bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ezh2 as an epigenetic checkpoint regulator during monocyte differentiation: a potential target to improve cardiac repair after myocardial infarction
Authors: Julie Rondeaux , Déborah Groussard , Sylvanie Renet , Virginie Tardif , Anaïs Dumesnil , Alphonse Chu , Jean-Paul Henry , Zina Badji , Claire Vézier , Delphine Béziau , Dominique Guerrot , Marjorie Brand , Vincent Richard , Eric Durand , Ebba Brakenhielm , Sylvain Fraineau 
Published: February 2021

AbstractEpigenetic regulation of histone H3K27 methylation has recently emerged as a key step during M2-like macrophage polarization, essential for cardiac repair after Myocardial Infarction (MI). We demonstrate for the first-time that EZH2, responsible for H3K27 methylation, has an ectopic cytoplasmic localization during monocyte differentiation in M2 macrophages. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, enhances bivalent genes, expression to promote human monocyte repair functions. GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction after MIin vivo. In conclusion, our study reveals that epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI.
The combined influence of viscoelasticity and adhesive cues on fibroblast spreading and focal adhesion formation
Authors: Hui Erica , Moretti Leandro , Barker Thomas H. , Caliari Steven R. 
Published: February 2021

AbstractTissue fibrosis is characterized by progressive extracellular matrix (ECM) stiffening and loss of viscoelasticity that ultimately results in reduced organ functionality. Cells bind to the ECM through integrins, where av integrin engagement in particular has been correlated with fibroblast activation into contractile myofibroblasts that drive fibrosis progression. There is a significant unmet need forin vitrohydrogel systems that deconstruct the complexity of native tissues to better understand the individual and combined effects of stiffness, viscoelasticity, and integrin engagement on fibroblast behavior. Here, we developed hyaluronic acid hydrogels with independently tunable cell-instructive properties (stiffness, viscoelasticity, ligand presentation) to address this challenge. Hydrogels with mechanics matching normal or fibrotic lung tissue were synthesized using a combination of covalent crosslinks and supramolecular interactions to tune viscoelasticity. Cell adhesion was mediated through incorporation of either RGD peptide or engineered fibronectin fragments promoting preferential integrin engagement via αvβ3 or α5β1. We showed that preferential αvβ3 engagement enabled human lung fibroblasts to assume a myofibroblast-like phenotype on fibrosis-mimicking stiff elastic hydrogels with increased spreading, actin stress fiber organization, and focal adhesion maturation as indicated by paxillin organization. In contrast, preferential α5β1 binding suppressed these metrics. Viscoelasticity, mimicking the mechanics of healthy tissue, largely curtailed fibroblast spreading and focal adhesion organization independent of adhesive ligand type, highlighting its role in preventing fibroblast activation. Together these results provide new insights into how mechanical and adhesive cues collectively guide disease-relevant cell behaviors.
Phosphatidylinositol phosphate binding domains exhibit complex dissociation properties at the inner leaflet of plasma membrane sheets
Authors: Sponholtz Madeline R. , Senning Eric N. 
Published: February 2021

AbstractThe pleckstrin homology (PH) domain is a lipid targeting motif that binds with high specificity to phosphatidylinositol phosphate (PIP) lipids. Using TIRF microscopy, we followed the dissociation of GFP-tagged PH domains from the plasma membranes of rapidly unroofed cells and found that AKT-PH and PLCδ1-PH dissociation kinetics can be distinguished by their effective koffvalues determined from fitting fluorescence traces to a single exponential equation. Our measurements for the koffof AKT-PH-GFP and PLCδ1-PH-GFP were significantly different (p < 0.05) at 0.39 ± 0.05 s−1and 0.56 ± 0.17 s−1, respectively. Furthermore, we identified substantial rebinding events in our measurements of PLCδ1-PH-GFP dissociation kinetics. By applying inositol triphosphate (IP3) to samples during the unroofing process, we measured a much faster koffof 1.54 ± 0.42 s−1for PLCδ1-PH-GFP, indicating that rebinding events are significantly depressed through competitive action by IP3for the same PH domain binding site as phosphatidylinositol (4,5)-bisphosphate (PIP2). We discuss the complex character of our PLCδ1-PH-GFP fluorescence decays in the context of membrane receptor and ligand theory to address the question of how free PIP2levels modulate the interaction between membrane associated proteins and the plasma membrane.
Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor
Authors: Personnaz Jean , Piccolo Enzo , Dortignac Alizée , Iacovoni Jason S. , Mariette Jérôme , Polizzi Arnaud , Batut Aurélie , Deleruyelle Simon , Paccoud Romain , Moreau Elsa , Martins Frédéric , Clouaire Thomas , Benhamed Fadila , Montagner Alexandra , Wahli Walter A. , Schwabe Robert F. , Yart Armelle , Castan-Laurell Isabelle , Postic Catherine , Moro Cédric , Legube Gaelle , Lee Chih-Hao , Guillou Hervé , Valet Philippe , Dray Cédric , Pradère Jean-Philippe 
Published: February 2021

AbstractDysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specificHmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion ofHmgb1gene enhances LXRα activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXRα. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXRα axis during NAFLD.
Timing of selective basal ganglia white matter loss in Huntington’s disease
Authors: Zeun Paul , McColgan Peter , Dhollander Thijs , Gregory Sarah , Johnson Eileanoir B , Papoutsi Marina , Nair Akshay , Scahill Rachael I , Rees Geraint , Tabrizi Sarah J ,   the TrackOn-HD and HD-YAS Investigators
Published: February 2021

AbstractObjectivesTo investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (WM) loss begins in premanifest Huntington’s disease (preHD), and which striatal and thalamic sub-region WM tracts are most vulnerable.MethodsWe performed fixel-based analysis, which allows resolution of crossing WM fibres at the voxel level, on diffusion tractography derived WM tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated.ResultsWe found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington’s disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated.ConclusionsOur findings suggest that the initiation of disease modifying therapies 25 years before onset could protect these important brain networks from undergoing neurodegeneration and highlight selectively vulnerable sub-regions of the striatum and thalamus that may be important targets for future therapies.
Host preferences of coexisting Perkinsea parasitoids during coastal dinoflagellate blooms
Authors: Reñé Albert , Timoneda Natàlia , Sampedro Nagore , Alacid Elisabet , Gallisai Rachele , Gordi Jordina , Fernández-Valero Alan Denis , Pernice Massimo Ciro , Flo Eva , Garcés Esther 
Published: February 2021

ABSTRACTParasites in aquatic systems are highly diverse and ubiquitous. In marine environments, parasite-host interactions contribute substantially to shaping microbial communities, but their nature and complexity remain poorly understood. In this study, we examined the relationship between Perkinsea parasitoids and bloom-forming dinoflagellate species. Our aim was to determine whether parasite-host species interactions are specific and whether the diversity and distribution of parasitoids are shaped by their dinoflagellate hosts. Several locations along the Catalan coast (NW Mediterranean Sea) were sampled during the blooms of five dinoflagellate species and the diversity of Perkinsea was determined by combining cultivation-based methods with metabarcoding of the V4 region of 18S rDNA. Most known species of Parviluciferaceae, and others not yet described, were detected, some of them coexisting in the same coastal location, and with a wide distribution. The specific parasite-host interactions determined for each of the studied blooms demonstrated the host preferences exhibited by parasitoids in nature. The dominance of a species within the parasitoid community is driven by the presence and abundances of its preferred host(s).The absence of parasitoid species, often associated with a low abundance of their preferred hosts, suggested that high infection rates are reached only under conditions that favour parasitoid propagation, especially dinoflagellate blooms.
A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain
Authors: Martins Daniel , Veronese Mattia , Turkheimer Federico , Howard Matthew A. , Williams Steven CR , Dipasquale Ottavia 
Published: February 2021

AbstractBackgroundChronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI (fMRI) has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, fMRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response.MethodsHere, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) to investigate whether neurotransmission-enriched functional connectivity (FC) mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. Chronic knee osteoarthritis (OA) pain patients (n=56) underwent pre-treatment brain scans in two clinical trials. Study 1 (n=17) was a 2-week single-blinded placebo pill trial. Study 2 (n=39) was a 3-month double-blinded randomized trial comparing placebo to duloxetine, a dual serotonin-noradrenaline reuptake inhibitor.ResultsAcross two independent studies, we found that chronic pain OA patients present FC alterations in the FC related to the serotonin (SERT) and noradrenaline (NET) transporters, when compared to age-matched healthy controls. Placebo responders presented with higher pre-treatment dopamine transporter (DAT)-enriched FC than non-responders. Duloxetine responders presented with higher pre-treatment SERT and NET-enriched FC than non-responders. Pre-treatment SERT and NET-enriched FC achieved predictive positive values of duloxetine response up to 85.71%.ConclusionNeurotransmission-enriched FC mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.
Hot days are associated with short-term adrenocortical responses in a Southern African arid-zone passerine bird
Authors: Moagi Lesedi L. , Bourne Amanda R. , Cunningham Susan J. , Jansen Ray , Ngcamphalala Celiwe A. , Ridley Amanda R. , McKechnie Andrew E. 
Published: February 2021

AbstractNon-invasive methods for investigating the biological effects of environmental variables are invaluable for understanding potential impacts of climate change on behavioural and physiological stress responses of free-ranging animals. Foraging efficiency, body mass maintenance and breeding success are compromised in Southern pied babblers Turdoides bicolor exposed to air temperatures between ~35°C and ~40°C. We tested the hypothesis that these very hot days are acute stressors for free-ranging babblers by quantifying the relationship between daily maximum air temperature (Tmax) and faecal glucocorticoid metabolite (fGCM) levels. We collected naturally-excreted droppings from free-ranging pied babblers and analysed fGCM levels. Levels of fGCMs in droppings collected after 3pm were independent of same-day Tmax < 38 °C and averaged 140.25 ng g−1 Dry Weight ± 56.92 ng g−1 DW (mean ± SD) over this range. Above an inflection Tmax = 38 °C, however, fGCM levels increased linearly with same-day Tmax and averaged 190.79 ng g−1 DW ± 70.13 ng g−1 DW. There was no relationship between Tmax on the previous day and fGCM levels in droppings collected the following morning. Group size, breeding stage, sex and rank did not predict variation in fGCM levels. These results suggest that very high Tmax may be linked to acute, but not chronic, heat stress responses. The fGCM levels we measured are likely to represent a biologically meaningful response to an environmental stressor (high Tmax), suggesting a physiological mechanism underlying observed changes in behaviour and reproductive success at high temperatures in this species.
Transcriptome analysis and connectivity mapping ofCissampelos pareiraL. provides molecular links of ESR1 modulation to viral inhibition
Authors: Haider Madiha , Dholakia Dhwani , Panwar Aleksha , Garg Parth , Gheware Atish , Singh Dayanidhi , Singhal Khushboo , Burse Shaunak A , Kumari Surekha , Anmol  , Ray Arjun , Medigeshi Guruprasad R. , Sharma Upendra , Prasher Bhavana , Mukerji Mitali 
Published: February 2021

AbstractBioactive fractions or compounds obtained from medicinal plants have been used for the treatment of multiple diseases. This effect could be due to common pathways underlying these conditions that are targeted by such medicines. In this study, we explored the molecular basis of action of one such herbal formulationCissampelos pareira, used for the treatment of female hormone disorders and fever. Genome-wide expression studies on MCF7 cell lines treated with Cipa extract were carried out using Affymetrix arrays. Transcriptome analysis revealed a downregulation of signatures of estrogen response governed by estrogen receptor α (ERα). Molecular docking analysis identified 38 constituent molecules in Cipa that potentially bind (ΔG< -7.5) with ERα at the same site as estrogen. Cipa transcriptome signatures show high positive connectivity (https://clue.io/) scores with protein translation inhibitors such as emetine (score: 99.61) and knockdown signatures of genes linked to the antiviral response such as ribosomal protein RPL7 (score: 99.92), which is also an ERα coactivator. Cipa exhibits antiviral activity in dengue infected MCF7 cells that is decreased upon ESR1 (estrogen receptor 1) gene knockdown. This approach reveals a novel pathway involving ESR1-RPL7 axis that could be a potential target in dengue viral infection.
Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures
Authors: Iacone Yasmine , Morais Tatiana P. , David François , Delicata Francis , Sandle Joanna , Raffai Timea , Parri H. Rheinallt , Weisser Johan Juhl , Bundgaard Christoffer , Klewe Ib Vestergaard , Tamás Gábor , Skøtt Thomsen Morten , Crunelli Vincenzo , Lőrincz Magor L. 
Published: February 2021

SummaryObjectiveHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a pro-absence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or inin vitromodel systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, that is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested followingin vivomicroinjection in the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices.MethodsWe used EEG recordings in freely moving Genetic Absence Epilepsy from Strasbourg Rats (GAERS) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected in the CIN and VB of GAERSin vivoand applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical layer 5/6 and thalamocortical neurons, respectively.ResultsOral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection in CIN abolished ASs and elicited small-amplitude 4-7 Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN-channel-dependent properties of cortical layer 5/6 pyramidal and thalamocortical neurons, respectively.SignificanceThese results provide the first demonstration of the anti-absence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.
Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave
Authors: Hohsfield Lindsay A. , Najafi Allison R. , Ghorbanian Yasamine , Soni Neelakshi , Crapser Joshua D. , Figueroa Velez Dario X. , Jiang Shan , Royer Sarah E. , Kim Sung Jin , Anderson Aileen J. , Gandhi Sunil P. , Mortazavi Ali , Inlay Matthew A. , Green Kim N. 
Published: February 2021

AbstractMicroglia, the brain’s resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using sustained colony-stimulating factor 1 receptor inhibition, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from an important neurogenic niche, the subventricular zone, and associated white matter areas. These cells exhibit tremendous chemotaxis potential, migrating radially and tangentially in a dynamic wave and filling the brain in a distinct pattern, to fully replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit distinct phenotypic and functional profiles to endogenous microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into myeloid cell dynamics in an empty microglial niche without contributions from bone marrow-derived cells.
Multistage classification identifies altered cortical phase- and amplitude-coupling in Multiple Sclerosis
Authors: Siems Marcus , Tünnerhoff Johannes , Ziemann Ulf , Siegel Markus 
Published: February 2021

AbstractDistinguishing groups of subjects or experimental conditions in a high-dimensional feature space is a common goal in modern neuroimaging studies. Successful classification depends on the selection of relevant features as not every neuronal signal component or parameter is informative about the research question at hand. Here, we developed a novel unsupervised multistage analysis approach that combines dimensionality reduction, bootstrap aggregating and multivariate classification to select relevant neuronal features. We tested the approach by identifying changes of brain-wide electrophysiological coupling in Multiple Sclerosis. Multiple Sclerosis is a demyelinating disease of the central nervous system that can result in cognitive decline and physical disability. However, related changes in large-scale brain interactions remain poorly understood and corresponding non-invasive biomarkers are sparse. We thus compared brain-wide phase- and amplitude-coupling of frequency specific neuronal activity in relapsing-remitting Multiple Sclerosis patients (n = 17) and healthy controls (n = 17) using magnetoencephalography. Our analysis approach allowed us to identify systematic and non-redundant changes of both phase- and amplitude-coupling in the diseased brain. Changes included both, increased and decreased neuronal coupling in wide-spread, bilateral neuronal networks across a broad range of frequencies. These changes allowed to successfully classify patients and controls with an accuracy of 84%. Furthermore, classification confidence predicted behavioral scores of disease severity. In sum, our results unravel systematic changes of large-scale phase- and amplitude coupling in Multiple Sclerosis. Furthermore, our results establish a new analysis approach to efficiently contrast high-dimensional neuroimaging data between experimental groups or conditions.HighlightsA novel multistage approach to analyze high-dimensional neuronal coupling data.Application to MEG recordings in relapsing-remitting Multiple Sclerosis patients.Identification of altered phase- and amplitude-coupling in Multiple Sclerosis.Classification of patients and controls with 84% accuracy.Classification confidence predicts behavioral scores of disease severity.
Escherichia colirobustly expresses ATP synthase at growth rate maximizing concentrations
Authors: Rabbers Iraes , Bruggeman Frank J 
Published: February 2021

AbstractImproved protein expression is an important evolutionary adaptation of bacteria. A key question is whether evolution has led to optimal protein expression that maximizes immediate growth rate (short-term fitness) across conditions. Alternatively, fitter genetic variants could display suboptimal short-term fitness, because they cannot do better or because they strive for long-term fitness maximization by, for instance, anticipating future conditions. To answer this question, we focus on the ATP-producing enzyme F1F0H+-ATPase, which is an abundant enzyme and ubiquitously expressed across conditions. We tested the optimality of H+-ATPase expression inEscherichia coliacross 27 different nutrient conditions. In all tested conditions, wild-typeE. coliexpresses its H+- ATPase remarkably close to optimal concentrations that maximize immediate growth rate. This work indicates that bacteria can achieve robust optimal protein expression for immediate growth- rate.