducing the number of variables. Microbial interactions are usually evaluated in hours or days, however, upon a first encounter, bacteria must respond in minutes, particularly when competition involves killing of neighboring cells. We generated a synthetic community of three species that allows the study of community dynamics in a 30 min frame. We denominated our model BARS as it comprises Bacillota strains that in paired interactions are Antagonist, Resistant, or Sensitive. Even though in paired interaction the antagonist kills the sensitive strain, in a triple interaction, the resistant strain provides stability to the community by neutralizing the antagonism. Therefore, BARS is a rapid response model with features of a complex system where the paired interactions do not predict the community dynamics and exhibit emergent properties.
The piRNA clustertorimochiis an expanding transposon in cultured silkworm cells
Authors: Shoji Keisuke , Umemura Yusuke , Tomari Yukihide 
Published: September 2022

ABSTRACTPIWI proteins and PIWI-interacting RNAs (piRNAs) play a central role in repressing transposable elements in animal germ cells. It is thought that piRNAs are mainly produced from discrete genomic loci named piRNA clusters, which often contain many “dead” transposon remnants from past invasions and have heterochromatic features. In the genome of silkworm ovary-derived cultured cells called BmN4, a well-established model for piRNA research,torimochiwas previously annotated as a unique and specialized genomic region that can capture transgenes and produce new piRNAs bearing a trans-silencing activity. However, the sequence identity oftorimochihas remained elusive. Here, we carefully characterizedtorimochiby utilizing the updated silkworm genome sequence and the long-read sequencer MinION. We found thattorimochiis in fact a full-length gypsy-like LTR retrotransposon, which is exceptionally active and has massively expanded its copy number in BmN4 cells. Many copies oftorimochiin BmN4 cells have features of open chromatin and the ability to produce piRNAs. Therefore,torimochimay represent a young, growing piRNA cluster, which is still “alive” and active in transposition yet capable of trapping other transposable elements to producede novopiRNAs. (185 words)
Natural statistics of head roll: implications for Bayesian inference in spatial orientation
Authors: Willemsen Sophie C.M.J. , Wijdenes Leonie Oostwoud , van Beers Robert J. , Koppen Mathieu , Medendorp W. Pieter 
Published: September 2022

AbstractWe previously proposed a Bayesian model of multisensory integration in spatial orientation (1). Using a Gaussian prior, centered on an upright head orientation, this model could explain various perceptual observations in roll-tilted participants, such as the subjective visual vertical, the subjective body tilt (1), the rod-and-frame effect (2), as well as their clinical (3) and age-related deficits (4). Because it is generally assumed that the prior reflects an accumulated history of previous head orientations, and recent work on natural head motion suggests non-Gaussian statistics, we examined how the model would perform with a non-Gaussian prior. In the present study, we first experimentally generalized the previous observations in showing that also the natural statistics of head orientation are characterized by long tails, best quantified as a t-location-scale distribution. Next, we compared the performance of the Bayesian model and various model variants using such a t-distributed prior to the original model with the Gaussian prior on their accounts of previously published data of the subjective visual vertical and subjective body tilt tasks. All of these variants performed substantially worse than the original model, suggesting a special value of the Gaussian prior. We provide computational and neurophysiological reasons for the implementation of such a prior, in terms of its associated precision–accuracy trade-off in vertical perception across the tilt range.New & NoteworthyIt has been argued that the brain uses Bayesian computations to process multiple sensory cues in vertical perception, including a prior centered on upright head orientation which is usually taken to be Gaussian. Here, we show that non-Gaussian prior distributions, although more akin to the statistics of head orientation during natural activities, provide a much worse explanation of such perceptual observations than a Gaussian prior.