bluuebunny/crossref_metadata_2025_split huggingface dataset:
All-trans retinoic acid (ATRA) reduces proliferative capacity and Brachyury levels in chordoma cells
Authors: Robinson Helena , McFarlane Ramsay J. , Wakeman Jane A. 
Published: January 2020

AbstractChordoma is a rare bone cancer for which there are no approved drugs. Surgery is the principle treatment but complete resection can be challenging due to the location of the tumours in the spine and therefore finding an effective drug treatment is a pressing unmet clinical need. A major recent study identified the transcription factor Brachyury as the primary vulnerability and drug target in chordoma. Previously, all-trans retinoic acid (ATRA) has been shown to negatively influence expression of the Brachyury gene,TBXT. Here we extend this finding and demonstrate that ATRA lowers Brachyury protein levels in chordoma cells and reduces proliferation of the chordoma cell line U-CH1 as well as causing a morphological change commensurate with differentiation. ATRA is available as a generic drug and is the first line treatment for acute promyelocytic leukaemia (APL). This study implies ATRA could have therapeutic value if repurposed for chordoma.
The wisdom of stalemates: consensus and clustering as filtering mechanisms for improving collective accuracy
Authors: Winklmayr Claudia , Kao Albert B. , Bak-Coleman Joseph B. , Romanczuk Pawel 
Published: January 2020

ABSTRACTGroups of organisms, from bacteria to fish schools to human societies, depend on their ability to make accurate decisions in an uncertain world. Most models of collective decision-making assume that groups reach a consensus during a decision-making bout, often through simple majority rule. In many natural and sociological systems, however, groups may fail to reach consensus, resulting in stalemates. Here, we build on opinion dynamics and collective wisdom models to examine how stalemates may affect the wisdom of crowds. For simple environments, where individuals have access to independent sources of information, we find that stalemates improve collective accuracy by selectively filtering out incorrect decisions. In complex environments, where individuals have access to both shared and independent information, this effect is even more pronounced, restoring the wisdom of crowds in regions of parameter space where large groups perform poorly when making decisions using majority rule. We identify network properties that tune the system between consensus and accuracy, providing mechanisms by which animals, or evolution, could dynamically adjust the collective decision-making process in response to the reward structure of the possible outcomes. Overall, these results highlight the adaptive potential ofstalemale filteringfor improving the decision-making abilities of group-living animals.
Modelling bioactivities of combinations of whole extracts of edibles with a simplified theoretical framework reveals the statistical role of molecular diversity and system complexity in their mode of action and their nearly certain safety
Authors: Mayer Pascal 
Published: January 2020

AbstractNetwork pharmacology and polypharmacology are emerging as novel drug discovery paradigms. The many discovery, safety and regulatory issues they raise may become tractable with polypharmacological combinations of natural compounds found in whole extracts of edible and mixes thereof. The primary goal of this work is to get general insights underlying the innocuity and the emergence of beneficial and toxic activities of combinations of many compounds in general and of edibles in particular. A simplified model of compounds’ interactions with an organism and of their desired and undesired effects is constructed by considering the departure from equilibrium of interconnected biological features. This model allows to compute the scaling of the probability of significant effects relative to nutritional diversity, organism complexity and synergy resulting from mixing compounds and edibles. It allows also to characterize massive indirect perturbation mode of action drugs as a potential novel multi-compound-multi-target pharmaceutical class, coined Ediceuticals when based on edibles. Their mode of action may readily target differentially organisms’ system robustness as such based on differential complexity for discovering nearly certainly safe novel antimicrobials and anti-cancer treatments. This very general model provides also a theoretical framework to several pharmaceutical and nutritional observations. In particular, it characterizes two classes of undesirable effects of drugs, and may question the interpretation of undesirable effects in healthy subjects. It also formalizes nutritional diversity as such as a novel statistical supra-chemical parameter that may contribute to guide nutritional health intervention. Finally, it is to be noted that a similar formalism may be further applicable to model whole ecosystems in general.
Peritonsillar abscess may not always be a complication of acute tonsillitis: A prospective cohort study
Authors: Sanmark Enni , Wikstén Johanna , Välimaa Hannamari , Aaltonen Leena-Maija , Ilmarinen Taru , Blomgren Karin 
Published: January 2020

ABSTRACTThe present study aimed to specify diagnostics for peritonsillar abscesses (PTAs) and to clarify the role of minor salivary glands. This prospective cohort study included 112 patients with acute tonsillitis (AT) and PTA recruited at a tertiary hospital emergency department between February and October 2017. All patients completed a questionnaire concerning their current disease. Serum amylase (S-Amyl) and C-reactive protein (S-CRP) levels, tonsillar findings, and pus aspirate samples and throat cultures were analyzed. Eight of 58 PTA patients (13.8%) had no signs of tonsillar infection. The absence of tonsillar erythema and exudate was associated with low S-CRP (p<0.001) and older age (p<0.001). We also observed an inverse correlation between S-Amyl and S-CRP levels (AT, r= −0.519; PTA, r= −0.353). Therefore, we observed a group of PTA patients without signs of tonsillar infection who had significantly lower S-CRP levels than other PTA patients. These findings support that PTA may be caused by an etiology other than AT. Variations in the S-Amyl levels and a negative correlation between S-Amyl and S-CRP levels may indicate that minor salivary glands are involved in PTA development.LEVEL OF EVIDENCE1b
Optogenetic low-frequency stimulation of dentate granule cells prevents seizure generation in experimental epilepsy
Authors: Paschen E , Elgueta C , Heining K , Vieira DM , Orcinha C , Häussler U , Bartos M , Egert U , Janz P , Haas CA 
Published: January 2020

AbstractMesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy in adults and is typically associated with hippocampal sclerosis and drug-resistant seizures. As an alternative to curative epilepsy surgery, brain stimulation evolves as a promising approach for seizure-interference. However, particularly in MTLE with severe hippocampal sclerosis, current stimulation protocols are often not effective. Here, we show that optogenetic low-frequency stimulation (oLFS) of entorhinal afferents exhibits unprecedented anti-ictogenic effects in chronically epileptic mice. Photostimulation at 1 Hz resulted in an almost complete suppression of focal seizures, independent of the degree of hippocampal sclerosis. Furthermore, by performing oLFS for 30 min before a pro-convulsive stimulus, seizure generalization was successfully prevented. Finally, acute slice experiments revealed a decreased excitability upon oLFS, which may partially explain the observed anti-epileptic effects. Taken together, our results suggest that oLFS of entorhinal afferents constitutes a promising approach for seizure control in MTLE.
How can noise alter neurophysiology in order to improve human behaviour? A combined tRNS and EEG study
Authors: Sheffield James G. , Raz Gal , Sella Francesco , Kadosh Roi Cohen 
Published: January 2020

AbstractRandom noise has been shown to improve the detection of suboptimal signals in humans and machines. Based on that, transcranial random noise stimulation (tRNS) has aimed to improve human behaviour by targeting neuronal activity. To uncover the poorly understood mechanistic underpinnings of tRNS, we recorded electroencephalography data during arithmetic training while delivering active or sham tRNS above the dorsolateral prefrontal cortex (dlPFC). By successfully removing the tRNS artefact in the time and frequency domains, we examined the mechanisms that underlie its behavioural improvement. We found that active tRNS improved arithmetic performance and impacts specific ERPs components that are associated with attentional mechanisms. Furthermore, the tRNS effect was maximal in individuals with suboptimal arithmetic ability and neurophysiological measures of top-down control and excitation/inhibition ratio. These results providing a novel mechanistic explanation for the effect of tRNS on human behaviour and highlight how suboptimal task-specific behaviour and neurophysiology predicts its effect.
ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet mediated degeneration
Authors: Muliyil Sonia , Levet Clémence , Düsterhöft Stefan , Dulloo Iqbal , Cowley Sally , Freeman Matthew 
Published: January 2020

AbstractAnimals have evolved multiple mechanisms to protect themselves from the cumulative effects of age-related cellular damage. Here we reveal an unexpected link between the TNF (tumour necrosis factor) inflammatory pathway, triggered by the metalloprotease ADAM17/TACE, and a lipid droplet (LD)-mediated mechanism of protecting retinal cells from age related degeneration. Loss of ADAM17, TNF and the TNF receptor Grindelwald in pigmented glial cells of theDrosophilaretina leads to age related degeneration of both glia and neurons, preceded by an abnormal accumulation of glial LDs. We show that the glial LDs initially buffer the cells against damage caused by neuronally generated reactive oxygen species (ROS), but that in later life the LDs dissipate, leading to the release of toxic peroxidated lipids. Finally, we demonstrate the existence of a conserved pathway in human iPS-derived microglia-like cells, which are central players in neurodegeneration. Overall, we have discovered a pathway mediated by TNF signalling acting not as a trigger of inflammation, but as a cytoprotective factor in the retina.
Mechanisms of Interaction of Staphylococcus Aureus With Human Mesenchymal Stem Cells and Their Differentiated Phenotypes
Authors: Khamees Nibras , Hill Darryl J. , Kafienah Wael 
Published: January 2020

AbstractMesenchymal stem cells (MSCs) are multipotent cells commonly derived from the bone marrow, adipose tissue and placenta. Human bone marrow derived MSCs migrate to a site of injury, release proinflammatory cytokines and modulate T-cell proliferation. At sites of injury, MSCs may well encounter bacterial pathogens most commonly the Gram positive pathogenStaphylococcus aureus. However, the precise molecular mechanism(s) of this interaction remain to be elucidated. In the present study we aim to show if a direct interaction occurs betweenS. aureusand bone marrow derived MSCs and identify if MSCRAMMs have a role in this interaction. We further aim to compareS. aureusinteraction with cells that differentiate from MSCs, namely; osteoblasts, adipocytes and chondrocytes, since MSCs co-exist in the niche of these cells. Our results showed that S. aureus is able to interact with MSCs in the form of adhesion and invasion to the cells, and that this interaction is largely dependent on the expression of fibronecting-binding protein (FnBP) by S. aureus. We also showed that the same mechanism of interaction to osteoblasts, adipocytes and chondrocytes that are directly differentiated from the same MSCs. Finally, we have found that the presence of 10% FBS in the infection medium is essential as it helps in achieving the best specific bacterial-cell association with the least background association. The results reveals a mechanism of interaction betweenS. aureusand MSCs that could pave the way for therapeutic intervention that minimises the burden of infection in inflammatory diseases.
Trial-by-trial predictions of subjective time from human brain activity
Authors: Sherman Maxine T. , Fountas Zafeirios , Seth Anil K. , Roseboom Warrick 
Published: January 2020

AbstractHuman experience of time exhibits systematic, context-dependent deviations from veridical clock time; for example, time is experienced differently at work than on holiday. Here we test the proposal that differences from clock time in subjective experience of time arise because time estimates are constructed by accumulating the same quantity that guides perception: salient events. Healthy human participants watched naturalistic, silent videos of up to ∼1 minute in duration and estimated their duration while fMRI was acquired. We were able to reconstruct trial-by-trial biases in participants’ duration reports, which reflect subjective experience of time (rather than veridical clock time), purely from salient events in their visual cortex BOLD activity. This was not the case for control regions in auditory and somatosensory cortex, despite being able to predict clock time from all three brain areas. Our results reveal that the information arising during sensory processing of our dynamic environment provides a sufficient basis for reconstructing human subjective time estimates.
Two synthetic 18-way outcrossed populations of diploid budding yeast with utility for complex trait dissection
Authors: Linder Robert A. , Majumder Arundhati , Chakraborty Mahul , Long Anthony 
Published: January 2020

AbstractAdvanced generation multi-parent populations (MPPs) are a valuable tool for dissecting complex traits, having more power than GWAS to detect rare variants, and higher resolution than F2linkage mapping. To extend the advantages of MPPs in budding yeast, we describe the creation and characterization of two outbred MPPs derived from eighteen genetically diverse founding strains. We carried outde novoassemblies of the genomes of the eighteen founder strains, such that virtually all variation segregating between these strains is known and represent those assemblies as Santa Cruz Genome Browser tracks. We discover complex patterns of structural variation segregating amongst the founders, including a large deletion within the vacuolar ATPaseVMA1, several different deletions within the osmosensorMSB2, a series of deletions and insertions atPRM7and the adjacentBSC1, as well as copy number variation at the dehydrogenaseALD2. Resequenced haploid recombinant clones from the two MPPs have a median unrecombined block size of 66kb, demonstrating the population are highly recombined. We pool sequenced the two MPPs to 3270X and 2226X coverage and demonstrate that we can accurately estimate local haplotype frequencies using pooled data. We further down-sampled the poolseq data to ~20-40X and show that local haplotype frequency estimates remain accurate, with median error rate 0.8% and 0.6% at 20X and 40X, respectively. Haplotypes frequencies are estimated much more accurately than SNP frequencies obtained directly from the same data. Deep sequencing of the two populations revealed that ten or more founders are present at a detectable frequency for over 98% of the genome, validating the utility of this resource for the exploration of the role of standing variation in the architecture of complex traits.
Response ofPseudomonas aeruginosato the innate immune system-derived oxidants hypochlorous acid and hypothiocyanous acid
Authors: Farrant Katie V. , Spiga Livia , Davies Jane C. , Williams Huw D. 
Published: January 2020

ABSTRACTPseudomonas aeruginosais a significant nosocomial pathogen and associated with lung infections in cystic fibrosis (CF). Once established,P. aeruginosainfections persist and are rarely eradicated despite the host immune cells producing antimicrobial oxidants, including hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). There is limited knowledge as to howP. aeruginosasenses, responds to, and survives attack from HOCl and HOSCN, and the contribution of such responses to its success as a CF pathogen. We investigated theP. aeruginosaresponse to these oxidants by screening 707 transposon mutants, with mutations in regulatory genes, for altered growth following HOCl exposure. We identified regulators involved in antibiotic resistance, methionine biosynthesis and catabolite repression, and PA14_07340, the homologue of theEscherichia coliHOCl-sensor RclR (30% identical), that were required for HOCl survival. We have shown that RclR (PA14_07340) protects specifically against HOCl and HOSCN stress, and responds to both oxidants by upregulating expression of a putative peroxiredoxin,rclX(PA14_07355). While there was specificity in the transcriptional response to HOCl (231 genes upregulated) and HOSCN (105 genes upregulated) there was considerable overlap, with 74 genes upregulated by both oxidants. These included genes encoding the type III secretion system (T3SS), sulphur and taurine transport, and the MexEF-OprN efflux pump. RclR coordinated the transcriptional response to HOCl and HOSCN, including upregulation of pyocyanin biosynthesis genes, and in response to HOSCN alone RclR downregulated chaperone genes. These data indicate that theP. aeruginosaresponse to HOCl and HOSCN is multifaceted, with RclR playing an essential role.
MicroRNA-574 Regulates FAM210A Expression and Influences Pathological Cardiac Remodeling
Authors: Wu Jiangbin , Subbaiah Kadiam C Venkata , Jiang Feng , Hadaya Omar , Mohan Amy , Yang Tingting , Welle Kevin , Ghaemmaghami Sina , Tang Wai Hong Wilson , Small Eric , Yan Chen , Yao Peng 
Published: January 2020

AbstractAberrant synthesis of mitochondrial proteins impairs cardiac function and causes heart disease. However, the mechanism of regulation of mitochondria encoded protein expression during cardiac disease remains underexplored. Here, we have shown that multiple pathogenic cardiac stressors induce the expression of miR-574 guide and passenger strands (miR-574-5p/3p) in both humans and mice. miR-574 knockout mice exhibit severe cardiac disorder under heart disease-triggering stresses. miR-574-5p/3p mimics that are delivered systematically using nanoparticles reduce cardiac pathogenesis under disease insults. Transcriptome analysis of miR-574-null hearts uncoversFAM210Aas a common target mRNA for both strands of miR-574. The interactome capture and translational state analyses suggest that FAM210A interacts with mitochondrial translation factors and regulates the protein expression of mitochondrial encoded electron transport chain genes. Using a human cardiomyocyte cell culture system, we discover that miR-574 regulates FAM210A expression and modulates mitochondrial encoded protein expression, which influences cardiac remodeling in heart failure.
Protein Targets of Inositol Pyrophosphate (5-IP7) in the parasiteTrypanosoma cruzi
Authors: Mantilla Brian S. , Brown Nathaniel , Fiedler Dorothea , Docampo Roberto 
Published: January 2020

ABSTRACTDiphosphoinositol-5-pentakisphosphate (5-PP-P5), also known as inositol heptakisphosphate (5-IP7), has been described as a high-energy phosphate metabolite that participates in the regulation of multiple cellular processes through protein binding or serine pyrophosphorylation, a post-translational modification involving aβ-phosphoryl transfer. In this study, utilizing an immobilized 5-IP7affinity reagent, we performed pull-down experiments coupled with mass spectrometry identification, and bioinformatic analysis, to reveal 5-IP7-regulated processes in the two proliferative stages of the unicellular parasiteTrypanosoma cruzi. Our protein screen clearly defined two cohorts of putative targets either in the presence of magnesium ions or in metal-free conditions. The highest number of protein targets was detected in the absence of metal ions, with an overrepresentation of proteins involved in purine metabolism, protein phosphorylation, nucleosome assembly, cell redox homeostasis, parasite-surface components, and exocytosis, and only a 37% overlap between the two proliferative stages. In the presence of magnesium, there was a lower enrichment with the isolation of about 30 proteins with overrepresented candidates involved in tRNA amino acylation, phosphate homeostasis, lipid and glucose catabolism, and cell division, and 15% overlap between proliferative stages. To validate the pull-down results, we endogenously tagged four protein candidates and immunopurified them. Among the most interesting targets, we identified a choline/o-acetyltransferase domain-containing phosphoprotein that undergoes 5-IP7-mediated phosphorylation events at a polyserine tract (Ser578-580). We also identified a novel SPX domain-containing phosphoribosyl transferase [EC 2.7.6.1] herein termed as TcPRPS4. Our data revealed new functional roles of 5-IP7in this divergent eukaryote, and provided potential new targets for chemotherapy.
NINJA: an inducible genetic model for creating neoantigensin vivo
Authors: Damo Martina , Fitzgerald Brittany , Lu Yisi , Nader Mursal , William Ivana , Cheung Julie , Connolly Kelli A. , Foster Gena G. , Akama-Garren Elliot , Lee Da-Yae , Chang Greg P. , Gocheva Vasilena , Schmidt Leah M. , Boileve Alice , Wilson Josephine H. , Cui Can , Monroy Isabel , Gokare Prashanth , Cabeceiras Peter , Jacks Tyler , Joshi Nikhil S. 
Published: January 2020

AbstractMouse models with inducible neoantigens have been historically difficult to generate because of leaky expression of antigens in the thymus, which causes central tolerance in developing CD8 and CD4 T cells. Attempts to resolve this problem using existing genetic tools have been unsuccessful. We developed the iNversion INducible Joined neoAntigen (NINJA) mouse model that uses RNA splicing, DNA recombination, and three levels of regulation to prevent neoantigen leakiness and allow tight control over the induction of neoantigen expression. We describe the development of these genetic tools and their use for obtaining tumor cell lines with inducible neoantigen expression. Moreover, we show that the genetic regulation in NINJA mice bypasses central and peripheral tolerance mechanisms and allows for robust endogenous CD8 and CD4 T cells responses upon neoantigen induction in peripheral tissues. Thus, NINJA fills a long-standing gap in the field and will enable studies of how T cells respond to defined neoantigens in the context of peripheral tolerance, autoimmune diseases, and developing tumors.