bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic diversity and global distribution of Saccharomyces eubayanus, the wild ancestor of hybrid lager-brewing yeasts
Authors: Langdon Quinn K. , Peris David , Eizaguirre Juan I. , Opulente Dana A. , Buh Kelly V. , Sylvester Kayla , Jarzyna Martin , Rodríguez María E. , Lopes Christian A. , Libkind Diego , Hittinger Chris Todd 
Published: July 2019

AbstractS. eubayanus, the wild, cold-tolerant parent of hybrid lager-brewing yeasts, has a complex and understudied natural history. The exploration of this diversity can be used both to develop new brewing applications and to enlighten our understanding of the dynamics of yeast evolution in the wild. Here, we integrate whole genome sequence and phenotypic data of 200 S. eubayanus strains, the largest collection to date. S. eubayanus has a multilayered population structure, consisting of two major populations that are further structured into six subpopulations. Four of these subpopulations are found exclusively in the Patagonian region of South America; one is found predominantly in Patagonia and sparsely in Oceania and North America; and one is specific to the Holarctic ecozone. S. eubayanus is most abundant and genetically diverse in Patagonia, where some locations harbor more genetic diversity than is found outside of South America. All but one subpopulation shows isolation-by-distance, and gene flow between subpopulations is low. However, there are strong signals of ancient and recent outcrossing, including two admixed lineages, one that is sympatric with and one that is mostly isolated from its parental populations. Despite S. eubayanus’ extensive genetic diversity, it has relatively little phenotypic diversity, and all subpopulations performed similarly under most conditions tested. Using our extensive biogeographical data, we constructed a robust model that predicted all known and a handful of additional regions of the globe that are climatically suitable for S. eubayanus, including Europe. We conclude that this industrially relevant species has rich wild diversity with many factors contributing to its complex distribution and biology.
Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration
Authors: Stuebler Antonia G. , Jansen Michaela 
Published: July 2019

AbstractBupropion, a FDA-approved antidepressant and smoking cessation aid, blocks dopamine and norepinephrine reuptake transporters and non-competitively inhibits nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT3) receptors. 5-HT3 receptors are pentameric ligand-gated ion channels that regulate synaptic activity in the central and peripheral nervous system pre- and postsynaptically. In the present study, we examined and compared the effect of bupropion and its active metabolite hydroxybupropion on homomeric 5-HT3A and heteromeric mouse 5-HT3AB receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp experiments. Co-application of bupropion or hydroxybupropion with 5-HT dose-dependently inhibited 5-HT-induced currents in 5-HT3ABRs (IC50 = 866 μM and 505 μM, respectively) but potentiated 5-HT-induced currents at low (30-50 μM) concentrations. The corresponding IC50s for bupropion and hydroxybupropion with 5-HT3AR were 10- and 5-fold lower, respectively (87 μM and 113 μM), and no potentiation was observed. The inhibition of 5-HT3AR and 5-HT3ABR was non-use dependent and voltage-independent, indicating bupropion is not an open channel blocker. The inhibition by bupropion was reversible and time-dependent. Of note, pre-incubation with a low concentration of bupropion that mimics therapeutic drug conditions significantly inhibited 5-HT induced currents in 5-HT3A and even more so 5-HT3AB receptors. In summary, our results indicate that bupropion inhibits 5-HT3ABR, as well as homomeric receptors, and that this inhibition takes place at clinically-relevant concentrations. Inhibition of 5-HT3 receptors by bupropion may contribute to its desired and/or undesired clinical effects.Significance Statement5-HT3AB receptors are found in brain areas involved in mood regulation. Clinical studies indicate that antagonizing these receptors was successful in treating mood and anxiety disorders. Some currently clinically available antidepressants and antipsychotics act as antagonists of 5-HT3 receptors. Previously, bupropion was shown to be an antagonist at homopentameric 5-HT3A receptors. The present work provides novel insights into the pharmacological effects bupropion exerts on heteromeric 5-HT3AB receptors. The results advance the knowledge on the clinical effect of bupropion as an antidepressant.
The AGE receptor, OST48 drives podocyte foot process effacement and basement membrane expansion in experimental diabetic kidney disease via promotion of endoplasmic reticulum stress
Authors: Zhuang Aowen , Yap Felicia YT , McCarthy Domenica , Penfold Sally A. , Sourris Karly C. , Coughlan Melinda T. , Schulz Benjamin L , Forbes Josephine M 
Published: July 2019

AbstractThe accumulation of advanced glycation end products is implicated in the development and progression of diabetic kidney disease. No study has examined whether stimulating advanced glycation clearance via receptor manipulation is reno-protective in diabetes. Podocytes, which are early contributors to diabetic kidney disease and could be a target for reno-protection. To examine the effects of increased podocyte oligosaccharyltransferase-48 on kidney function, glomerular sclerosis, tubulointerstitial fibrosis and proteome (PXD011434), we generated a mouse with increased oligosaccharyltransferase-48kDa subunit abundance in podocytes driven by the podocin promoter. Despite increased urinary clearance of advanced glycation end products, we observed a decline in renal function, significant glomerular damage including glomerulosclerosis, collagen IV deposition, glomerular basement membrane thickening and foot process effacement and tubulointerstitial fibrosis. Analysis of isolated glomeruli identified enrichment in proteins associated with collagen deposition, endoplasmic reticulum stress and oxidative stress. Ultra-resolution microscopy of podocytes revealed denudation of foot processes where there was co-localization of oligosaccharyltransferase-48kDa subunit and advanced glycation end-products. These studies indicate that increased podocyte expression of oligosaccharyltransferase-48kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function.
Eukaryotic virus composition can predict the efficiency of carbon export in the global ocean
Authors: Kaneko Hiroto , Blanc-Mathieu Romain , Endo Hisashi , Chaffron Samuel , Delmont Tom O. , Gaia Morgan , Henry Nicolas , Hernández-Velázquez Rodrigo , Nguyen Canh Hao , Mamitsuka Hiroshi , Forterre Patrick , Jaillon Olivier , de Vargas Colomban , Sullivan Matthew B. , Suttle Curtis A. , Guidi Lionel , Ogata Hiroyuki 
Published: July 2019

SummaryThe biological carbon pump, in which carbon fixed by photosynthesis is exported to the deep ocean through sinking, is a major process in Earth’s carbon cycle. The proportion of primary production that is exported is termed the carbon export efficiency (CEE). Based on in-lab or regional scale observations, viruses were previously suggested to affect the CEE (i.e., viral “shunt” and “shuttle”). In this study, we tested associations between viral community composition and CEE measured at a global scale. A regression model based on relative abundance of viral marker genes explained 67% of the variation in CEE. Viruses with high importance in the model were predicted to infect ecologically important hosts. These results are consistent with the view that the viral shunt and shuttle functions at a large scale and further imply that viruses likely act in this process in a way dependent on their hosts and ecosystem dynamics.
PgRC: Pseudogenome based Read Compressor
Authors: Kowalski Tomasz , Grabowski Szymon 
Published: July 2019

AbstractMotivationThe amount of sequencing data from High-Throughput Sequencing technologies grows at a pace exceeding the one predicted by Moore’s law. One of the basic requirements is to efficiently store and transmit such huge collections of data. Despite significant interest in designing FASTQ compressors, they are still imperfect in terms of compression ratio or decompression resources.ResultsWe present Pseudogenome-based Read Compressor (PgRC), an in-memory algorithm for compressing the DNA stream, based on the idea of building an approximation of the shortest common superstring over high-quality reads. Experiments show that PgRC wins in compression ratio over its main competitors, SPRING and Minicom, by up to 18 and 21 percent on average, respectively, while being at least comparably fast in decompression.AvailabilityPgRC can be downloaded from https://github.com/kowallus/PgRC.Contacttomasz.kowalski@p.lodz.pl
Optogenetics reveals Cdc42 local activation by scaffold-mediated positive feedback and Ras GTPase
Authors: Lamas Iker , Merlini Laura , Vještica Aleksandar , Vincenzetti Vincent , Martin Sophie G 
Published: July 2019

AbstractThe small GTPase Cdc42 is critical for cell polarization. Scaffold-mediated positive feedback regulation was proposed to mediate symmetry-breaking to a single active zone in budding yeast cells. In rod-shaped fission yeast S. pombe cells, active Cdc42-GTP localizes to both cell poles, where it promotes bipolar growth. Here, we implement the CRY2-CIBN optogenetic system for acute light-dependent protein recruitment to the plasma membrane, which allowed to directly demonstrate positive feedback. Indeed, optogenetic recruitment of constitutively active Cdc42 leads to co-recruitment of the GEF Scd1, in a manner dependent on the scaffold protein Scd2. We show that Scd2 function is completely bypassed and positive feedback restored by an engineered interaction between the GEF and a Cdc42 effector, the Pak1 kinase. Remarkably, such re-wired cells are viable and grow in a bipolar manner even when lacking otherwise essential Cdc42 activators. Interestingly, these cells reveal that Ras1 GTPase plays a dual role in localizing and activating the GEF, thus potentiating the feedback. We conclude that scaffold-mediated positive feedback, gated by Ras activity, is minimally required for rod-shape formation.
Shared genetic underpinnings between genetic generalized epilepsy and background EEG oscillations
Authors: Stevelink Remi , Luykx Jurjen J. , Lin Bochao D. , Leu Costin , Lal Dennis , Smith Alexander , Schijven Dick , Carpay Johannes A. , Rademaker Koen , Baldez Roiza A. Rodrigues , Devinsky Orrin , Braun Kees P.J. , Jansen Floor E. ,   ILAE Consortium on Complex Epilepsies,   Epi25 Collaborative, Smit Dirk , Koeleman Bobby P.C. 
Published: July 2019

AbstractObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a GWAS on epilepsy (n=12,803 people with epilepsy and 24,218 controls) with that from a GWAS on background EEG (n=8,425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta and theta. We replicated our findings in an independent epilepsy replication dataset (n=4851 people with epilepsy and 20,428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations between genetic generalized epilepsy (GGE) with background EEG oscillations, primarily with the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic work-up of epilepsy.
Infant diet promotesBifidobacteriumcommunity cooperation within a single ecosystem
Authors: Lawson Melissa AE , O’Neill Ian J , Kujawska Magdalena , Wijeyesekera Anisha , Flegg Zak , Chalklen Lisa , Hall Lindsay J 
Published: July 2019

AbstractDiet-microbe interactions play an important role in modulating the early life microbiota, withBifidobacteriumstrains and species dominating the gut microbiota of breast-fed infants. Here, we sought to explore how infant diet drives distinct bifidobacterial community composition and dynamics within individual infant ecosystems. Genomic characterisation of 19 strains isolated from breast-fed infants revealed a diverse genomic architecture enriched in carbohydrate metabolism genes, which was distinct to each strain, but collectively formed a pangenome across infants. Presence of gene clusters implicated in digestion of human milk oligosaccharides (HMOs) varied between species, with growth studies indicating within infant differences in the ability to utilise 2’FL and LNnT HMOs between strains. We also performed cross-feeding experiments using metabolic products from growth on 2’FL or LNnT for non-HMO degrading isolates, these compounds were identified to include fucose, galactose, acetate and N-acetylglucosamine. These data highlight the cooperative nature of individual bifidobacterial ‘founder’ strains within an infant ecosystem, and how sharing resources maximises nutrient consumption from the diet. We propose that this social behaviour contributes to the diversity and dominance ofBifidobacteriumin early life and suggests avenues for development of new diet and microbiota based therapies to promote infant health.
Comparison of Chemotherapy Effects on Mechanical Sensitivity and Food-Maintained Operant Responding in Male and Female Rats
Authors: Legakis LP , Diester CM , Townsend EA , Karim-Nejad L , Negus SS 
Published: July 2019

AbstractObjectiveChemotherapies of varying classes often cause neuropathy and debilitating chemotherapy-induced neuropathic pain (CINP) sufficient to limit treatment and reduce quality of life for many patients battling cancer. There are currently no effective preventative or alleviative treatments for CINP. Preclinical models have been developed to test candidate CINP treatments; however, studies using these models rarely provide direct comparisons of effects of different chemotherapies or assess the degree to which chemotherapies produce clinically relevant signs of pain-depressed behavior.MethodsMale and female Sprague-Dawley rats received four injections of vehicle, paclitaxel, oxaliplatin, vincristine, or bortezomib on alternate days. Mechanical hypersensitivity, body weight, and food-maintained operant responding were evaluated before, during, and for up to 42 days after initiation of treatment. Morphine potency and effectiveness to reverse chemotherapy-induced effects were also evaluated.ResultsAll four chemotherapies produced dose-dependent and sustained mechanical hypersensitivity in all rats. Vincristine and oxaliplatin produced transient weight loss and decreases in food-maintained operant responding in all rats, whereas paclitaxel and bortezomib produced lesser or no effect. At four weeks after treatment, operant responding was depressed only in paclitaxel-treated males. Morphine reversed mechanical hypersensitivity in all rats but failed to reverse paclitaxel-induced depression of operant responding in males.ConclusionsChemotherapy treatments sufficient to produce sustained mechanical hypersensitivity failed to produce sustained or morphine-reversible behavioral depression in rats. Insofar as pain-related behavioral depression is a cardinal sign of CINP in humans, these results challenge the presumption that these chemotherapy-dosing regimens are sufficient to model clinically relevant CINP in rats.
Regulation of neuronal mRNA splicing and Tau isoform ratio by ATXN3 through deubiquitylation of splicing factors
Authors: Neves-Carvalho Andreia , Duarte-Silva Sara , Silva Joana M. , Meireles-Costa Liliana , Monteiro-Fernandes Daniela , Correia Joana S. , Rodrigues Beatriz , Heetveld Sasja , Almeida Bruno , Savytska Natalia , Da Silva Jorge Diogo , Teixeira-Castro Andreia , Sotiropoulos Ioannis , Carvalho Ana Luísa , Heutink Peter , Li Ka Wan , Maciel Patrícia 
Published: July 2019

AbstractThe ubiquitylation/deubiquitylation balance in cells is maintained by deubiquitylating enzymes, including ATXN3. The precise role of this protein, mutated in spinocerebellar ataxia type 3 (SCA3), remains elusive, as few substrates for its deubiquitylating activity were identified. Here, we characterized the ubiquitome of neuronal cells lacking ATXN3, and found altered polyubiquitylation in a large proportion of proteins involved in RNA metabolism, including splicing factors. Using transcriptomic analysis and reporter minigenes we confirmed that splicing was globally altered in these cells. Among the candidate targets of ATXN3 was SRSF7 (9G8), a key regulator of MAPT (Tau) exon 10 splicing. Loss-of-function of ATXN3 led to reduced SRSF7 levels and a deregulation of MAPT exon 10 splicing, resulting in a decreased 4R/3R-Tau ratio. Similar alterations were found in cellular models of expanded polyQ ATXN3 and SCA3 patient brains, pointing to a relevant role of this mechanism in SCA3, and establishing a previously unsuspected link between two key proteins involved in different neurodegenerative disorders.
Collagen hydrogel confinement of amyloid-βaccelerates aggregation and reduces cytotoxic effects
Authors: Simpson Laura W. , Szeto Gregory L. , Boukari Hacene , Good Theresa A. , Leach Jennie B. 
Published: July 2019

AbstractAlzheimer’s disease (AD) is the most common form of dementia and is associated with the accumulation of amyloid-β (Aβ), a peptide whose aggregation has been associated with neurotoxicity. Drugs targeting Aβ have shown great promise in 2Din vitromodels and mouse models, yet preclinical and clinical trials for AD have been highly disappointing. We propose that currentin vitroculture systems for discovering and developing AD drugs have significant limitations; specifically, that Aβ aggregation is vastly different in these 2D cultures carried out on flat plastic or glass substrates vs. in a 3D environment, such as brain tissue, where Aβ confinement very likely alters aggregation kinetics and thermodynamics. In this work, we identified attenuation of Aβ cytotoxicity in 3D hydrogel culture compared to 2D cell culture. We investigated Aβ structure and aggregation in solution vs. hydrogel using Transmission Electron Microscopy (TEM), Fluorescence Correlation Spectroscopy (FCS), and Thioflavin T (ThT) assays. Our results reveal that the equilibrium is shifted to stable β-sheet aggregates in hydrogels and away from the relatively unstable/unstructured presumed toxic oligomeric Aβ species in solution. Volume exclusion imparted by hydrogel confinement stabilizes unfolded, presumably toxic species, promoting stable extended β-sheet fibrils. These results, taken together with the many recent reports that 3D hydrogel cell cultures enable cell morphologies and epigenetic changes that are more similar to cellsin vivocompared to 2D cultures, strongly suggest that AD drugs should be tested in 3D culture systems as a step along the development pathway towards new, more effective therapeutics.
Listeria monocytogenesexploits the MICOS complex subunit Mic10 to promote mitochondrial fragmentation and cellular infection
Authors: Carvalho Filipe , Spier Anna , Chaze Thibault , Matondo Mariette , Cossart Pascale , Stavru Fabrizia 
Published: July 2019

AbstractMitochondrial function adapts to cellular demands and is affected by the ability of the organelle to undergo fusion and fission in response to physiological and non-physiological cues. We previously showed that infection with the human bacterial pathogenListeria monocytogeneselicits transient mitochondrial fission and a drop in mitochondrial-dependent energy production through a mechanism requiring the bacterial pore-forming toxin listeriolysin O (LLO). Here, we performed quantitative mitochondrial proteomics to search for host factors involved inL. monocytogenes-induced mitochondrial fission. We found that Mic10, a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex, is significantly enriched in mitochondria isolated from cells infected with wild-type but not with LLO-deficientL. monocytogenes. Increased mitochondrial Mic10 levels did not correlate with upregulated transcription, suggesting a post-transcriptional regulation. We showed that Mic10 is necessary forL. monocytogenes-induced mitochondrial network fragmentation, and that it contributes toL. monocytogenescellular infection independently of MICOS proteins Mic13, Mic26 and Mic27. Together,L. monocytogenesinfection allowed us to uncover a role for Mic10 in mitochondrial fission.ImportancePathogenic bacteria can target host cell organelles to take control of key cellular processes and promote their intracellular survival, growth, and persistence. Mitochondria are essential, highly dynamic organelles with pivotal roles in a wide variety of cell functions. Mitochondrial dynamics and function are intimately linked. Our previous research showed thatListeria monocytogenesinfection impairs mitochondrial function and triggers fission of the mitochondrial network at an early infection stage, in a process that is independent of the main mitochondrial fission protein Drp1. Here, we analyzed how mitochondrial proteins change in response toL. monocytogenesinfection and found that infection raises the levels of Mic10, a mitochondrial inner membrane protein involved in formation of cristae. We show that Mic10 is important forL. monocytogenes-dependent mitochondrial fission and infection of host cells. Our findings thus offer new insight into the mechanisms used byL. monocytogenesto hijack mitochondria to optimize host infection.