bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma
Authors: Weaver Davis T. , Pishas Kathleen I. , Williamson Drew , Scarborough Jessica , Lessnick Stephen L. , Dhawan Andrew , Scott Jacob G. 
Published: November 2019

ABSTRACTMicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of the broad effects miRNAs may have on different cells and tissues, trials of miRNA therapies have struggled due to severe toxicity and unanticipated immune response. In order to overcome this hurdle, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets while avoiding repression of essential housekeeping genes. We first characterized 6 Ewing sarcoma cell lines using mRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential. We then identified miRNAs and combinations of miRNAs that preferentially act to repress mRNA targets with the greatest influence on network potential. Our analysis identified TRIM25, APP, ELAV1, RNF4, and HNRNPL as ideal mRNA targets for Ewing sarcoma therapy. Using predicted miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as candidate optimal miRNAs for preferential repression of these targets. Ultimately, our work, as exemplified in the case of Ewing sarcoma, describes a novel pipeline by which personalized miRNA cocktails can be designed to maximally perturb gene networks contributing to cancer progression.Author SummaryPrecision medicine in cancer aims to find the right treatment, for the right patient, at the right time. Substantial variation between patient tumors, even of the same disease site, has limited the application of precision medicine in the clinic. In this study, we present novel computational tools for the identification of targets for cancer therapy using widely available sequencing data. We used a network-science based approach that leveraged multiple types of ’omic data to identify functionally relevant disease targets. Further, we developed algorithms to identify potential miRNA-based therapies that inhibit these predicted disease targets. We applied this pipeline to a novel Ewing Sarcoma transcriptomics data-set as well as publicly available patient data from the St. Jude Cloud. We identified a number of promising therapeutic targets for this rare disease, including EWSR1, the proposed driver of Ewing Sarcoma development. These novel data and methods will provide researchers with new tools for the development of precision medicine treatments in a variety of cancer systems.
En bloc preparation of Drosophila brains enables high-throughput FIB-SEM connectomics
Authors: Lu Zhiyuan , Xu C. Shan , Hayworth Kenneth J. , Rivlin Patricia , Plaza Stephen M. , Scheffer Louis , Rubin Gerald M. , Hess Harald F. , Meinertzhagen Ian A. 
Published: November 2019

AbstractDeriving the detailed synaptic connections of the entire nervous system has been a long term but unrealized goal of the nascent field of connectomics. For Drosophila, in particular, three sample preparation problems must be solved before the requisite imaging and analysis can even begin. The first is dissecting the brain, connectives, and ventral nerve cord (roughly comparable to the brain, neck, and spinal cord of vertebrates) as a single contiguous unit. Second is fixing and staining the resulting specimen, too large for previous techniques such as flash freezing, so as to permit the necessary automated segmentation of neuron membranes. Finally the contrast must be sufficient to support synapse detection at imaging speeds that enable the entire connectome to be collected. To address these issues, we report three major novel methods to dissect, fix, dehydrate and stain this tiny but complex nervous system in its entirety; together they enable us to uncover a Focused Ion-Beam Scanning Electron Microscopy (FIB-SEM) connectome of the entire Drosophila brain. They reliably recover fixed neurons as round profiles with darkly stained synapses, suitable for machine segmentation and automatic synapse detection, for which only minimal human intervention is required. Our advanced procedures use: a custom-made jig to microdissect both regions of the central nervous system, dorsal and ventral, with their connectives; fixation and Durcupan embedment, followed by a special hot-knife slicing protocol to reduce the brain to dimensions suited to FIB; contrast enhancement by heavy metals; together with a progressive lowering of temperature protocol for dehydration. Collectively these optimize the brain’s morphological preservation, imaging it at a usual resolution of 8nm per voxel while simultaneously speeding the formerly slow rate of FIB-SEM. With these methods we could recently obtain a FIB-SEM image stack of the Drosophila brain eight times faster than hitherto, at approximately the same rate as, but without the requirement to cut, nor imperfections in, EM serial sections.
A Decentralised Neural Model Explaining Optimal Integration of Navigational Strategies in Insects
Authors: Sun Xuelong , Yue Shigang , Mangan Michael 
Published: November 2019

AbstractInsect navigation arises from the coordinated action of concurrent guidance systems but the neural mechanisms through which each functions, and are then coordinated, remains unknown. We propose that insects require distinct strategies to retrace familiar routes (route-following) and directly return from novel to familiar terrain (homing) using different aspects of frequency encoded views that are processed in different neural pathways. We also demonstrate how the Central Complex and Mushroom Bodies regions of the insect brain may work in tandem to coordinate the directional output of different guidance cues through a contextually switched ring-attractor inspired by neural recordings. The resultant unified model of insect navigation reproduces behavioural data from a series of cue conflict experiments in realistic animal environments and offers testable hypotheses of where and how insects process visual cues, utilise the different information that they provide and coordinate their outputs to achieve the adaptive behaviours observed in the wild.
Dopamine and stress signalling interplay patterns social organization in mice
Authors: Battivelli Dorian , Vernochet Cécile , Nguyen Claire , Zayed Abdallah , Meirsman Aura Carole , Messaoudene Sarah , Fieggen Alexandre , Dreux Gautier , Marti Fabio , Contesse Thomas , Barik Jacques , Tassin Jean-Pol , Faure Philippe , Parnaudeau Sébastien , Tronche François 
Published: November 2019

AbstractThe rules leading to the emergence of a social organization and the role of social hierarchy on normal and pathological behaviours remain elusive. Here we show that groups of four isogenic male mice rapidly form enduring social ranks in a dominance hierarchy. Highest ranked individuals display enhanced anxiety and working memory, are more social and more susceptible to stress-related maladaptive behaviours. Are these differences causes or consequences to social life? We show that anxiety emerges from life in colony whereas sociability is a pre-existing trait. Strikingly, highest ranked individuals exhibit lower bursting activity of VTA dopamine neurons. Both pharmacogenetic inhibition of this neuronal population and the genetic inactivation of glucocorticoid receptor signalling in dopamine-sensing brain areas promote the accession to higher social ranks. Altogether, these results indicate that the shaping of social fate relies upon the interplay of dopamine system and stress response, impacting individual behaviour and potentially mental health.
Self-other representation in the social brain reflects social connection
Authors: Courtney Andrea L. , Meyer Meghan L. 
Published: November 2019

Social connection is critical to well-being, yet how the brain reflects our attachment to other people remains largely unknown. We combined univariate and multivariate brain imaging analyses to assess whether and how the brain organizes representations of others based on how connected they are to our own identity. During an fMRI scan, participants (N=43) completed a self- and other-reflection task for 16 targets: the self, five close others, five acquaintances, and five celebrities. In addition, they reported their subjective closeness to each target and their own trait loneliness. We examined neural responses to the self and others in a brain region that has been associated with self-representation (medial prefrontal cortex; MPFC) and across the whole brain. The structure of self-other representation in the MPFC and across the social brain appeared to cluster targets into three social categories: the self, social network members (including close others and acquaintances), and celebrities. Moreover, both univariate activation in MPFC and multivariate self-other similarity in MPFC and across the social brain increased with subjective self-other closeness ratings. Critically, participants who were less socially connected (i.e. lonelier) showed altered self-other mapping in social brain regions. Most notably, in MPFC, loneliness was associated with reduced representational similarity between the self and others. The social brain apparently maintains information about broad social categories as well as closeness to the self. Moreover, these results point to the possibility that feelings of chronic social disconnection may be mirrored by a ‘lonelier’ neural self-representation.Significance StatementSocial connection is critical to well-being, yet how the brain reflects our attachment to people remains unclear. We found that the social brain stratifies neural representations of people based on our subjective connection to them, separately clustering people who are and are not in our social network. Moreover, the people we feel closest to are represented most closely to ourselves. Finally, lonelier individuals also appeared to have a ‘lonelier’ neural self-representation in the MPFC, as loneliness attenuated the closeness between self and other neural representations in this region. The social brain appears to map our interpersonal ties, and alterations in this map may help explain why lonely individuals endorse statements such as ‘people are around me but not with me’.
Ensemble Machine Learning Modeling for the Prediction of Artemisinin Resistance in Malaria
Authors: Ford Colby T. , Janies Daniel 
Published: November 2019

ABSTRACTAntiparasitic resistance in malaria is a growing concern affecting many areas of the eastern world. Since the emergence of artemisinin resistance in the late 2000s in Cambodia, research into the underlying mechanisms has been underway.The 2019 Malaria Dream Challenge posited the task of developing computational models that address important problems in advancing the fight against malaria. The first goal was to accurately predict Artemisinin drug resistance levels of Plasmodium falciparum isolates, as quantified by the IC50. The second goal was to predict the parasite clearance rate of malaria parasite isolates based on in vitro transcriptional profiles.In this work, we develop machine learning models using novel methods for transforming isolate data and handling the tens of thousands of variables that result from these data transformation exercises. This is demonstrated by using massively parallel processing of the data vectorization for use in scalable machine learning. In addition, we show the utility of ensemble machine learning modeling for highly effective predictions of both goals of this challenge. This is demonstrated by the use of multiple machine learning algorithms combined with various scaling and normalization preprocessing steps. Then, using a voting ensemble, multiple models are combined to generate a final model prediction.
Trophic cascade driven by behavioural fine-tuning as naïve prey rapidly adjust to a novel predator
Authors: Jolly Chris J. , Smart Adam S. , Moreen John , Webb Jonathan K. , Gillespie Graeme R. , Phillips Ben L. 
Published: November 2019

AbstractThe arrival of novel predators can trigger trophic cascades driven by shifts in prey numbers. Predators also elicit behavioural change in prey populations, via phenotypic plasticity and/or rapid evolution, and such changes may also contribute to trophic cascades. Here we document rapid demographic and behavioural changes in populations of a prey species (grassland melomys Melomys burtoni, a granivorous rodent) following the introduction of a novel marsupial predator (northern quoll Dasyurus hallucatus). Within months of quolls appearing, populations of melomys exhibited reduced survival and population declines relative to control populations. Quoll-invaded populations (n = 4) were also significantly shyer than nearby, quoll-free populations (n = 3) of conspecifics. This rapid but generalised response to a novel threat was replaced over the following two years with more threat-specific antipredator behaviours (i.e. predator-scent aversion). Predator-exposed populations, however, remained more neophobic than predator-free populations throughout the study. These behavioural responses manifested rapidly in avoidance of seeds associated with quoll scent, with discrimination playing out over a spatial scale of tens of metres. Presumably the significant and novel predation pressure induced by quolls drove melomys populations to fine-tune behavioural responses to be more predator-specific through time. These behavioural shifts could reflect individual plasticity (phenotypic flexibility) in behaviour or may be adaptive shifts from natural selection imposed by quoll predation. Our study provides a rare insight into the rapid ecological and behavioural shifts enacted by prey to mitigate the impacts of a novel predator and shows that trophic cascades can be strongly influenced by behavioural changed rates of seed predation by melomys across treatments. Quoll-invaded melomys populations exhibited lower per-capita seed take rates, and rapidly developed an as well as numerical responses.
Trem-2 modulation of gut microbiota is blunted during hepatotoxic injury and uncoupled from liver repair responses
Authors: Coelho Inês , Duarte Nádia , Macedo Maria Paula , Penha-Gonçalves Carlos 
Published: November 2019

AbstractThe involvement of gut microbiota in liver disease has been addressed in the context of the “leaky gut hypothesis” postulating that dysbiosis allow microbial components to elicit liver inflammatory responses and hepatic tissue damage. Conversely, commensal gut microbiota acting on innate immune receptors protect against hepatotoxic insults. Given that mice deficient for the triggering receptor expressed on myeloid cells-2 (Trem-2) show increased vulnerability to experimental drug-induced hepatic damage we explored the possibility that Trem-2 is a modulator of gut microbiota composition.We found that microbiota composition in untreated Trem-2 KO mice differs from the wild-type showing overall decrease in microbiota diversity and increased representation of Verrucomicrobia. Interestingly, induction of liver damage with hepatotoxic drugs blunted this microbiota diversity difference and altered phyla composition with increased representation of Verrucomicrobia during acute hepatic injury and Proteobacteria during chronic challenge. Furthermore, co-housing experiments that homogenized microbiota diversity showed that the increased liver tissue vulnerability to hepatotoxic insults in Trem-2 KO mice was not dependent on microbiota composition. This work uncouples Trem-2 dependent alterations in gut commensal microbiota from Trem-2 pro-recovery effects in the damaged liver tissue. These findings support the possibility that unlinked actions of innate immune receptors contribute to disease association with microbiota alterations, particularly with the Verrucomicrobia phylum.ImportanceTrem-2 is a mammalian innate immunity receptor involved in development and resolution of tissue damage, namely in the brain and in the liver. Nevertheless, it is not known whether gut microbiota is contributing to these Trem-2 mediated phenotypes. We found that Trem-2 KO mice spontaneously display different gut microbiota composition as compared to wild-type mice, namely with increased abundance of the phylum Verrucomicrobia. Notably these differences do not impact the control of Trem-2 on liver tissue vulnerability to hepatotoxic insults. This work uncouples Trem-2 modulation of gut microbiota and the role of Trem-2 on responses to liver damage. This work brings new insights on role of innate immune receptors on the association of organic and systemic diseases with gut microbiota.
Host community assembly modifies the relationship between host and parasite richness
Authors: Halliday Fletcher W. , Heckman Robert W. , Wilfahrt Peter A. , Mitchell Charles E. 
Published: November 2019

AbstractHost and parasite richness are generally positively correlated, but the stability of this relationship during community assembly remains untested. The composition of host communities can alter parasite transmission, and the relationship between host and parasite richness is sensitive to parasite transmission. Thus, changes in composition during host community assembly could strengthen or weaken the relationship between host and parasite richness. Host community assembly, in turn, can be driven by many processes, including resource enrichment. To test the hypothesis that host community assembly can alter the relationship between host and parasite richness, we experimentally crossed host diversity and resource supply to hosts, then allowed communities to assemble. As previously shown, initial host diversity and resource supply determined the trajectory of host community assembly, altering post-assembly host species richness, richness-independent host phylogenetic diversity, and colonization by exotic host species. Throughout community assembly, host richness predicted parasite richness. As predicted, this effect was moderated by exotic abundance: communities dominated by exotic species exhibited a stronger positive relationship between post-assembly host and parasite richness. Ultimately, these results suggest that, by modulating parasite transmission, community assembly can modify the relationship between host and parasite richness, providing a novel mechanism to explain contingencies in this relationship.
A limited set of transcriptional programs define major cell types
Authors: Breschi Alessandra , Muñoz-Aguirre Manuel , Wucher Valentin , Davis Carrie A. , Garrido-Martín Diego , Djebali Sarah , Gillis Jesse , Pervouchine Dmitri D. , Vlasova Anna , Dobin Alexander , Zaleski Chris , Drenkow Jorg , Danyko Cassidy , Scavelli Alexandra , Reverter Ferran , Snyder Michael P. , Gingeras Thomas R. , Guigó Roderic 
Published: November 2019

AbstractWe have produced RNA sequencing data for a number of primary cells from different locations in the human body. The clustering of these primary cells reveals that most cells in the human body share a few broad transcriptional programs, which define five major cell types: epithelial, endothelial, mesenchymal, neural and blood cells. These act as basic components of many tissues and organs. Based on gene expression, these cell types redefine the basic histological types by which tissues have been traditionally classified. We identified genes whose expression is specific to these cell types, and from these genes, we estimated the contribution of the major cell types to the composition of human tissues. We found this cellular composition to be a characteristic signature of tissues, and to reflect tissue morphological heterogeneity and histology. We identified changes in cellular composition in different tissues associated with age and sex and found that departures from the normal cellular composition correlate with histological phenotypes associated to disease.One Sentence SummaryA few broad transcriptional programs define the major cell types underlying the histology of human tissues and organs.
A commonly used photosynthetic inhibitor fails to block electron flow to photosystem I in intact systems
Authors: Fitzpatrick Duncan , Aro Eva-Mari , Tiwari Arjun 
Published: November 2019

AbstractIn plant science, 2,4-dinitrophenylether of iodonitrothymol (DNP-INT) is frequently used as an alternative to 2,5-dibromo-6-isopropyl-3-methyl-1,4-benzoquinone (DBMIB) to examine the capacity of plastoquinol and semiquinone to reduce O2. DNP-INT is considered an effective inhibitor of the photosynthetic electron transfer chain (PETC) through its binding at the Q0 site of Cyt-b6f. The binding and action of DNP-INT has been previously characterized spectroscopically in purified Cyt-b6f complex reconstituted with Plastocyanin, PSII membranes and plastoquinone, as well as in isolated thylakoids based on its property to block MV-mediated O2 consumption. Contrary to the conclusions made from these experiments, we observed clear reduction of P700+ in samples incubated with DNP-INT during our recent investigation into the sites of oxygen consumption in isolated thylakoids. Therefore, we carried out an extensive investigation of DNP-INT’s chemical efficacy in isolated thylakoids and intact leaves. This included examination of its capacity to block the PETC before PSI, and therefore its inhibition of CO2 fixation. P700 redox kinetics were measured using Dual-PAM whilst Membrane Inlet Mass Spectrometry (MIMS) was used for simultaneous determination of the rates of O2 evolution and O2 consumption in isolated thylakoids and CO2 fixation in intact leaves, using two stable isotopes of oxygen (16O2,18O2) and CO2 (12C,13C), respectively. Based on these investigations we confirmed that DNP-INT is unable to completely block the PETC and CO2 fixation, therefore its use may produce artefacts if applied to isolated thylakoids or intact cells, especially when determining the locations of reactive oxygen species formation in the photosynthetic apparatus.
Murine lupus is Neutrophil Elastase-independent in the MRL.Faslpr model
Authors: Gordon Rachael A. , Tilstra Jeremy S. , Marinov Anthony , Nickerson Kevin M. , Bastacky Sheldon I. , Shlomchik Mark J. 
Published: November 2019

AbstractLoss of tolerance to nuclear antigens and multisystem tissue destruction is a hallmark of systemic lupus erythematosus (SLE). Although the source of autoantigen in lupus remains elusive, a compelling hypothetical source is dead cell debris that drives autoimmune activation. Prior reports suggest that neutrophil extracellular traps (NETs) and their associated death pathway, NETosis, are sources of autoantigen in SLE. However, others and we have shown that inhibition of NETs by targeting the NADPH oxidase complex and peptidylarginine deiminase 4 (PADI4) did not ameliorate disease in spontaneous murine models of SLE. Furthermore, myeloperoxidase and PADI4 deletion did not inhibit induced lupus. Since NET formation may occur independently of any one mediator, to address this controversy, we genetically deleted an additional important mediator of NETs and neutrophil effector function, neutrophil elastase (ELANE), in the MRL.Faslpr model of SLE. ELANE deficiency, and by extension ELANE-dependent NETs, had no effect on SLE nephritis, dermatitis, anti-self response, or immune composition in MRL.Faslpr mice. Taken together with prior data from our group and others, these data further challenge the paradigm that NETs and neutrophils are pathogenic in SLE.