bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluid administration guided by inferior vena cava ultrasound before spinal anaesthesia may reduce post procedural hypotension rate
Authors: Favre Mathieu , Ceruti Samuele , Biggiogero Maira , Musiari Michele , Glotta Andrea , Gimigliano Isabella , Aguirre José , Borgeat Alain , Saporito Andrea 
Published: June 2021

ABSTRACTPURPOSEThis study was conducted to estimate the incidence of hypotension after spinal anaesthesia after inferior vena cava ultrasound (IVCUS) guided volaemic optimization compared with a control group in patients undergoing elective surgery. According to ESICM guidelines, hypotension was defined as two systolic arterial pressure (SAP) measurements < 80 mmHg and / or a mean arterial pressure (MAP) < 60 mmHg, or a drop in SAP of more than 50 mmHg or more than 25% from baseline, or a decrease in MAP by more than 30% from baseline and / or clinical signs/symptoms of inadequate perfusion.MATERIALS AND METHODSFrom May 2014 to February 2019, a prospective, controlled, randomised, three-arm, parallel-group trial was performed in our tertiary hospital. In the IVCUS group (I, 132 patients) and passive leg raising test group (L, 148 patients), a pre-anaesthesia volume optimization was achieved following a fluid response protocol. In control group (C, 149 patients), no specific intervention was performed.RESULTS474 patients were collected. In group I, hypotension rate was 35%. In group L hypotension rate was 44%. In group C hypotension rate was 46%. An 11% reduction rate in hypotension (95% CI -1 to -24%, P=0.047) was observed between the group I and the group C. A 2% reduction rate in hypotension (95% CI -3 to -5%, P=0.428) was observed between group L and the group C. Total fluid amount administered was greater in the I group I than in the group C (593 ml versus 453 ml, P=0.015) and greater in the group L than the group C (511 ml versus 453 ml, P=0.11).CONCLUSIONIVCUS guided fluid optimisation decrease the incidence of arterial hypotension after spinal anaesthesia.
Impacts of Mycoplasma agalactiae restriction-modification systems on pan-epigenome dynamics and genome plasticity
Authors: Dordet-Frisoni Emilie , Vandecasteele Céline , Contarin Rachel , Sagné Eveline , Baranowski Eric , Klopp Christophe , Nouvel Laurent Xavier , Citti Christine 
Published: June 2021

AbstractDNA methylation plays an important role in the biology of bacteria. Often associated with restriction modification (RM) systems, they also provide a defence against foreign DNA. Little is known regarding the methylome of the mycoplasma genus, which encompasses several pathogenic species with small genomes. Here, single molecule real-time (SMRT) and bisulphite sequencing combined with whole-genome analysis identified 19 methylated motifs associated with three orphan methyltransferases (MTases) and eight RM systems in Mycoplasma agalactiae, a ruminant pathogen and a model organism. All systems had a homolog in at least one phylogenetically distinct Mycoplasma spp. Our study also revealed that several superimposed genetic events may participate in the M. agalactiae dynamic epigenome landscape. These included (i) DNA shuffling and frameshift mutations that affect the MTase and restriction endonuclease content of a clonal population and (ii) gene duplication, erosion, and horizontal transfer that modulate MTase and RM repertoires of the species. Some of these systems were experimentally shown to play a major role in mycoplasma conjugative, horizontal DNA transfer. While the versatility of DNA methylation may contribute to regulating essential biological functions at cell and population levels, RM systems may be key in mycoplasma genome evolution and adaptation by controlling horizontal gene transfers.
Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses
Authors: Schulz Rouven , Korkut-Demirbaş Medina , Colombo Gloria , Siegert Sandra 
Published: June 2021

AbstractG protein-coupled receptors (GPCRs) regulate multiple processes ranging from cell growth and immune responses to neuronal signal transmission. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additional challenges exist to dissect cell type-specific responses when the same GPCR is expressed on different cells within the body. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that selectively bind their agonist clozapine-N-oxide (CNO) and mimic a GPCR-of-interest. We show that the chimeric DREADD-β2-adrenergic receptor (β2AR/ADRB2) triggers comparable responses to levalbuterol on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Moreover, we successfully recapitulate β2AR-mediated filopodia formation in microglia, a β2AR-expressing immune cell that can drive inflammation in the nervous system. To further dissect microglial inflammation, we compared DREADD-β2AR with two additionally designed DREADD-based chimeras mimicking GPR65 and GPR109A/HCAR2, both enriched in microglia. DREADD-β2AR and DREADD-GPR65 modulate the inflammatory response with a similar profile as endogenously expressed β2AR, while DREADD-GPR109A had no impact. Our DREADD-based approach allows investigation of cell type-dependent signaling pathways and function without known endogenous ligands.
Emotion increases the similarity between neural representations of pictures, but not their perceived similarity
Authors: Riberto Martina , Paz Rony , Pobric Gorana , Talmi Deborah 
Published: June 2021

AbstractStimuli that evoke the same feelings can nevertheless look different and have different semantic meanings. Although we know much about the neural representation of emotion, the neural underpinnings that govern judgements of emotional similarity are unknown. One possibility is that the same brain regions will represent similarity between emotional and neutral stimuli, perhaps with different strengths. Alternatively, emotional similarity could be coded in separate regions, possibly those known to express emotional valence and arousal preferentially. In behaviour, the extent to which people consider similarity along the emotional dimension when they evaluate the overall similarity between stimuli has never been investigated. While the emotional features of stimuli may dominate explicit ratings of similarity, it is also possible that people neglect the emotional dimension as irrelevant. We contrasted these hypotheses with two measures of similarity and two different databases of complex negative and neutral pictures, the second of which afforded exquisite control over semantic and visual attributes. Emotion increased neural similarity in a set of regions that represented both emotional and neutral stimuli, including the inferior temporal cortex, the fusiform face area, and the precuneus. Emotion also increased neural similarity in early visual cortex, anterior insula and dorsal anterior cingulate cortex, despite no increase in BOLD-signal amplitudes in these regions. Despite the stronger neural similarity between emotional stimuli, participants rated pictures taken from two distinct emotional categories as equally similar. These results contribute to our understanding of how emotion is represented within a general conceptual workspace.
VarGenius-HZD allows accurate detection of rare homozygous or hemizygous deletions in targeted sequencing leveraging breadth of coverage
Authors: Musacchia Francesco , Karali Marianthi , Torella Annalaura , Laurie Steve , Policastro Valeria , Pizzo Mariateresa , Beltran Sergi , Casari Giorgio , Nigro Vincenzo , Banfi Sandro 
Published: June 2021

AbstractMotivationHomozygous deletions (HDs) may be the cause of rare diseases and cancer and their discovery in targeted sequencing is a challenging task. Different tools have been developed to disentangle HD discovery but a sensitive caller is still lacking.ResultsWe present VarGenius-HZD, a sensitive and scalable algorithm that leverages breadth-of-coverage for the detection of rare homozygous and hemizygous single-exon deletions (HDs). To assess its effectiveness we detected both real and synthetic rare HDs in fifty exomes from the 1000 Genomes Project obtaining higher sensitivity in comparison with state-of-the-art algorithms which missed at least one event each. We then applied our tool on targeted sequencing data from patients with Inherited Retinal Dystrophies and solved five cases that still lacked a genetic diagnosis.Availability and implementationWe provide VarGenius-HZD either stand-alone or integrated within our recently developed software enabling the automated selection of samples using the internal database. Hence, it could be extremely useful for both diagnostic and research purposes. Our tool is available under GNU General Public License, version 3 at: https://github.com/frankMusacchia/VarGenius-HZDContact: francesco.musacchia@iit.itSupplementary information is available online.
Identification of the stress granule transcriptome via RNA-editing in single cells andin vivo
Authors: van Leeuwen Wessel , VanInsberghe Michael , Battich Nico , Salmén Fredrik , van Oudenaarden Alexander , Rabouille Catherine 
Published: June 2021

ABSTRACTStress granules are phase separated assemblies formed around mRNAs whose identities remain elusive. The techniques available to identify the RNA content of stress granules rely on their physical purification, and are therefore not suitable for single cells and tissues displaying cell heterogeneity. Here, we adapted TRIBE (Target of RNA-binding proteins Identified by Editing) to detect stress granule RNAs by fusing a stress granule RNA-binding protein (FMR1) to the catalytic domain of an RNA-editing enzyme (ADAR). RNAs colocalized with this fusion are edited, producing mutations that are detectable by sequencing. We first optimized the expression of this fusion protein so that RNA editing preferentially occurs in stress granules. We then show that this purification-free method can reliably identify stress granule RNAs in bulk and single S2 cells, and in Drosophila tissues, such as 398 neuronal stress granule mRNAs encoding ATP binding, cell cycle and transcription factors. This new method opens the possibility to identify the RNA content of stress granules as well other RNA based assemblies in single cells derived from tissues.
Diversity and evolution of pigment types and the phycobilisome rod gene region of marine Synechococcus cyanobacteria
Authors: Grébert Théophile , Garczarek Laurence , Daubin Vincent , Humily Florian , Marie Dominique , Ratin Morgane , Devailly Alban , Farrant Gregory K. , Mary Isabelle , Mella-Flores Daniella , Tanguy Gwen , Labadie Karine , Wincker Patrick , Kehoe David M. , Partensky Frédéric 
Published: June 2021

AbstractSynechococcus picocyanobacteria are ubiquitous and abundant photosynthetic organisms in the marine environment and contribute for an estimated 16% of the ocean net primary productivity. Their light-harvesting complexes, called phycobilisomes (PBS), are composed of a conserved allophycocyanin core from which radiates six to eight rods with variable phycobiliprotein and chromophore content. This variability allows Synechococcus to optimally exploit the wide variety of spectral niches existing in marine ecosystems. Seven distinct pigment types or subtypes have been identified so far in this taxon, based on the phycobiliprotein composition and/or the proportion of the different chromophores in PBS rods. Most genes involved in their biosynthesis and regulation are located in a dedicated genomic region called the PBS rod region. Here, we examined the variability of gene sequences and organization of this genomic region in a large set of sequenced isolates and natural populations of Synechococcus representative of all known pigment types. All regions start with a tRNA-PheGAA and some possess mobile elements including tyrosine recombinases, suggesting that their genomic plasticity relies on a tycheposon-like mechanism. Comparison of the phylogenies obtained for PBS and core genes revealed that the evolutionary history of PBS rod genes differs from the rest of the genome and is characterized by the co-existence of different alleles and frequent allelic exchange. We propose a scenario for the evolution of the different pigment types and highlight the importance of population-scale mechanisms in maintaining a wide diversity of pigment types in different Synechococcus lineages despite multiple speciation events.
Conformational decoupling in acid-sensing ion channels uncovers mechanism and stoichiometry of PcTx1-mediated inhibition
Authors: Heusser Stephanie A. , Borg Christian B. , Colding Janne M. , Pless Stephan A. 
Published: June 2021

AbstractAcid-sensing ion channels (ASICs) are trimeric proton-gated cation channels involved in fast synaptic transmission. Pharmacological inhibition of ASIC1a reduces neurotoxicity and stroke infarct volumes, with the cysteine knot toxin Psalmotoxin-1 (PcTx1) being one of the most potent and selective inhibitors. PcTx1 binds at the subunit interface in the extracellular domain (ECD), but the mechanism and conformational consequences of the interaction, as well as the number of toxin molecules required for inhibition remain unknown. Here we use voltage-clamp fluorometry and subunit concatenation to decipher the mechanism and stoichiometry of PcTx1 inhibition of ASIC1a. Besides the known inhibitory binding mode, we propose PcTx1 to have at least two additional binding modes that are decoupled from the pore. One of these modes induces a long-lived ECD conformation that reduces the activity of an endogenous neuropeptide. This long-lived conformational state is proton-dependent and can be destabilized by a mutation that decreases PcTx1 sensitivity. Lastly, the use of concatemeric channel constructs reveal that disruption of a single PcTx1 binding site is sufficient to destabilize the toxin-induced conformation, while functional inhibition is not impaired until two or more binding sites are mutated. Together, our work provides insight into the mechanism of PcTx1 inhibition of ASICs and uncovers a prolonged conformational change with possible pharmacological implications.
Assessing neuromodulation effects of theta burst stimulation to the prefrontal cortex using TMS-evoked potentials
Authors: Moffa Adriano H. , Nikolin Stevan , Martin Donel , Loo Colleen , Boonstra Tjeerd W. 
Published: June 2021

AbstractTheta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (TMS), is capable of non-invasively modulating cortical excitability. TBS is gaining popularity as a therapeutic tool for psychiatric disorders such as depression, in which the dorsolateral prefrontal cortex (DLPFC) is the main therapeutic target. However, the neuromodulatory effects of TBS on prefrontal regions remain unclear. An emerging tool to assess neuromodulation in non-motor regions is concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to measure TMS-evoked potentials (TEPs). We assessed twenty-four healthy participants (13 males, mean age 25.2±9.9 years) following intermittent TBS, continuous TBS, and sham applied to the left DLPFC using a double-blinded crossover design. TEPs were obtained at baseline and 2-, 15-, and 30-min post-stimulation. Four TEP components (N40, P60, N100 and P200) were analysed using mixed effects repeated measures models (MRMM). Results indicate no significant effects for any assessed components (all p>.05). The largest effect size (Cohen’s d = −0.5) comparing iTBS and sham was obtained for the N100 component at 15 minutes post-stimulation. This result was in the same direction but smaller than found in previous studies, suggesting that the true effect size may be lower than previously reported. Accurate estimates of the effects sizes and inter-individual heterogeneity will critically inform clinical applications using TEPs to assess the neuromodulatory effects of TBS.
Identification of the key role of white matter alteration in the pathogenesis of Huntington’s Disease
Authors: Pérot Jean-Baptiste , Célestine Marina , Palombo Marco , Dhenain Marc , Humbert Sandrine , Brouillet Emmanuel , Flament Julien 
Published: June 2021

AbstractPathogenesis of the inherited neurodegenerative disorder Huntington’s Disease (HD) is complex and progressive, with a long presymptomatic phase in which subtle changes occur in the brain of gene carriers up to 15 years before the onset of symptoms. Thus, there is a need of early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. In particular, recent studies have shown that white matter may be affected early in HD. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, Diffusion Tensor Imaging (DTI), Chemical Exchange Saturation Transfer of glutamate (gluCEST) and Magnetization Transfer (MT) imaging, in order to assess white matter integrity over the life of this very progressive mouse model. Our results show early defects of diffusion properties in the anterior part of the corpus callosum, preceding gluCEST defects in the same region (−10.8% at 8 months, −19% at 12 months) that spread to adjacent regions. At 12 months, frontal (−7.3%) and piriform (−16.7%) cortices showed reduced gluCEST, as well as the pallidum (−21.0%). MT imaging showed reduced signal in the septum (−21.7%) at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the pivotal role of white matter, in the pathogenesis of HD and the pertinence of gluCEST and DTI as biomarkers in HD.Highlights–A knock-in mouse model of Huntington’s disease is longitudinally characterized–A multimodal MRI protocol is performed to identify biomarkers of the disease–The white matter plays a pivotal role in the pathogenesis of the disease–The cortico-striatal pathway seems particularly vulnerable in Huntington’s disease
A novel binary k-mer approach for classification of coding and non-coding RNAs across diverse species
Authors: Periwal Neha , Sharma Priya , Arora Pooja , Pandey Saurabh , Kaur Baljeet , Sood Vikas 
Published: June 2021

ABSTRACTClassification among coding (CDS) and non-coding RNA (ncRNA) sequences is a challenge and several machine learning models have been developed for the same. Since the frequency of curated coding sequences is many-folds as compared to that of the ncRNAs, we devised a novel approach to work with the complete datasets from fifteen diverse species. In our proposed novel binary approach, we replaced all the ‘A’s and ‘T’s with ‘0’s and ‘G’s and ‘C’s with ‘1’s to obtain a binary form of coding and ncRNAs. The k-mer analysis of these binary sequences revealed that the frequency of binary patterns among the coding and ncRNAs can be used as features to distinguish among them. Using insights from these distinguishing frequencies, we used k-nearest neighbour classifier to classify among them. Our strategy is not only time-efficient but leads to significantly increased performance metrics including Matthews correlation coefficient (MCC) for some species like P. paniscus, M. mulatta, M. lucifugus, G. gallus, C. japonica, C. abingdonii, A. carolinensis, D. melanogaster and C. elegans when compared with the conventional ATGC approach. Additionally, we also show that the values of MCC obtained for diverse species tested on the model based on H. sapiens correlated with the geological evolutionary timeline thereby further strengthening our approach. Therefore, we propose that CDS and ncRNAs can be efficiently classified using “2-character” frequency as compared to “4-character” frequency of ATGC approach. Thus, our highly efficient binary approach can replace the more complex ATGC approach successfully.
A streamlined CRISPR workflow to introduce mutations and generate isogenic iPSCs for modeling amyotrophic lateral sclerosis
Authors: Deneault Eric , Chaineau Mathilde , Montiel Maria José Castellanos , Flores Anna Kristyna Franco , Haghi Ghazal , Chen Carol X-Q , Abdian Narges , Nicouleau Michael , Shlaifer Irina , Beitel Lenore K. , Durcan Thomas M. 
Published: June 2021

AbstractAmyotrophic lateral sclerosis (ALS) represents a complex neurodegenerative disorder with significant genetic heterogeneity. To date, both the genetic etiology and the underlying molecular mechanisms driving this disease remain poorly understood, although in recent years a number of studies have highlighted a number of genetic mutations causative for ALS. With these mutations pointing to potential pathways that may be affected within individuals with ALS, having the ability to generate human neurons and other disease relevant cells containing these mutations becomes even more critical if new therapies are to emerge. Recent developments with the advent of induced pluripotent stem cells (iPSCs) and clustered regularly interspaced short palindromic repeats (CRISPR) gene editing fields gave us the tools to introduce or correct a specific mutation at any site within the genome of an iPSC, and thus model the specific contribution of risk mutations. In this study we describe a rapid and efficient way to either introduce a mutation into a control line, or to correct a mutation, generating an isogenic control line from patient-derived iPSCs with a given mutation. The mutations introduced were the G93A mutation into SOD1 or H517Q into FUS, and the mutation corrected was a patient iPSC line with I114T in SOD1. A combination of small molecules and growth factors were used to guide a stepwise differentiation of the edited cells into motor neurons in order to demonstrate that disease-relevant cells could be generated for downstream applications. Through a combination of iPSCs and CRISPR editing, the cells generated here will provide fundamental insights into the molecular mechanisms underlying neuron degeneration in ALS.