bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression
Authors: Wall Mark J. , Hill Emily , Huckstepp Robert , Barkan Kerry , Deganutti Giuseppe , Leuenberger Michele , Preti Barbara , Winfield Ian , Carvalho Sabrina , Suchankova Anna , Wei Haifeng , Safitri Dewi , Huang Xianglin , Imlach Wendy , La Mache Circe , Dean Eve , Hume Cherise , Hayward Stephanie , Oliver Jess , Zhao Fei-Yue , Spanswick David , Reynolds Christopher A. , Lochner Martin , Ladds Graham , Frenguelli Bruno G. 
Published: April 2020

SummaryThe development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, BnOCPA, is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA’s unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.Short summaryWe describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.
Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation
Authors: Grieve Adam G , Yeh Yi-Chun , Zarcone Lucrezia , Breuning Johannes , Johnson Nicholas , Stříšovský Kvido , Brown Marion H , Parekh Anant B , Freeman Matthew 
Published: April 2020

SummaryCalcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease, RHBDL2. We show that RHBDL2 prevents stochastic signalling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved, disease-linked proline residue is responsible for RHBDL2 recognising only the active conformation of Orai1, and cleavage by RHBDL2 is required to sharpen switch-like signalling triggered by store-operated calcium entry. Loss of RHBDL2 control of Orai1 causes severe dysregulation of CRAC channel effectors including transcription factor activation, inflammatory cytokine expression and T cell activation. We propose that this seek-and-destroy function may represent an ancient activity of rhomboid proteases in degrading unwanted signalling proteins.
Topological Analysis of Differential Effects of Ketamine and Propofol Anesthesia on Brain Dynamics
Authors: Varley Thomas F. , Denny Vanessa , Sporns Olaf , Patania Alice 
Published: April 2020

AbstractResearch has found that the vividness of conscious experience is related to brain dynamics. Despite both being anesthetics, propofol and ketamine produce different subjective states: we explore the different effects of these two anaesthetics on the structure of dynamic attractors reconstructed from electrophysiological activity recorded from cerebral cortex of two macaques. We used two methods: the first embeds the recordings in a continuous high-dimensional manifold on which we use topological data analysis to infer the presence of higher-order dynamics. The second reconstruction, an ordinal partition network embedding, allows us to create a discrete state-transition network, which is amenable to information-theoretic analysis and contains rich information about state-transition dynamics. We find that the awake condition generally had the “richest” structure, visiting the most states, the presence of pronounced higher-order structures, and the least deterministic dynamics. In contrast, the propofol condition had the most dissimilar dynamics, transitioning to a more impoverished, constrained, low-structure regime. The ketamine condition, interestingly, seemed to combine aspects of both: while it was generally less complex than the awake condition, it remained well above propofol in almost all measures. These results provide provides deeper and more comprehensive insights than what is typically gained by using point-measures of complexity.
Automatic subtyping of individuals with Primary Progressive Aphasia
Authors: Themistocleous Charalambos , Ficek Bronte , Webster Kimberly , den Ouden Dirk-Bart , Hillis Argye E. , Tsapkini Kyrana 
Published: April 2020

AbstractBackgroundThe classification of patients with Primary Progressive Aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists.ObjectiveThe aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA.MethodsIn this paper, we present a machine learning model based on Deep Neural Networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as expert clinicians’ classifications.ResultsThe DNN model outperformed the other machine learning models with 80% classification accuracy, providing reliable subtyping of patients with PPA into variants and it even outperformed auditory classification of patients into variants by clinicians.ConclusionsWe show that the combined speech and language markers from connected speech productions provide information about symptoms and variant subtyping in PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick and inexpensive classification of patients with PPA.
Neural dynamics of phoneme sequences: Position-invariant code for content and order
Authors: Gwilliams Laura , King Jean-Remi , Marantz Alec , Poeppel David 
Published: April 2020

AbstractSpeech consists of a continuously-varying acoustic signal. Yet human listeners experience it as a sequence of discrete units (phonemes and words). To identify how the brain continuously represents and updates speech units, we recorded two-hour magnetoencephalograms from 21 subjects listening to short narratives. Our encoding and decoding analyses show that the human brain uses a dynamic coding scheme to represent approximately three successive phonetic features at each time sample. These dynamic phonetic representations, not directly accessible from the acoustic signal, are active earlier when phonemes are more predictable, and are sustained when lexical identity is uncertain. The results reveal how phoneme sequences in natural speech are neurally represented and shed new light on how the human brain combines them to probe the mental lexicon.One sentence summaryThe human brain keeps track of the relative order of speech sound sequences by jointly encoding content and elapsed processing time
Microbial dark matter driven degradation of carbon fiber polymer composites
Authors: Breister Adam M. , Imam Muhammad A. , Zhou Zhichao , Anantharaman Karthik , Prabhakar Pavana 
Published: April 2020

AbstractPolymer composites have become attractive for structural applications in the built environment due to their lightweight and high strength properties but can suffer from degradation due to environmental factors. While impacts of abiotic factors like temperature and moisture are well studied, little is known about the influence of naturally occurring microbial communities on their structural integrity. Here we apply complementary time-series multi-omics of biofilms growing on polymer composites and materials characterization to elucidate, for the first time, the processes driving their degradation. We measured a reduction in mechanical properties due to molecular chain breakage and reconstructed 121 microbial genomes to describe microbial diversity and pathways associated with their degradation. The composite microbiome is dominated by four bacterial groups including the Candidate Phyla Radiation that possess pathways for breakdown of acrylate, esters, and bisphenol, abundant in composites. Overall, we provide a foundation for understanding interactions of next-generation structural materials with their natural environment that can predict their durability and drive future designs.
Neural mechanisms underlying distractor inhibition on the basis of feature and/or spatial expectations
Authors: van Moorselaar Dirk , Daneshtalab Nasim , Slagter Heleen A. 
Published: April 2020

AbstractA rapidly growing body of research indicates that inhibition of distracting information may not be under flexible, top-down control, but instead heavily relies on expectations derived from past experience about the likelihood of events. Yet, how expectations about distracting information influence distractor inhibition at the neural level remains unclear. To determine how expectations induced by distractor features and/or location regularities modulate distractor processing, we measured EEG while participants performed two variants of the additional singleton paradigm. Critically, in these different variants, target and distractor features either randomly swapped across trials, or were fixed, allowing for the development of distractor feature-based expectations. Moreover, the task was initially performed without any spatial regularities, after which a high probability distractor location was introduced. Our results show that both distractor feature- and location regularities contributed to distractor inhibition, as indicated by corresponding reductions in distractor costs during visual search and an earlier distractor-evoked Pd component. Yet, control analyses showed that while observers were sensitive to regularities across longer time scales, the observed effects to a large extent reflected intertrial repetition. Large individual differences further suggest a functional dissociation between early and late Pd components, with the former reflecting early sensory suppression related to intertrial priming and the latter reflecting suppression sensitive to expectations derived over a longer time scale. Also, counter to some previous findings, no increase in anticipatory alpha-band activity was observed over visual regions representing the expected distractor location, although this effect should be interpreted with caution as the effect of spatial statistical learning was also less pronounced than in other studies. Together, these findings suggest that intertrial priming and statistical learning may both contribute to distractor suppression and reveal the underlying neural mechanisms.
CovProfile: profiling the viral genome and gene expressions of SARS-COV-2
Authors: Yu Yonghan , Li Zhengtu , Li Yinhu , Yu Le , Jia Wenlong , Jiang Yiqi , Ye Feng , Li Shuai Cheng 
Published: April 2020

AbstractThe SARS-CoV-2 virus has infected more than one million people worldwide to date. Knowing its genome and gene expressions is essential to understand the virus’ mechanism. Here, we propose a computational tool CovProfile to detect the viral genomic variations as well as viral gene expressions from the sequences obtained from Nanopore devices. We applied CovProfile to 11 samples, each from a terminally ill patient, and discovered that all the patients are infected by multiple viral strains, which might affect the reliability of phylogenetic analysis. Moreover, the expression of viral genes ORF1ab gene, S gene, M gene, and N gene are high among most of the samples. While performing the tests, we noticed a consistent abundance of transcript segments of MUC5B, presumably from the host, across all the samples.
Natural gene drives offer potential pathogen control strategies in plants
Authors: Gardiner Donald M. , Rusu Anca , Barrett Luke , Hunter Gavin C. , Kazan Kemal 
Published: April 2020

SummaryGlobally, fungal pathogens cause enormous crop losses and current control practices are not always effective, economical or environmentally sustainable. Tools enabling genetic management of wild pathogen populations could potentially solve many problems associated with plant diseases.A natural gene drive from a heterologous species can be used in the globally important cereal pathogen,Fusarium graminearum, to remove pathogenic traits from contained populations of the fungus. The gene drive element became fixed in a freely crossing populations in only three generations.Repeat induce point mutation, a natural genome defence mechanism in fungi, may be useful to recall the gene drive following release, should a failsafe mechanism be required.We propose that gene drive technology is a potential tool to control plant pathogens.
Contact lenses can cause the reverse Pulfrich effect and anti-Pulfrich monovision corrections can eliminate it
Authors: Rodriguez-Lopez Victor , Dorronsoro Carlos , Burge Johannes 
Published: April 2020

AbstractInterocular differences in image blur can cause dramatic misperceptions of the distance and three-dimensional direction of moving objects. This new illusion—the reverse Pulfrich effect—is caused by the optical conditions induced by monovision, a common correction for presbyopia. Fortunately, anti-Pulfrich monovision corrections, in which the blurring lens is slightly darkened, can eliminate the illusion for a wide range of viewing conditions. However, the reverse Pulfrich effect and the efficacy of anti-Pulfrich corrections have previously been demonstrated only with trial lenses. This situation should be addressed, for both clinical and scientific reasons. First, monovision is most commonly prescribed with contact lenses. It is important to replicate these effects in the most common monovision delivery system. Second, trial lenses of different powers, unlike contacts, cause large magnification differences between the eyes. To confidently attribute the reverse Pulfrich effect to differences in optical blur between the eyes, and to ensure that the reported effect sizes are reliable, one must control for magnification. Here, in a within observer study with five separate experiments, we demonstrate i) that contact lenses induce reverse Pulfrich effects that are indistinguishable from those induced by trial lenses, ii) that overall magnification differences do not cause or impact the Pulfrich effect, and iii) that anti-Pulfrich corrections (i.e. darkening the blurring lens) are equally effective when induced by contact lenses and by trial lenses.
Investigating TRSV Phytoalexin Infusions as a Novel Treatment for Alzheimer’s Disease Using ApoE4 Plasmid Transfections in Neuro2a Cell Complexes
Authors: Gandhi Om 
Published: April 2020

AbstractBecause the accumulation of amyloid plaques plays a central role in the pathogenesis of Alzheimer’s disease (AD) and is responsible for many of its neurodegenerative effects, this project aims to evaluate the effectiveness of TRSV phytoalexin infusions as a novel treatment for the disease by comparing three separate agents and determining its impact on the accumulation of amyloid plaques in mouse Neuro2a cells. The experimental model is as follows: Neuro2a cells were first thawed using incubation and centrifugation techniques. The subculturing protocol was then performed to maximize cellular viability using DPBS and TrypLE dissociation reagents. The cells were transfected with pCMV4-ApoE4 bacterial plasmid using Opti-MEM medium and Lipofectamine LTX while also being treated with phytoalexin agents. Bradford’s assay was performed on the samples using CBB G-250 reagent, and they were run through a spectrophotometer and a Python low-pass filter to generate readings. The experimental data showed that natural grape seed phytoalexin extract was the most effective treating agent, followed by curcumin extract and synthetic RDS phytoalexin. All treating agents lessened the accumulation of the amyloid plaques significantly, supporting the novel infusion protocol as a treatment for AD.
Natural image statistics at depth edges modulate perceptual stability
Authors: Başgöze Zeynep , White David N. , Burge Johannes , Cooper Emily A. 
Published: April 2020

AbstractBinocular fusion relies on matching points in the two eyes that correspond to the same physical feature in the world. However, not all world features are binocularly visible. In particular, at depth edges parts of a scene are often visible to only one eye (so-calledhalf occlusions). Accurate detection of these monocularly visible regions is likely to be important for stable visual perception. If monocular regions are not detected as such, the visual system may attempt to binocularly fuse non-corresponding points, which can result in unstable percepts. We investigated the hypothesis that the visual system capitalizes upon statistical regularities associated with depth edges in natural scenes to aid binocular fusion and facilitate perceptual stability. By sampling from a large set of stereoscopic natural image patches, we found evidence that monocularly visible regions near depth edges in natural scenes tend to have features more visually similar to the adjacent binocularly visible background region than to the adjacent binocularly visible foreground. The generality of these results was supported by a parametric study of three-dimensional (3D) viewing geometry in simulated environments. In two perceptual experiments, we examined if this statistical regularity may be leveraged by the visual system. The results show that perception tended to be more stable when the visual properties of the depth edge were statistically more likely. Exploiting regularities in natural environments may allow the visual system to facilitate fusion and perceptual stability of natural scenes when both binocular and monocular regions are visible.PrecisWe report an analysis of natural scenes and two perceptual studies aimed at understanding how the visual statistics of depth edges impact perceptual stability. Our results suggest that the visual system exploits natural scene regularities to aid binocular fusion and facilitate perceptual stability.
Actin bundles play different role in shaping scale as compare to bristle in mosquitoAedes aegypti
Authors: Djokic Sanja , Anna Bakhrat , Zurim Ido , Urakova Nadya , Rasgon Jason L. , Abdu Uri 
Published: April 2020

AbstractInsect epithelial cells contain cellular extensions such as bristles, hairs and scales. It has been suggested that these cellular extensions are homologous structures that differ in morphology and function. These cellular extensions contain actin bundles that dictate their cellular morphology; bristle and hair are cylindrical in shape, while scales are wider and flattened. While the organization, function and identity of the major actin bundling protein in bristles and hairs is known, this information in scales is unknown. In this study, we characterized the development of scales and the role of actin bundles in the mosquito,Aedes aegypti. We show that scales undergo drastic morphological changes during development, from cylindrical shape to flat shape with longer membrane invagination. Scale actin bundle distribution changes during development, from symmetrical organization of actin bundles located throughout the bristle membrane, to asymmetrical organization of the actin bundles. By chemically inhibiting actin polymerization and by knocking-out theforkedgene in the mosquito (Ae-Forked;a known actin bundling protein), by CRISPR-Cas9 gene editing, we showed that actin bundles are required for shaping bristle, hair and scale morphology. We demonstrated that actin bundles andAe-Forkedare required for bristle elongation, but not that of scales. In scales, actin bundles are required for width formation. Our results reveal a differential requirement of actin bundles in shaping mosquito scales compared to bristles.
Comparative analyses of two primate species diverged by more than 60 million years show different rates but similar distribution of genome-wide UV repair events
Authors: Akkose Umit , Kaya Veysel Ogulcan , Lindsey-Boltz Laura , Karagoz Zeynep , Brown Adam D. , Larsen Peter A. , Yoder Anne D. , Sancar Aziz , Adebali Ogun 
Published: April 2020

AbstractNucleotide excision repair is the primary DNA repair mechanism that removes bulky DNA adducts such as UV-induced pyrimidine dimers. Correspondingly, genome-wide mapping of nucleotide excision repair with eXcision Repair sequencing (XR-seq), provides comprehensive profiling of DNA damage repair. A number of XR-seq experiments at a variety of conditions for different damage types revealed heterogenous repair in the human genome. Although human repair profiles were extensively studied, how repair maps vary between primates is yet to be investigated. Here, we characterized the genome-wide UV-induced damage repair in gray mouse lemur,Microcebus murinus, in comparison to human. Mouse lemurs are strictly nocturnal, are the world’s smallest living primates, and last shared a common ancestor with humans at least 60 million years ago. We derived fibroblast cell lines from mouse lemur, exposed them to UV irradiation. The following repair events were captured genome-wide through the XR-seq protocol. Mouse lemur repair profiles were analyzed in comparison to the equivalent human fibroblast datasets. We found that overall UV sensitivity, repair efficiency, and transcription-coupled repair levels differ between the two primates. Despite this, comparative analysis of human and mouse lemur fibroblasts revealed that genome-wide repair profiles of the homologous regions are highly correlated. This correlation is stronger for the highly expressed genes. With the inclusion of an additional XR-seq sample derived from another human cell line in the analysis, we found that fibroblasts of the two primates repair UV-induced DNA lesions in a more similar pattern than two distinct human cell lines do. Our results suggest that mouse lemurs and humans, and possibly primates in general, share a homologous repair mechanism as well as genomic variance distribution, albeit with their variable repair efficiency. This result also emphasizes the deep homologies of individual tissue types across the eukaryotic phylogeny.