bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ursolic acid inhibits cell migration and promotes JNK-dependent lysosomal associated cell death in Glioblastoma multiforme cells
Authors: Conway Gillian E. , Zizyte Deimante , Mae Mondala Julie Rose , He Zhonglei , Lynam Lorna , Lecourt Mathilde , Barcia Carlos , Howe Orla , Curtin James F 
Published: March 2020

AbstractUrsolic acid (UA) is a bioactive compound which has demonstrated therapeutic efficacy in a variety of cancer cell lines. UA activates various signalling pathways in Glioblastoma multiforme (GBM), however, the relationship between cell death and migration has yet to be elucidated. UA induces a dose dependent cytotoxic response demonstrated by flow cytometry and biochemical cytotoxicity assays. Inhibitor and fluorescent probe studies demonstrated that UA induces a caspase independent, JNK dependent, mechanism of cell death. Migration studies established that UA inhibits GBM cell migration in a time dependent manner that is independent of the JNK signalling pathway. The cytotoxic insult induced by UA resulted in the formation of acidic vesicle organelles (AVOs), speculating activation of autophagy. However, inhibitor and spectrophotometric analysis demonstrated that autophagy was not responsible for the formation of the AVOs and confocal microscopy identified the AVO’s as lysosomes. Further investigation using isosurface visualisation of confocal imaging determined co-localisation of lysosomes with the previously identified acidic vesicles, thus providing evidence that lysosomes are likely to be playing a role in UA induced cell death.Collectively, our data identifies that UA rapidly induces a lysosomal associated mechanism of cell death in addition to UA acting as an inhibitor of GBM cell migration.Abstract Figure
Role of syndecan-1 in the interaction between dendritic cells and T cells
Authors: Kouwenberg M , Rops A , Bakker-van Bebber M , Diepeveen L , Götte M , Hilbrands L , van der Vlag J 
Published: March 2020

AbstractSyndecan-1 (Sdc-1) is a heparan sulfate proteoglycan that can bind cytokines and chemokines via its heparan sulfate side chains, and has immunomodulatory properties in experimental models. Sdc-1 expression has been reported on dendritic cells (DC) and T cells. The potential role of Sdc-1 in DC - T cell interaction has not been investigated yet. We postulate that Sdc-1 is involved in DC – T cell interaction and may influence graft survival in an allogeneic transplant model.Sdc-1 expression on bone marrow-derived DC and T cells was analyzed by flow cytometry. Unstimulated and LPS stimulated Sdc-1 deficient DC were evaluatedin vitrofor phenotype and stimulatory capacity in mixed lymphocyte reaction. Sdc-1 deficient T cells were evaluated for proliferative capacity and differentiation in a mixed lymphocyte reaction and a proliferation assay. Allograft survival was evaluated in a fully MHC mismatched heterotopic heart transplant model, with either Sdc-1 deficient donors or recipients.Sdc-1 is expressed on the cell surface of unstimulated and LPS matured DC. Sdc-1 deficiency had no effect on expression of co-stimulatory molecules, cytokine production or T cell stimulatory capacity as compared to WT DC. Sdc-1 expression was not detectable on WT T cells, although intracellular Sdc-1 expression could be demonstrated after ConA activation. Sdc-1 deficient T cells showed reduced proliferation upon DC or ConA stimulation and reduced IL-17 production upon ConA stimulation, compared to WT T cells. Sdc-1 deficiency of either allograft or recipient did not prolong allograft survival.In conclusion, Sdc-1 is expressed on the cell surface of DC, where its absence does not affect DC phenotype or T cell stimulatory capacity. Sdc-1 is intracellularly expressed in ConA activated T cells. Sdc-1 deficiency in T cells results in a reduced proliferative responsein vitro, as induced by DC and ConA. Sdc-1 deficiency in donor or recipient does not affect allograft survival.
Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis
Authors: Wu M , Minkowicz S , Dumrongprechachan V , Hamilton P , Xiao L , Kozorovitskiy Y 
Published: March 2020

AbstractEscaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters plasticity, neuromodulatory signaling, and neuronal activity in distributed networks, yet the field lacks a unifying framework for its varied consequences. Here we describe neuromodulatory and plasticity changes following aversive learning by using a learned helplessness paradigm, where ketamine restores escape behavior. Dopaminergic neuron activity in the ventral tegmental area systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine’s effects are blocked by chemogenetic inhibition of dopamine signaling and mimicked by optogenetic activation. We use 2-photon glutamate uncaging/imaging to interrogate structural plasticity in medial prefrontal cortex, revealing that dendritic spinogenesis on pyramidal neurons is both regulated by aversive experience and recovered by ketamine in a dopamine-dependent manner. Together, these data describe recurrent circuits that causally link neuromodulatory dynamics, aversive learning, and plasticity enhancements driven by a therapeutically promising antidepressant.
Soil-microbes-mediated invasional meltdown in plants
Authors: Zhang Zhijie , Liu Yanjie , Brunel Caroline , van Kleunen Mark 
Published: March 2020

AbstractWhile most alien species fail to establish, some invade native communities and become widespread. Many of these communities have been invaded by multiple aliens, suggesting that aliens may cause invasional meltdowns. Here, we tested whether and how a third plant species affects the competitive outcome between alien and native plants through its soil legacy. We first conditioned soil with one of ten species (six natives and four aliens) or without plants. Then, we grew on these 11 soils, five aliens and five natives without competition, and with intra- or interspecific competition (all pairwise alien-native combinations). We found that aliens were not more competitive than natives when grown on soil conditioned by other natives or on non-conditioned soil. However, aliens were more competitive than natives on soil conditioned by other aliens. Although soil conditioning rarely affected the strength of competition between later plants, soil conditioned by aliens changed the competitive outcomes by affecting growth of aliens less negatively than that of natives. Microbiome analysis confirmed this finding by showing that the soil-legacy effects of one species on later species were less negative when their fungal endophyte communities were less similar; and that fungal endophyte communities were less similar between two aliens than between aliens and natives. Our study suggests that coexistence between aliens and natives is less likely with more alien species. Such invasional meltdown is likely mediated by spill-over of fungal endophytes, some of which are pathogenic.
Exact mapping of Illumina blind spots in theMycobacterium tuberculosisgenome reveals platform-wide and workflow-specific biases
Authors: Modlin Samuel J. , Robinhold Cassidy , Morrissey Christopher , Mitchell Scott N. , Ramirez-Busby Sarah M. , Shmaya Tal , Valafar Faramarz 
Published: March 2020

ABSTRACTWhole genome sequencing (WGS) is fundamental toM. tuberculosisbasic research and many clinical applications. Coverage across Illumina-sequencedM. tuberculosisgenomes is known to vary with sequence context, but this bias is poorly characterized. Here, through a novel application of phylogenomics that distinguishes genuine coverage bias from deletions, we discern Illumina “blind spots” in theM. tuberculosisreference genome for seven sequencing workflows. We find blind spots to be widespread, affecting 529 genes, and provide their exact coordinates, enabling salvage of unaffected regions. Fifty-seven PE/PPE genes (the primary families assumed to exhibit Illumina bias) lack blind spots entirely, while remaining PE/PPE genes account for 55.1% of blind spots. Surprisingly, we find coverage bias persists in homopolymers as short as 6 bp, shorter tracts than previously reported. While GC-rich regions challenge all Illumina sequencing workflows, a modified Nextera library preparation that amplifies DNA with a high-fidelity polymerase markedly attenuates coverage bias in GC-rich and homopolymeric sequences, expanding the “Illumina-sequencable” genome. Through these findings, and by defining workflow-specific exclusion criteria, we spotlight effective strategies for handling bias inM. tuberculosisIllumina WGS. This empirical analysis framework may be used to systematically evaluate coverage bias in other species using existing sequencing data.
Phenotypic Shifts in Neurons of the Dorsal Motor Nucleus of the Vagus Resulting from Chronic Cardiac Ischemia
Authors: Gorky Jonathan , Vadigepalli Rajanikanth , Schwaber James 
Published: March 2020

AbstractHeart disease remains the number one cause of mortality in the world in spite of significant efforts aimed at treatment. The use of vagal stimulation in the treatment of heart failure has shown mixed successes (Dicarlo et al. 2013; Zannad et al. 2015), suggesting that the treatment has potential, but that the mechanism incompletely understood. Vagal activity confers a robust cardioprotective effect in both humans and animal models, preferentially originating specifically from the dorsal motor nucleus of the vagus (DMV) and deriving a significant benefit from intact gut projections, not just cardiac (Shinlapawittayatorn et al. 2013; Mastitskaya et al. 2012; Basalay et al. 2012). In order to examine the DMV response to heart failure, myocardial infarction was induced in male Sprague Dawley rats. DMV neurons were isolated in small pools of single cells using laser capture microdissection 1 week and 3 weeks after infarction and their gene expression assayed. The results show a transcriptional shift towards a neurosecretory phenotype starting at 1 week and increasing in recruitment of neurons to 3 weeks. The LAD ligation shift appears mediated in part by upregulation of Pax4a, a transcription factor most active during stem cell development of neurosecretory cells during embryonic development. This phenotype is characterized by upregulation of Cacna1d (Cav1.3) and Hcn2 along with increased expression of Cck and Sst. This work suggests that the neurons of the DMV adaptively respond to the dynamics present in the periphery, elucidating the means by which the nature of vagal activity responds to heart failure.Significance StatementThe autonomic nervous system plays a significant role in the pathogenesis of cardiovascular disease. Through demonstration of shifting neuronal phenotypes in central neurons in response to peripheral stimuli, we suggest that neuron peptide or neurotransmitter phenotypes are not static in adult rodents. This suggests that even “reflexes” are modifiable dynamic systems. With such plasticity in the transcriptional programming existing in autonomic brain regions there can be new potential therapeutic interventions for cardiovascular disease aimed at leveraging the autonomic nervous system.
A dual-mechanism antibiotic targets Gram-negative bacteria and avoids drug resistance
Authors: Martin James K. , Wilson Maxwell Z. , Moore Gabriel M. , Sheehan Joseph P. , Mateus André , Li Sophia Hsin-Jung , Bratton Benjamin P. , Kim Hahn , Rabinowitz Joshua D. , Typas Athanasios , Savitski Mikhail M. , Gitai Zemer 
Published: March 2020

ABSTRACTThe rise of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. In an animal host model, SCH-79797 reduces pathogenesis ofAcinetobacter baumannii, a drug-resistant Gram-negative pathogen. To characterize the MoA of SCH-79797 we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline shows that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments with other antifolates and membrane disruptors in killing MRSA persisters. Thus, SCH-79797 represents a promising lead antibiotic and suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to target challenging bacterial pathogens.
Filtering Variables for Supervised Sparse Network Analysis
Authors: Towle-Miller Lorin M. , Miecznikowski Jeffrey C. , Zhang Fan , Tritchler David L. 
Published: March 2020

AbstractMotivationWe present a method for dimension reduction designed to filter variables or features such as genes considered to be irrelevant for a downstream analysis designed to detect supervised gene networks in sparse settings. This approach can improve interpret-ability for a variety of analysis methods. We present a method to filter genes and transcripts prior to network analysis. This method has applications in a setting where the downstream analysis may include sparse canonical correlation analysis.ResultsFiltering methods specifically for cluster and network analysis are introduced and compared by simulating modular networks with known statistical properties. Our proposed method performs favorably eliminating irrelevant features but maintaining important biological signal under a variety of different signal settings. We show that the speed and accuracy of methods such as sparse canonical correlation are increased after filtering, thus greatly improving the scalability of these approaches.AvailabilityCode for performing the gene filtering algorithm described in this manuscript may be accessed through the geneFiltering R package available on Github athttps://github.com/lorinmil/geneFiltering. Functions are available to filter genes and perform simulations of a network system. For access to the data used in this manuscript, contact corresponding author.Contactlorinmil@buffalo.edu,jcm38@buffalo.edu,fzhang8@buffalo.edu, anddlt6@buffalo.edu
Progressive changes in hippocampal stem cell properties ensure lifelong neurogenesis
Authors: Harris Lachlan , Rigo Piero , Stiehl Thomas , Gaber Zachary , Austin Sophie H. L. , del Mar Masdeu Maria , Edwards Amelia , Urbán Noelia , Marciniak-Czochra Anna , Guillemot François 
Published: March 2020

SUMMARYNeural stem cell numbers fall rapidly in the hippocampus of juvenile mice but stabilise during adulthood, ensuring lifelong hippocampal neurogenesis. We show that this reduction in stem cell depletion rate is the result of multiple coordinated changes in stem cell behaviour. In particular, while active neural stem cells divide only once or twice before differentiating rapidly in juveniles, they increasingly return to a resting state of shallow quiescence and progress through additional self-renewing divisions in adulthood. Single-cell transcriptomic, mathematical modelling and label-retention analyses indicate that resting cells have a higher activation rate and greater contribution to neurogenesis than dormant cells, which have not left quiescence. These progressive changes in stem cell behaviour result from reduced expression of the pro-activation protein ASCL1 due to increased post-translational degradation. These mechanisms help reconcile current contradictory models of hippocampal NSC dynamics and may contribute to the different rates of decline of hippocampal neurogenesis in mammalian species including humans.
Rapid changes in brain activity during learning of grapheme-phoneme associations in adults
Authors: Xu Weiyong , Kolozsvari Orsolya Beatrix , Oostenveld Robert , Hämäläinen Jarmo Arvid 
Published: March 2020

ABSTRACTLearning to associate written letters with speech sounds is crucial for the initial phase of acquiring reading skills. However, little is known about the cortical reorganization for supporting letter-speech sound learning, particularly the brain dynamics during the learning of grapheme-phoneme associations. In the present study, we trained 30 Finnish participants (mean age: 24.33 years, SD: 3.50 years) to associate novel foreign letters with familiar Finnish speech sounds on two consecutive days (first day ~ 50 minutes; second day ~ 25 minutes), while neural activity was measured using magnetoencephalography (MEG). Two sets of audiovisual stimuli were used for the training in which the grapheme-phoneme association in one set (Learnable) could be learned based on the different learning cues provided, but not in the other set (Control). The learning progress was tracked at a trial-by-trial basis and used to segment different learning stages for the MEG source analysis. The learning-related changes were examined by comparing the brain responses to Learnable and Control uni/multi-sensory stimuli, as well as the brain responses to learning cues at different learning stages over the two days. We found dynamic changes in brain responses related to multi-sensory processing when grapheme-phoneme associations were learned. Further, changes were observed in the brain responses to the novel letters during the learning process. We also found that some of these learning effects were observed only after memory consolidation the following day. Overall, the learning process modulated the activity in a large network of brain regions, including the superior temporal cortex and the dorsal (parietal) pathway. Most interestingly, middle- and inferior-temporal regions were engaged during multi-sensory memory encoding after the cross-modal relationship was extracted from the learning cues. Our findings highlight the brain dynamics and plasticity related to the learning of letter-speech sound associations and provide a more refined model of grapheme-phoneme learning in reading acquisition.
Site-specific machine learning predictive fertilization models for potato crops in Eastern Canada
Authors: Coulibali Zonlehoua , Cambouris Athyna Nancy , Parent Serge-Étienne 
Published: March 2020

1AbstractStatistical modeling is commonly used to relate the performance of potato (Solanum tuberosumL.) to fertilizer requirements. Prescribing optimal nutrient doses is challenging because of the involvement of many variables including weather, soils, land management, genotypes, and severity of pests and diseases. Where sufficient data are available, machine learning algorithms can be used to predict crop performance. The objective of this study was to predict tuber yield and quality (size and specific gravity) as impacted by nitrogen, phosphorus and potassium fertilization as well as weather, soils and land management variables. We exploited a data set of 273 field experiments conducted from 1979 to 2017 in Quebec (Canada). We developed, evaluated and compared predictions from a hierarchical Mitscherlich model,k-nearest neighbors, random forest, neuronal networks and Gaussian processes. Machine learning models returned R2values of 0.49–0.59 for tuber marketable yield prediction, which were higher than the Mitscherlich model R2(0.37). The models were more likely to predict medium-size tubers (R2= 0.60–0.69) and tuber specific gravity (R2= 0.58–0.67) than large-size tubers (R2= 0.55–0.64) and marketable yield. Response surfaces from the Mitscherlich model, neural networks and Gaussian processes returned smooth responses that agreed more with actual evidence than discontinuous curves derived fromk-nearest neighbors and random forest models. When marginalized to obtain optimal dosages from dose-response surfaces given constant weather, soil and land management conditions, some disagreements occurred between models. Due to their built-in ability to develop recommendations within a probabilistic risk-assessment framework, Gaussian processes stood out as the most promising algorithm to support decisions that minimize economic or agronomic risks.
Varicella zoster virus encodes a viral decoy RHIM to inhibit cell death
Authors: Steain Megan , Baker Max O.D.G. , Pham Chi L.L. , Gambin Yann , Sierecki Emma , McSharry Brian P. , Avdic Selmir , Slobedman Barry , Sunde Margaret , Abendroth Allison 
Published: March 2020

AbstractHerpesviruses are known to encode a number of inhibitors of host cell death, including Rip Homotypic Interaction Motif (RHIM)-containing proteins. Varicella zoster virus (VZV) is a member of the alphaherpesvirus subfamily and is responsible for causing chickenpox and shingles. We have identified a novel viral RHIM in the VZV capsid triplex protein open reading frame (ORF) 20 that acts as a host cell death inhibitor. Like the human cellular RHIMs in RIPK1 and RIPK3 that stabilise the necrosome in TNF-induced necroptosis, and the viral RHIM in M45 from murine cytomegalovirus that inhibits cell death, the ORF20 RHIM is capable of forming fibrillar functional amyloid complexes. Notably, the ORF20 RHIM forms hybrid amyloid complexes with human ZBP1, a cytoplasmic sensor of viral nucleic acid. Although VZV can inhibit TNF-induced necroptosis, the ORF20 RHIM does not appear to be responsible for this inhibition. In contrast, the ZBP1 pathway is identified as important for VZV infection. Mutation of the ORF20 RHIM renders the virus incapable of efficient spread in ZBP1-expressing HT-29 cells, an effect which can be reversed by the inhibition of caspases. Therefore we conclude that the VZV ORF20 RHIM is important for preventing ZBP1-driven apoptosis during VZV infection, and propose that it mediates this effect by sequestering ZBP1 into decoy amyloid assemblies.Author SummaryRip homotypic interaction motifs (RHIMs) are found in host proteins that can signal for programmed cell death and in viral proteins that can prevent it. Complexes stabilized by intermolecular interactions involving RHIMs have a fibrillar amyloid structure. We have identified a novel RHIM within the ORF20 protein expressed by Varicella zoster virus (VZV) that forms amyloid-based complexes with human cellular RHIMs. Whereas other herpesvirus RHIMs inhibit TNF-driven necroptosis, this new VZV RHIM targets the host RHIM-containing protein ZBP1 to inhibit apoptosis during infection. This is the first study to demonstrate the importance of the ZBP1 pathway in VZV infection and to identify the role of a viral RHIM in apoptosis inhibition. It broadens our understanding of host defense pathways and demonstrates how a decoy amyloid strategy is employed by pathogens to circumvent the host response.
Major stages of vertebrate adaptive radiation are assembled from a disparate spatiotemporal landscape
Authors: Richards Emilie J. , McGirr Joseph A. , Wang Jeremy R. , St. John Michelle E. , Poelstra Jelmer W. , Solano Maria J. , O’Connell Delaney C. , Turner Bruce J. , Martin Christopher H. 
Published: March 2020

AbstractTo investigate the origins and stages of vertebrate adaptive radiation, we reconstructed the spatial and temporal histories of genetic variants underlying major phenotypic axes of diversification from the genomes of 202 Caribbean pupfishes. Ancient standing variation from disparate spatial sources was reassembled into new combinations which are under strong selection for adaptation to novel trophic niches on only a single island throughout the Caribbean. This occurred in three stages: first, standing variation associated with feeding behavior swept, then standing variation regulating craniofacial development and pigmentation, and finally de novo variation for craniofacial development. Our results provide clear support for two longstanding hypotheses about adaptive radiation and demonstrate how ancient alleles maintained for millennia in distinct environmental refugia can be assembled into new adaptive combinations.One Sentence SummaryAncient origins of adaptive radiation