bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific targeting of intestinalPrevotella copriby aListeria monocytogenesbacteriocin
Authors: Rolhion Nathalie , Chassaing Benoit , Nahori Marie-Anne , de Bodt Jana , Moura Alexandra , Lecuit Marc , Dussurget Olivier , Bérard Marion , Marzorati Massimo , Fehlner-Peach Hannah , Littman Dan R. , Gewirtz Andrew T. , Van de Wiele Tom , Cossart Pascale 
Published: July 2019

AbstractDeciphering the specific function of every microorganism in microbial gut communities is a key issue to interrogate their role during infection. Here, we report the discovery of aListeriabacteriocin, Lmo2776, that specifically targets the abundant gut commensalPrevotella copriand affectsListeriainfection. Oral infection of conventional mice with a Δlmo2776mutant leads to a thinner intestinal mucus layer and higherListerialoads both in the intestinal content and deeper tissues compared to WTListeria, while no difference is observed in germ-free mice. This microbiota-dependent effect is phenocopied by precolonization of germ-free mice beforeListeriainfection, withP. copri, but not with other commensals,. Together, these data unveil a role forPrevotellain controlling intestinal infection, highlighting that pathogens may selectively deplete microbiota to avoid excessive inflammation.
Mesenchymal stem cells therapy for spinal cord contusion: a comparative study on small and large animal models
Authors: Mukhamedshina Yana , Shulman Iliya , Ogurcov Sergei , Kostennikov Alexander , Zakirova Lena , Akhmetzyanova Elvira , Rogozhin Alexander , Masgutova Galina , James Victoria , Masgutov Ruslan , Lavrov Igor , Rizvanov Albert 
Published: July 2019

AbstractHere, we provided a first comparative study of the therapeutic potential of allogeneic mesenchymal stem cells derived from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), and dental pulp (DP-MSCs) embedded in fibrin matrix in a small (rat) and large (pig) spinal cord injury (SCI) model during sub-acute period of spinal contusion. Results of behavioral, electrophysiological, histological assessment, as well as results of immunohistochemistry and RT-PCR analysis suggest that application of AD-MSCs combined with a fibrin matrix in a subacute period in rats (2 weeks after injury) provides significantly higher post-traumatic regeneration compared to a similar application of BM-MSCs or DP-MSCs. Within the rat model, use of AD-MSCs resulted in a marked change in (1) restoration of locomotor activity and conduction along spinal axons, (2) reduction of post-traumatic cavitation and enhancing tissue retention, and (3) modulation of microglial and astroglial activation. The effect of therapy with an autologous application of AD-MSCs was also confirmed in subacute period after spinal contusion in pigs (6 weeks after injury), however, with only partial replication of the findings observed in rats, i.e. (1) partial restoration of the somatosensory spinal pathways, (2) reduction of post-traumatic cavitation and enhancing tissue retention, and (3) modulation of astroglial activation in dorsal root entry zone. The results of this study suggest that application of AD-MSCs embedded in fibrin matrix at the site of SCI during the subacute period can facilitate regeneration of nervous tissue in rats and pigs. These results, for the first time, provide robust support for the use of AD-MSC to treat subacute SCI.
Type I interferons are important co-stimulatory signals during T cell receptor mediated MAIT cell activation
Authors: Lamichhane Rajesh , Galvin Henry , Hannaway Rachel F , de la Harpe Sara M , Munro Fran , Tyndall Joel DA , Vernall Andrea J , McCall John L , Husain Matloob , Ussher James E 
Published: July 2019

AbstractMucosal associated invariant T (MAIT) cells are abundant unconventional T cells which can be stimulated either via their T cell receptor (TCR) or by innate cytokines. The MAIT cell TCR recognises a pyrimidine ligand, derived from riboflavin synthesising bacteria, bound to MR1. In infection, bacteria not only provide the pyrimidine ligand but also co-stimulatory signals, such as Toll-like receptor agonists, that can modulate TCR-mediated activation. Recently, type I interferons (T1-IFNs) have been identified as contributing to cytokine-mediated MAIT cell activation. However, it is unknown whether T1-IFNs also have a role during TCR-mediated MAIT cell activation. In this study, we investigated the co-stimulatory role of T1-IFNs during TCR-mediated activation of MAIT cells by the MR1 ligand 5-amino-6-D-ribitylaminouracil/methylglyoxal (5-A-RU/MG). We found that T1-IFNs were able to boost interferon-γ and granzyme B production in 5-A-RU/MG-stimulated MAIT cells. Similarly, influenza virus-induced T1-IFNs enhanced TCR-mediated MAIT cell activation. An essential role of T1-IFNs in regulating MAIT cell activation by riboflavin synthesising bacteria was also demonstrated. The co-stimulatory role of T1-IFNs was confirmed using liver-derived MAIT cells. T1-IFNs acted directly on MAIT cells to enhance their response to TCR stimulation. Overall, our findings establish an important immunomodulatory role of T1-IFNs during TCR-mediated MAIT cell activation.
Joint Motion Estimation and Source Identification using Convective Regularisation with an Application to the Analysis of Laser Nanoablations
Authors: Lang Lukas F. , Dutta Nilankur , Scarpa Elena , Sanson Bénédicte , Schönlieb Carola-Bibiane , Étienne Jocelyn 
Published: July 2019

AbstractWe propose a variational method for joint motion estimation and source identification in one-dimensional image sequences. The problem is motivated by fluorescence microscopy data of laser nanoablations of cell membranes in live Drosophila embryos, which can be conveniently—and without loss of significant information—represented in space-time plots, so called kymographs. Based on mechanical models of tissue formation, we propose a variational formulation that is based on the nonhomogenous continuity equation and investigate the solution of this ill-posed inverse problem using convective regularisation. We show existence of a minimiser of the minimisation problem, derive the associated Euler–Lagrange equations, and numerically solve them using a finite element discretisation together with Newton’s method. Based on synthetic data, we demonstrate that source estimation can be crucial whenever signal variations can not be explained by advection alone. Furthermore, we perform an extensive evaluation and comparison of various models, including standard optical flow, based on manually annotated kymographs that measure velocities of visible features. Finally, we present results for data generated by a mechanical model of tissue formation and demonstrate that our approach reliably estimates both a velocity and a source.
Bach2 is a potent repressor of Nrf2-mediated antioxidant enzyme expression in dopaminergic neurons
Authors: Waxman Elisa A. 
Published: July 2019

AbstractNuclear factor erythroid 2–related factor 2 (Nrf2) is a transcriptional activator of antioxidant response elements (ARE), which function to increase expression of antioxidant enzymes. Recent works suggests Nrf2 activation is a promising protective mechanism against the progressive neurodegeneration in Parkinson’s disease (PD). While Nrf2 inducers show some promising results in animal models of PD, the response is limit in dopaminergic neurons with the protection mostly conferred by surrounding glia. The present study characterizes ARE transcriptional repressors Bach1 and Bach 2 (Broad complex– Tramtrack–Bric-a-brac and Cap n’ Collar homology, basic leucine zipper transcription factors 1 and 2) as a potential explanation for limited Nrf2 activity in these neurons. The current work identified Bach1 and Bach2 in dopaminergic neurons of the human substantia nigra by immunocytochemical analyses. We further identified Bach2 as a more robust inhibitor of Nrf2 responses. The effects of both Bach1 and Bach2 were dependent on their DNA-binding domains, but the DNA-binding domains did not entirely explain the differences in their relative repressor activities. Using IMR-32 neuroblastoma cells, we found differentiation into a dopaminergic neuronal phenotype resulted in increased Bach2 expression, decreased full-length Bach1 expression, increased truncated Bach1, and blunted Nrf2-mediated responses. Bach inhibitors cobalt protoporphyrin or cadmium chloride, which were more effective against Bach1 than Bach2, did not rescue Nrf2 responses. These results provide a novel mechanism for the lack of antioxidant responses and sensitivity of dopaminergic neurons to oxidative damage, in addition to proposing Bach2 as a novel drug target for the treatment of PD.SignificanceOxidative stress and damage are unifying contributors to explain the progressive loss of dopaminergic neurons in Parkinson’s disease (PD). Although increased transcription of antioxidant enzymes by nuclear factor erythroid 2-related factor 2 (Nrf2) shows potential in combating oxidative damage, Nrf2 protection is mostly conferred by surrounding glia with a relative inability of neurons to mount a protective response. This work characterizes transcriptional repressors Bach1 and Bach2 that inhibit Nrf2 responses and prevent antioxidant enzyme production. This study supports Bach2 as a major factor in preventing antioxidant production in neurons and as a novel drug target to protect against PD.
Shortening injection matrix for serial crystallography
Authors: Nam Ki Hyun 
Published: July 2019

AbstractSerial crystallography (SX) allows crystal structures to be observed at room temperature through the steady delivery of crystals to the X-ray interaction point. Viscous delivery media are advantageous because they afford efficient sample delivery from an injector or syringe at a low flow rate. Hydrophobic delivery media, such as lipidic cubic phase (LCP) or grease, provide a very stable injection stream and are widely used. The development of new hydrophobic delivery materials can expand opportunities for future SX studies with various samples. Here, I introduce fat-based shortening as a delivery medium for SX experiments. This material is commercially available at low cost and is straightforward to handle because its phase (i.e., solid or liquid) can be controlled by temperature. Shortening was extruded from a syringe needle in a very stable injection stream even below 200 nl/min. X-ray exposed shortening produced several background scattering rings, which have similar or lower intensities than those of LCP and contribute negligibly to data processing. Serial millisecond crystallography was performed using two shortening delivery media, and the room temperature crystal structures of lysozyme and glucose isomerase were successfully determined at resolutions of 1.5–2.0 Å. Therefore, shortening can be used as a sample delivery medium in SX experiments.
A large single-participant fMRI dataset for probing brain responses to naturalistic stimuli in space and time
Authors: Seeliger K. , Sommers R. P. , Güçlü U. , Bosch S. E. , van Gerven M. A. J. 
Published: July 2019

AbstractVisual and auditory representations in the human brain have been studied with encoding, decoding and reconstruction models. Representations from convolutional neural networks have been used as explanatory models for these stimulus-induced hierarchical brain activations. However, none of the fMRI datasets currently available has adequate amounts of data for sufficiently sampling their representations. We recorded a densely sampled large fMRI dataset (TR=700 ms) in a single individual exposed to spatiotemporal visual and auditory naturalistic stimuli (30 episodes of BBC’s Doctor Who). The data consists of 120.830 whole-brain volumes (approx. 23 h) of single-presentation data (full episodes, training set) and 1.178 volumes (11 min) of repeated narrative short episodes (test set, 22 repetitions), recorded with fixation over a period of six months. This rich dataset can be used widely to study the way the brain represents audiovisual input across its sensory hierarchies.
Predictive and Aetiological Potential of Polygenic Strata with Extreme and Moderate Disease Risks Predictions:Case Study of Coeliac Disease GWAS
Authors: Kowalczyk Adam 
Published: July 2019

SummaryWe show by using example of coeliac disease (CD) that a genomic risk assessment could significantly improve efficiency of disease diagnosing. It can detect novel highly deleterious rare variants (penetrance 100%, frequency ∼1:6,700) as well as common protective variants (penetrance 0.03%, frequency ∼1:3). However, the major translational gains with potential for multi-billion-dollar cost savings in Australia or USA alone, could be in assessing patients in cohorts with moderately elevated CD risk (3% −10%) exhibiting clinical symptoms or with family history of CD. The gains result from judicious re-direction of expensive confirmatory testing towards ∼30% of the cohort with the highest likelihood of the condition (∼90% of cohort CD cases), while avoiding costs, inconvenience and risk of side-complications for the remaining majority of ∼70%.We build our estimates using concrete results of CD Genome Wide Association Studies (GWAS) already in the public domain1–4. The largest of five Genomic Risk Score (GRS) models1considered here deploys 228 directly genotyped Simple Nucleotide Polymorphisms (SNPs), while the simplest2uses only 6 SNPs. Thus, a DNA profile supporting all these models can be easily accommodated on any commodity, Direct-to-Consumer5(DTC), saliva-based genotyping platform. Once generated, such a generic profile of over 600,000 SNPs could assist medical practitioners in diagnosing this as well as thousands of other diseases on demand, virtually genotyping cost free.
Gene Transfer Agents in Plant Pathogenic Bacteria: Comparative Mobilomics, Genomic Survey and Recombinogenic Impacts
Authors: Jibrin Mustafa O. , Minsavage Gerald V. , Goss Erica M. , Roberts Pamela D. , Jones Jeffrey B. 
Published: July 2019

AbstractBackgroundGene transfer agents (GTAs) are phage-like mediators of gene transfer in bacterial species. Typically, strains of a bacteria species which have GTA shows more recombination than strains without GTAs. GTA-mediated gene transfer activity has been shown for few bacteria, with Rhodobacter capsulatus being the prototypical GTA. GTA have not been previously studied in plant pathogenic bacteria. A recent study inferring recombination in strains of the bacterial spot xanthomonads identified a Nigerian lineage which showed unusual recombination background. We initially set out to understand genomic drivers of recombination in this genome by focusing on mobile genetic elements.ResultsWe identified a unique cluster which was present in the Nigerian strain but absent in other sequenced strains of bacterial spot xanthomonads. The protein sequence of a gene within this cluster contained the GTA_TIM domain that is present in bacteria with GTA. We identified GTA clusters in other Xanthomonas species as well as species of Agrobacterium and Pantoea. Recombination analyses showed that generally, strains of Xanthomonas with GTA have more inferred recombination events than strains without GTA, which could lead to genome divergence.ConclusionThis study identified GTA clusters in species of the plant pathogen genera Xanthomonas, Agrobacterium and Pantoea which we have named XpGTA, AgGTA and PaGTA respectively. Our recombination analyses suggest that Xanthomonas strains with GTA generally have more inferred recombination events than strains without GTA. The study is important in understanding the drivers of evolution of bacterial plant pathogens.
High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation
Authors: Abeler-Dörner Lucie , Laing Adam G. , Lorenc Anna , Ushakov Dmitry S. , Clare Simon , Speak Anneliese , Duque Maria , White Jacqui K. , Ramirez-Solis Ramiro , Saran Namita , Bull Katherine R. , Morón Belén , Iwasaki Jua , Barton Philippa R. , Caetano Susana , Hng Keng I. , Cambridge Emma , Forman Simon , Crockford Tanya L. , Griffiths Mark , Kane Leanne , Harcourt Katherine , Brandt Cordelia , Notley George , Babalola Kolawole O. , Warren Jonathan , Mason Jeremy C. , Meeniga Amrutha , Karp Natasha A. , Melvin David , Cawthorne Eleanor , Weinrick Brian , Rahim Albina , Drissler Sibyl , Meskas Justin , Yue Alice , Lux Markus , Song-Zhao George , Chan Anna , Reviriego Carmen Ballesteros , Abeler Johannes , Wilson Heather , Przemska-Kosicka Agnieszka , Edmans Matthew , Strevens Natasha , Pasztorek Markus , Meehan Terrence F. , Powrie Fiona , Brinkman Ryan , Dougan Gordon , Jacobs William , Lloyd Clare , Cornall Richard J. , Maloy Kevin , Grencis Richard , Griffiths Gillian M. , Adams David , Hayday Adrian C. 
Published: July 2019

ABSTRACTBy developing a high-density murine immunophenotyping platform compatible with high-throughput genetic screening, we have established profound contributions of genetics and structure to immune variation. Specifically, high-throughput phenotyping of 530 knockout mouse lines identified 140 monogenic “hits” (>25%), most of which had never hitherto been implicated in immunology. Furthermore, they were conspicuously enriched in genes for which humans show poor tolerance to loss-of-function. The immunophenotyping platform also exposed dense correlation networks linking immune parameters with one another and with specific physiologic traits. By limiting the freedom of individual immune parameters, such linkages impose genetically regulated “immunological structures”, whose integrity was found to be associated with immunocompetence. Hence, our findings provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease.
Unbiased analysis of C. elegans behavior reveals the use of distinct turning strategies during magnetic Orientation
Authors: Bainbridge C , McDonald J , Ahlert A. , Benefield Z , Stein W , Vidal-Gadea AG 
Published: July 2019

AbstractTo successfully navigate their surroundings, animals detect and orient to environmental stimuli possessing unique physical properties. Most animals can derive directional information from spatial or temporal changes in stimulus intensity (e.g. chemo- and thermo-taxis). However, some biologically relevant stimuli have constant intensity at most organismal scales. The gravitational and magnetic fields of the earth are examples of uniform stimuli that remain constant at most relevant scales. While devoid of information associated with intensity changes, the vectorial nature of these fields intrinsically encodes directional information. While much is known about behavioral strategies that exploit changes in stimulus intensity (gradients), less is understood about orientation to uniform stimuli. Nowhere is this truer than with magnetic orientation. While many organisms are known to orient to the magnetic field of the earth, how these animals extract information from the earth’s magnetic field remains unresolved.Here we use the nematode C. elegans to investigate behavioral strategies for orientation to magnetic fields, and compare our findings to the better characterized chemical and thermal orientation strategies. We used an unbiased cluster analysis to categorize, quantify, and compare behavioral components underlying different orientation strategies as a way to quantify and compare animal orientation to distinct stimuli. We find that in the presence of an earth-like magnetic field, worms perform acute angle turns (140-171°) that significantly improved their alignment with the direction of an imposed magnetic vector. In contrast, animals performed high amplitude turns (46-82°) that significantly increased alignment of their trajectory with the preferred migratory angle. We conclude that C. elegans orients to earth-strength magnetic fields using two independent behavioral strategies, in contrast to orientation strategies to graded stimuli. Understanding how C. elegans detects and orients to magnetic fields will provide useful insight into how many species across taxa accomplish this fascinating sensory feat.
Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade
Authors: Dakhel Sheila , Ongaro Tiziano , Gouyou Baptiste , Matasci Mattia , Villa Alessandra , Neri Dario , Cazzamalli Samuele 
Published: July 2019

AbstractIntroductionCytokine-based products are gaining importance for cancer immunotherapy. L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Here, we describe an innovative approach to transiently inhibit off-target toxicity of L19-TNF, while maintaining antitumor activity.MethodsGSK’963, a potent small molecule inhibitor of RIPK1, was tested in tumor-bearing mice for its ability to reduce acute toxicity associated with TNF signaling. The biological effects of L19-TNF on tumor cells, lymphocytes and tumor vessels were investigated with the aim to enable the administration of TNF doses, which would otherwise be lethal.ResultsTransient inhibition of RIPK1 allowed to increase the maximal tolerated dose of L19-TNF. The protective effect of GSK’963 did not affect the selective localization of the immunocytokine to tumors as evidenced by quantitative biodistribution analysis and allowed to reach high local TNF concentrations around tumor blood vessels, causing diffused vascular shutdown and hemorrhagic necrosis within the neoplastic mass.ConclusionsThe selective inhibition of RIPK1 with small molecule inhibitors can be used as a pharmaceutical tool to transiently mask TNF activity and improve the therapeutic window of TNF-based biopharmaceuticals. Similar approaches may be applicable to other pro-inflammatory cytokines.