bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment
Authors: Mournetas Virginie , Massouridès Emmanuelle , Dupont Jean-Baptiste , Kornobis Etienne , Polvèche Hélène , Jarrige Margot , Gosselin Maxime R. F. , Manousopoulou Antigoni , Garbis Spiros D. , Górecki Dariusz C. , Pinset Christian 
Published: August 2019

ABSTRACTDuchenne muscular dystrophy (DMD) causes severe disability of children and death of young men, with an incidence of approximately 1/5,000 male births. Symptoms appear in early childhood, with a diagnosis made around 4 years old, a time where the amount of muscle damage is already significant, preventing early therapeutic interventions that could be more efficient at halting disease progression. In the meantime, the precise moment at which disease phenotypes arise – even asymptomatically – is still unknown. Thus, there is a critical need to better define DMD onset as well as its first manifestations, which could help identify early disease biomarkers and novel therapeutic targets.In this study, we have used human induced pluripotent stem cells (hiPSCs) from DMD patients to model skeletal myogenesis, and compared their differentiation dynamics to that of healthy control cells by a comprehensive multi-omic analysis. Transcriptome and miRnome comparisons combined with protein analyses at 7 time points demonstrated that hiPSC differentiation 1) mimics described DMD phenotypes at the differentiation endpoint; and 2) homogeneously and robustly recapitulates key developmental steps - mesoderm, somite, skeletal muscle - which offers the possibility to explore dystrophin functions and find earlier disease biomarkers.Starting at the somite stage, mitochondrial gene dysregulations escalate during differentiation. We also describe fibrosis as an intrinsic feature of skeletal muscle cells that starts early during myogenesis. In sum, our data strongly argue for an early developmental manifestation of DMD whose onset is triggered before the entry into the skeletal muscle compartment, data leading to a necessary reconsideration of dystrophin functions during muscle development.
Apolipoprotein A-I Mimetic 4F Peptide Generates Amyloid Cytotoxins by Forming Hetero-oligomers with β-amyloid
Authors: Sahoo Bikash Ranjan , Bekier Michael E. , Liu Zichen , Kocman Vojc , Stoddard Andrea K. , Anantharamaiah G. M. , Nowick James , Fierke Carol A. , Wang Yanzhuang , Ramamoorthy Ayyalusamy 
Published: August 2019

AbstractApolipoproteins are involved in pathological conditions of Alzheimer’s disease (AD), truncated apolipoprotein fragments and β-amyloid (Aβ) peptides coexist as neurotoxic heteromers within the plaques. Therefore, it is important to investigate these complexes at the molecular level to better understand their properties and roles in the pathology of AD. Here, we present a mechanistic insight into such heteromerization using a structurally homologue apolipoprotein fragment of apoA-I (4F) complexed with Aβ(M1-42) and characterize their toxicity. The 4F peptide slows down the aggregation kinetics of Aβ(M1-42) by constraining its structural plasticity. NMR and CD experiments identified 4F-Aβ(M1-42) heteromers as being comprised of unstructured Aβ(M1-42) and helical 4F. A uniform ≈2-fold reduction in Aβ4215N/1H NMR signal intensities with no observable chemical shift perturbation indicated the formation of a large complex, which was further confirmed by diffusion NMR experiments. Microsecond scale atomistic molecular dynamics simulations showed that 4F interaction with Aβ(M1-42) is electrostatically driven and induces unfolding of Aβ(M1-42). Neurotoxicity profiling of Aβ(M1-42) complexed with 4F confirms a significant reduction in cell-viability and neurite growth. The molecular architecture of heteromerization between 4F and Aβ(M1-42) discovered in this study provides evidence towards our understanding of the role of apolipoproteins or their truncated fragments in exacerbating AD pathology.
Organoid-derived Duodenum Intestine-Chip for preclinical drug assessment in a human relevant system
Authors: Kasendra Magdalena , Luc Raymond , Yin Jianyi , Manatakis Dimitris V. , Apostolou Athanasia , Sunuwar Laxmi , Obrigewitch Jenifer , Hamilton Geraldine A. , Donowitz Mark , Karalis Katia 
Published: August 2019

AbstractInduction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organ-Chip technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo-relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.
Characterization of TAG-63 and its role on axonal transport inC. elegans
Authors: Bhan Prerana , Shanmugam Muniesh Muthaiyan , Wang Ding , Bayansan Odvogmed , Chen Chih-Wei , Wagner Oliver Ingvar 
Published: August 2019

ABSTRACTModel organisms are increasingly used to study and understand how neurofilament (NF)-based neurological diseases develop. However, whether a NF homolog exists inC. elegansremains unclear. We characterize TAG-63 as a NF-like protein with sequence homologies to human NEFH carrying various coiled coils as well as clustered phosphorylation sites. TAG-63 also exhibits features of NFL such as a molecular weight of around 70 kD, the lack of KSP repeats and the ability to form 10 nm filamentous structures in transmission electron micrographs. An anti-NEFH antibody detects a band at the predicted molecular weight of TAG-63 in Western blots of whole worm lysates and this band cannot be detected intag-63knockout worms. A transcriptionaltag-63reporter expresses in a broad range of neurons, and various anti-NFH antibodies stain worm neurons with an overlapping expression of axonal vesicle transporter UNC-104(KIF1A). Cultured neurons grow shorter axons when incubating with drugs known to disintegrate the NF network and rhodamine-labeledin vitroreconstituted TAG-63 filaments disintegrate upon drug exposure. Speeds of UNC-104 motors are diminished intag-63mutant worms with visibly increased accumulations of motors along axons. UNC-104/TAG-63 and SNB-1/TAG-63 not only co-localize in neurons but also revealed positive BiFC (bimolecular fluorescence assay) signals.
“Deciphering the amyloid foldome of TDP-43”
Authors: Mompeán Miguel , Buratti Emanuele , Laurents Douglas V. 
Published: August 2019

ABSTRACTTDP-43 is an essential regulator of RNA splicing and metabolism and its aggregates play key roles in devastating diseases, including Amyotrophic Lateral Sclerosis (ALS)1, Frontotemporal Dementia (FTD) and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)2. Besides this pathological aggregation, TDP-43’s oligomerization also serves vital functions3, which adds urgency to determine pathological conformations of TDP-43. The recently published cryo-EM study by Cao, Eisenberg and coworkers now reveals amyloid structures of putative pathological aggregates from TDP-43’s C-terminal region4. Whereas the Cao et al.’s cryo-EM structures contain both the hydrophobic and Q/N-rich segments, the data were interpreted mainly through the lens of hydrophobic contacts. However, the Q/N-rich region can form amyloid on its own5,6 and therefore additional considerations of the Q/N-rich segment’s contributions will advance our understanding of TDP-43 aggregation.
Dynamics of activating and repressive histone modifications in Drosophila neural stem cell lineages and brain tumors
Authors: Abdusselamoglu Merve Deniz , Landskron Lisa , Bowman Sarah K. , Eroglu Elif , Burkard Thomas , Kingston Robert E. , Knoblich Juergen A. 
Published: August 2019

AbstractDuring central nervous system (CNS) development, spatiotemporal gene expression programs mediate specific lineage decisions to generate neuronal and glial cell types from neural stem cells (NSCs). However, little is known about the epigenetic landscape underlying these highly complex developmental events. Here, we perform ChIP-seq on distinct subtypes of Drosophila FACS-purified neural stem cells (NSCs) and their differentiated progeny to dissect the epigenetic changes accompanying the major lineage decisions in vivo. By analyzing active and repressive histone modifications, we show that stem cell identity genes are silenced during differentiation by loss of their activating marks and not via repressive histone modifications. Our analysis also uncovers a new set of genes specifically required for altering lineage patterns in type II neuroblasts, one of the two main Drosophila NSC identities. Finally, we demonstrate that this subtype specification in NBs, unlike NSC differentiation, requires Polycomb-group (PcG)-mediated repression.Summary statementDynamic epigenetic landscape of Drosophila neural stem cell lineages.
Correction of Niemann-Pick type C1 disease with the histone deacetylase inhibitor valproic acid
Authors: Subramanian Kanagaraj , Hutt Darren M , Gupta Vijay , Mao Shu , Balch William E. 
Published: August 2019

AbstractNiemann-Pick type C (NPC) disease is primarily caused by mutations in the NPC1 gene and is characterized by the accumulation of unesterified cholesterol and lipids in the late endosomal (LE) and lysosomal (Ly) compartments. The most prevalent disease-linked mutation is the I1061T variant of NPC1, which exhibits defective folding and trafficking from the endoplasmic reticulum to the LE/Ly compartments. We now show that the FDA-approved histone deacetylase inhibitor (HDACi) valproic acid (VPA) corrects the folding and trafficking defect associated with I1061T-NPC1 leading to restoration of cholesterol homeostasis, an effect that is largely driven by a reduction in HDAC7 expression. The VPA-mediated trafficking correction is in part associated with an increase in the acetylation of lysine residues in the cysteine-rich domain of NPC1. The HDACi-mediated correction is synergistically improved by combining it with the FDA-approved anti-malarial, chloroquine, a known lysosomotropic compound, which improved the stability of the LE/Ly-localized fraction of the I1061T variant. We posit that combining the activity of VPA, to modulate epigentically the cellular acetylome, with chloroquine, to alter the lysosomal environment to favor stability of the trafficked I1061T variant protein, can have a significant therapeutic benefit in patients carrying at least one copy of the I1061T variant of NPC1, the most common disease-associated mutation leading to NPC disease. Given its ability to cross the blood brain barrier, we posit VPA provides a potential mechanism to improve the response to 2-hydroxypropyl-β-cyclodextrin, by restoring functional NPC1 to cholesterol managing compartment as an adjunct therapy.
Origin of Conformational Dynamics in a Globular Protein
Authors: Damry Adam M. , Mayer Marc M. , Broom Aron , Goto Natalie K. , Chica Roberto A. 
Published: August 2019

AbstractProtein structures are dynamic, undergoing specific motions that can play a vital role in function. However, the link between primary sequence and conformational dynamics remains poorly understood. Here, we studied how conformational dynamics can arise in a globular protein by evaluating the impact of individual substitutions of core residues in DANCER-3, a streptococcal protein G domain β1 (Gβ1) variant that we previously designed to undergo a specific mode of conformational exchange that has never been observed in the wild-type protein. Using a combination of solution NMR experiments and molecular dynamics simulations, we demonstrate that only two mutations are necessary to create this conformational exchange, and that these mutations work synergistically, with one destabilizing the native Gβ1 structure and the other allowing two new conformational states to be accessed on the energy landscape. Overall, our results show how conformational dynamics can appear in a stable globular fold, a critical step in the molecular evolution of new dynamics-linked functions.
Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma
Authors: Jerby-Arnon Livnat , Neftel Cyril , Shore Marni E. , McBride Matthew J. , Haas Brian , Izar Benjamin , Weissman Hannah R. , Volorio Angela , Boulay Gaylor , Cironi Luisa , Richman Alyssa R. , Broye Liliane C. , Gurski Joseph M. , Luo Christina C. , Mylvaganam Ravindra , Nguyen Lan , Mei Shaolin , Melms Johannes c. , Georgescu Christophe , Cohen Ofir , Buendia-Buendia Jorge E. , Cuoco Michael S. , Labes Danny , Zollinger Daniel R. , Beechem Joseph M. , Nielsen G. Petur , Chebib Ivan , Cote Gregory , Choy Edwin , Letovanec Igor , Cherix Stéphane , Wagle Nikhil , Sorger Peter K. , Haynes Alex B. , Mullen John T. , Stamenkovic Ivan , Rivera Miguel N. , Kadoch Cigall , Rozenblatt-Rosen Orit , Suvà Mario L. , Riggi Nicolò , Regev Aviv 
Published: August 2019

ABSTRACTSynovial sarcoma is an aggressive mesenchymal neoplasm, driven by the SS18-SSX fusion, and characterized by immunogenic antigens expression and exceptionally low T cell infiltration levels. To study the cancer-immune interplay in this disease, we profiled 16,872 cells from 12 human synovial sarcoma tumors using single-cell RNA-sequencing (scRNA-Seq). Synovial sarcoma manifests antitumor immunity, high cellular plasticity and a core oncogenic program, which is predictive of low immune levels and poor clinical outcomes. Using genetic and pharmacological perturbations, we demonstrate that the program is controlled by the SS18-SSX driver and repressed by cytokines secreted by macrophages and T cells in the tumor microenvironment. Network modeling predicted that SS18-SSX promotes the program through HDAC1 and CDK6. Indeed, the combination of HDAC and CDK4/6 inhibitors represses the program, induces immunogenic cell states, and selectively targets synovial sarcoma cells. Our study demonstrates that immune evasion, cellular plasticity, and cell cycle are co-regulated and can be co-targeted in synovial sarcoma and potentially in other malignancies.
Arabidopsis ECERIFERUM3 (CER3) Plays a Critical Role in Maintaining Hydration for Pollen-Stigma Recognition during Fertilization
Authors: Xu Faqing , Li Xiaojing , Yang Zhongnan , Zhang Sen 
Published: August 2019

ABSTRACTPlants distinguish the pollen grains that land on their stigmas, only allowing compatible pollen to fertilize female gametes. To analyze the underlying mechanism, conditional male-sterile mutations with affected pollen coat and disrupted pollen-stigma recognition were isolated and described. The mutant pollen failed to germinate, but germinated in vitro, suggesting that they are viable. In mutants, stigma cells that contacted their own pollen generated callose, a carbohydrate produced in response to foreign pollen. High humidity restored pollen hydration and successful fertilization, indicating defective dehydration in pollen-stigma interaction. Further analysis results from mixed pollination experiments demonstrated that the mutant pollen specifically lacked a functional pollen-stigma recognition system. The sterile plants lacked stem waxes and displayed postgenital fusion between aerial floral organs. In addition, the mutant pollen was deficient in long-chain lipids and had excess tryphine. Transmission electron microscopy observation showed that mutant pollen had almost the same surface structure as the wild type at bicellular pollen stage. However, abnormal plastoglobuli were observed in the plastids of the mutant tapetum, which was indicative of altered lipid accumulation. CER3 transcript was found in anther tapetum and microspores at development stage 9 while CER3-GFP fusion protein was localized to the cell plasma membrane. Our data reveal that CER3 is required for biosynthesis of tryphine lipids which play a critical role in maintaining hydration for pollen-stigma recognition during fertilization.
Structure determination from lipidic cubic phase embedded microcrystals by MicroED
Authors: Zhu Lan , Bu Guanhong , Jing Liang , Shi Dan , Gonen Tamir , Liu Wei , Nannenga Brent L. 
Published: August 2019

AbstractThe lipidic cubic phase (LCP) technique has proved to facilitate the growth of high-quality crystals that are otherwise difficult to grow by other methods. Because crystals grown in LCP can be limited in size, improved techniques for structure determination from these small crystals are important. Microcrystal electron diffraction (MicroED) is a technique that uses a cryo-TEM to collect electron diffraction data and determine high-resolution structures from very thin micro and nanocrystals. In this work, we have used modified LCP and MicroED protocols to analyze crystals embedded in LCP. Proteinase K in LCP was used as a model system, and several LCP sample preparation strategies were tested. Among these, treatment with 2-Methyl-2,4-pentanediol (MPD) and lipase were both able to reduce the viscosity of the LCP and produce quality cryo-EM grids with well-diffracting crystals. These results set the stage for the use of MicroED to analyze other microcrystalline samples grown in LCP.
WT and A53T α-synuclein systems: Melting Diagram and its new interpretation
Authors: Bokor M. , Tantos Á. , Tompa P. , Han K.-H. , Tompa K. 
Published: August 2019

AbstractParkinson’s disease is connected with abnormal α-synuclein (αS) aggregation. Energetics of potential barriers governing motions of hydration water is examined. Information about the distributions and heights of potential barriers is gained by a thermodynamical approach. The ratios of the heterogeneous water-binding interfaces measure proteins’ structural disorder. All αS forms possess secondary structural elements though they are intrinsically disordered. Monomers are functional at the lowest potential barriers, where mobile hydration water exists, with monolayer coverage of mobile hydration. The αS monomer contains 33% secondary structure and is more compact than a random coil. A53T αS monomer has a more open structure than the wild type. Monomers realize all possible hydrogen bonds. Half of the mobile hydration water amount for monomers is missing in αS oligomers and αS amyloids. Oligomers are ordered by 66%. Mobile water molecules in the first hydration shell of amyloids are the weakest bound compared to other forms. Wild type and A53T amyloids show identical, low-level hydration, and are considered as disordered to 75%.Statement of SignificanceAggregation of α-synuclein into oligomers, amyloid fibrils is a hallmark of Parkinson’s disease. A thermodynamic approach provides information on the heterogeneity of protein-water bonds in the wild type and A53T mutant monomers, oligomers, amyloids. This information can be related to ratios of heterogeneous water-binding interfaces, which measure the proteins’ structural disorder. Both α-synuclein monomers are intrinsically disordered. The monomers nevertheless have 33% secondary structure. They are functional as long as mobile water molecules surround them. They realize every possible H-bonds with water. Oligomers are like globular proteins with 66% ordered structure. Amyloids are disordered to 75% and are poorly hydrated with loosely bound water. Their hydration is identical. Oligomers, amyloids have only half as much hydrating mobile water as monomers.
Exploring endocytic compartment morphology with systematic genetics and single cell image analysis
Authors: Usaj Mojca Mattiazzi , Sahin Nil , Friesen Helena , Pons Carles , Usaj Matej , Masinas Myra Paz , Shuteriqi Ermira , Shkurin Aleksei , Aloy Patrick , Morris Quaid , Boone Charles , Andrews Brenda J. 
Published: August 2019

ABSTRACTEndocytosis is a conserved process that mediates the internalization of nutrients and plasma membrane components, including receptors, for sorting to endosomes and the vacuole (lysosome). We combined systematic yeast genetics, high-content screening, and neural network-based image analysis of single cells to screen for genes that influence the morphology of four main endocytic compartments: coat proteins, actin patches, late endosome, and vacuole. This unbiased approach identified 17 mutant phenotypes and ∼1600 genes whose perturbation affected at least one of the four compartments. Numerous mutants were associated with multiple phenotypes, indicating that morphological pleiotropy is often seen within the endocytic pathway. Morphological profiles based on the 17 aberrant phenotypes were highly correlated for functionally related genes, enabling prediction of gene function. Incomplete penetrance was prevalent, and single-cell analysis enabled exploration of the mechanisms underlying cellular heterogeneity, which include replicative age, organelle inheritance, and stress response.
Effective design and development of hybrid ABC-CSO-based capacitor placement with load forecasting based on artificial neural network
Authors: Sharma Sarika , Ghosh Smarajit 
Published: August 2019

PurposeThis paper aims to develop a capacitor position in radial distribution networks with a specific end goal to enhance the voltage profile, diminish the genuine power misfortune and accomplish temperate sparing. The issue of the capacitor situation in electric appropriation systems incorporates augmenting vitality and peak power loss by technique for capacitor establishments.Design/methodology/approachThis paper proposes a novel strategy using rough thinking to pick reasonable applicant hubs in a dissemination structure for capacitor situation. Voltages and power loss reduction indices of distribution networks hubs are shown by fuzzy enrollment capacities.FindingsA fuzzy expert system containing a course of action of heuristic rules is then used to ascertain the capacitor position appropriateness of each hub in the circulation structure. The sizing of capacitor is solved by using hybrid artificial bee colony–cuckoo search optimization.Practical implicationsFinally, a short-term load forecasting based on artificial neural network is evaluated for predicting the size of the capacitor for future loads. The proposed capacitor allocation is implemented on 69-node radial distribution network as well as 34-node radial distribution network and the results are evaluated.Originality/valueSimulation results show that the proposed method has reduced the overall losses of the system compared with existing approaches.