bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simulation of FUS protein condensates with an adapted coarse-grained model
Authors: Benayad Zakarya , von Bülow Sören , Stelzl Lukas S. , Hummer Gerhard 
Published: October 2020

AbstractDisordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor ofαc≈ 0.6, FUS LCD condensation is observed, whereα= 1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factorα= 0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01 to 0.4mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02Pas for the FUS LCD droplets with scaling factorsαin the range of 0.625 to 0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
Extended and dynamic linker histone-DNA interactions control chromatosome compaction
Authors: Rudnizky Sergei , Khamis Hadeel , Ginosar Yuval , Goren Efrat , Melamed Philippa , Kaplan Ariel 
Published: October 2020

AbstractChromatosomes play a fundamental role in chromatin regulation, but a detailed understanding of their structure is lacking, partially due to their complex dynamics. Using single-molecule DNA unzipping with optical tweezers, we reveal that linker histone interactions with DNA are remarkably extended, with the C-terminal domain binding both DNA linkers as far as ~ ±140 bp from the dyad. In addition to a symmetrical compaction of the nucleosome core governed by globular domain contacts at the dyad, the C-terminal domain compacts the nucleosome’s entry and exit. These interactions are dynamic, exhibiting rapid binding and dissociation, sensitive to phosphorylation of a specific residue, and crucial to determining the symmetry of the chromatosome’s core. Extensive unzipping of the linker DNA, which mimics its invasion by motor proteins, shifts H1 into an asymmetric, off-dyad configuration and triggers nucleosome decompaction, highlighting the plasticity of the chromatosome structure and its potential regulatory role.
Lis1 mutation prevents basal radial glia-like cell production in the mouse
Authors: Penisson Maxime , Hirotsune Shinji , Francis Fiona , Belvindrah Richard 
Published: October 2020

AbstractHuman cortical malformations are associated with progenitor proliferation and neuronal migration abnormalities. Progenitor cells include apical radial glia, intermediate progenitors and basal (or outer) radial glia (bRGs or oRGs). bRGs are few in number in lissencephalic species (e.g. the mouse) but abundant in gyrencephalic brains. TheLIS1gene coding for a dynein regulator, is mutated in human lissencephaly, associated also in some cases with microcephaly. LIS1 was shown to be important during cell division and neuronal migration. Here, we generated bRG-like cells in the mouse embryonic brain, investigating the role of Lis1 in their formation. This was achieved byin uteroelectroporation of a hominoid-specific geneTBC1D3(coding for a RAB-GAP protein) at mouse embryonic day (E) 14.5. We first confirmed thatTBC1D3expression in wild-type (WT) brain generates numerous Pax6+bRG-like cells that are basally localized. Second, using the same approach, we assessed the formation of these cells in heterozygoteLis1 mutant brains. Our novel results show thatLis1 depletion in the forebrain from E9.5 prevented subsequentTBC1D3-induced bRG-like cell amplification. Indeed, we observe disruption of the ventricular zone (VZ) in the mutant.Lis1 depletion altered adhesion proteins and mitotic spindle orientations at the ventricular surface and increased the proportion of abventricular mitoses. Progenitor outcome could not be further altered by TBC1D3. We conclude that perturbation ofLis1/LIS1 dosage is likely to be detrimental for appropriate progenitor number and position, contributing to lissencephaly pathogenesis.
Aberrant replication licensing drives Copy Number Gains across species
Authors: Nathanailidou Patroula , Petropoulos Michalis , Maxouri Styliani , Kasselimi Eirini , Symeonidou Ioanna Eleni , Preza Ourania , Spiliopoulou-Sdougkou Iris , Beneš Vladimir , Taraviras Stavros , Lygerou Zoi 
Published: October 2020

AbstractCopy Number Gains (CNGs) lead to genetic heterogeneity, driving evolution and carcinogenesis. The mechanisms promoting CNG formation however remain poorly characterized. We show that abnormal expression of the replication licensing factor Cdc18 in fission yeast, which leads to genome-wide re-replication, drives the formation of CNGs at different genomic loci, promoting the acquisition of new selectable traits. Whole genome sequencing reveals Mb long, primarily extrachromosomal amplicons. Genetic analysis shows that homology-mediated repair is required to resolve re-replication intermediates into heritable CNGs. Consistently, we show that in mammalian cells overexpression of CDC6 and/or CDT1 leads to CNGs and promotes drug resistance. In human cells, multiple repair pathways are activated upon rereplication and act antagonistically, with RAD52 promoting and 53BP1 inhibiting CNG formation. In tumours, CDT1 and/or CDC6 overexpression correlates with copy number gains genome-wide. We propose re-replication as an evolutionary-conserved driver of CNGs, highlighting a link between aberrant licensing, CNGs and cancer.
Innate Behavior Sequence Progression by Peptide-Mediated Interorgan Crosstalk
Authors: Heredia Fabiana , Volonté Yanel , Pereirinha Joana , Fernandez-Acosta Magdalena , Casimiro Andreia P. , Belém Cláudia G. , Viegas Filipe , Tanaka Kohtaro , Menezes Juliane , Arana Maite , Cardoso Gisele A. , Macedo André , Kotowicz Malwina , Prado Spalm Facundo H. , Dibo Marcos J. , Monfardini Raquel D. , Torres Tatiana T. , Mendes César S. , Garelli Andres , Gontijo Alisson M. 
Published: October 2020

AbstractInnate behaviors consist of a succession of genetically-hardwired motor and physiological subprograms that can be coupled to drastic morphogenetic changes. How these integrative responses are orchestrated is not completely understood. Here, we provide insight into these mechanisms by studying pupariation, a multi-step innate behavior of fly larvae that is critical for survival during metamorphosis. We find that the steroid-hormone ecdysone triggers parallel pupariation neuromotor and morphogenetic subprograms, which include the induction of the relaxin-peptide hormone, Dilp8, in the epidermis. Dilp8 acts on six Lgr3-positive thoracic interneurons to couple both subprograms in time and to instruct neuromotor subprogram switching during behavior. Our work reveals that interorgan feedback gates progression between subunits of an innate behavior and points to an ancestral neuromodulatory function of relaxin signaling.
sc-REnF:An entropy guided robust feature selection for clustering of single-cell rna-seq data
Authors: Lall Snehalika , Ghosh Abhik , Ray Sumanta , Bandyopadhyay Sanghamitra 
Published: October 2020

ABSTRACTMany single-cell typing methods require pure clustering of cells, which is susceptible towards the technical noise, and heavily dependent on high quality informative genes selected in the preliminary steps of downstream analysis. Techniques for gene selection in single-cell RNA sequencing (scRNA-seq) data are seemingly simple which casts problems with respect to the resolution of (sub-)types detection, marker selection and ultimately impacts towards cell annotation. We introducesc-REnF, a novel androbustentropy basedfeature (gene) selection method, which leverages the landmark advantage of ‘Renyi’ and ‘Tsallis’ entropy achieved in their original application, in single cell clustering. Thereby, gene selection is robust and less sensitive towards the technical noise present in the data, producing a pure clustering of cells, beyond classifying independent and unknown sample with utmost accuracy. The corresponding software is available at:https://github.com/Snehalikalall/sc-REnF
Introducing and benchmarking the accuracy of cayenne: a Python package for stochastic simulations
Authors: Kishore Dileep , Chandrasekaran Srikiran 
Published: October 2020

AbstractBiological systems are intrinsically noisy and this noise may determine the qualitative outcome of the system. In the absence of analytical solutions to mathematical models incorporating noise, stochastic simulation algorithms are useful to explore the possible trajectories of these systems. Algorithms used for such stochastic simulations include the Gillespie algorithm and its approximations. In this study we introduce cayenne, an easy to use Python package containing accurate and fast implementations of the Gillespie algorithm (direct method), the tau-leaping algorithm and a tau-adaptive algorithm. We compare the accuracy of cayenne with other stochastic simulation libraries (BioSimulator.jl, GillespieSSA and Tellurium) and find that cayenne offers the best trade-off between accuracy and speed. Additionally, we highlight the importance of performing accuracy tests for stochastic simulation libraries, and hope that it becomes standard practice when developing the same.The cayenne package can be found athttps://github.com/Heuro-labs/cayennewhile the bench-marks can be found athttps://github.com/Heuro-labs/cayenne-benchmarks
The Synergism Between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia
Authors: Gaidano Valentina , Houshmand Mohammad , Vitale Nicoletta , Carrà Giovanna , Morotti Alessandro , Tenace Valerio , Rapelli Stefania , Sainas Stefano , Pippione Agnese Chiara , Giorgis Marta , Boschi Donatella , Lolli Marco Lucio , Cignetti Alessandro , Saglio Giuseppe , Circosta Paola 
Published: October 2020

AbstractBackgroundDihydroorotate Dehydrogenase (DHODH) is a key enzyme of thede novopyrimidine biosynthesis, whose inhibition was recently found to induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors were previously investigated in solid tumors, where they showed promising antiproliferative activity, bothin vitroandin vivo. However, their effectiveness was not confirmed in clinical trials, probably due to the pyrimidine salvage pathway that cancer cells could exploit to survive. In this study we investigated the pro-apoptotic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we challenged our model mimickingin vivoconditions, and looked for synergic combination to boost apoptosis.MethodsWe evaluated the apoptotic rate of multiple AML cell lines and AML primary cells treated with MEDS433 or other DHODH inhibitors, alone and in combination with classical antileukemic drugs or with dipyridamole, a blocker of the pyrimidine salvage pathway. Experiments were also performed mimickingin vivoconditions, i.e., in the presence of physiological uridine plasma levels (5μM).ResultsMEDS433 showed a strong apoptotic effect against multiple AML cell lines, which was at least partially independent from the differentiation process. Its combination with classical antileukemic agents resulted in a further increase of the apoptotic rate. However, when MEDS433 was tested in the presence of 5μM uridine and/or in primary AML cells, results were less impressive. On the contrary, the combination of MEDS433 with dipyridamole resulted in an outstanding synergistic effect, with a dramatic increase of the apoptotic rate both in AML cell lines and AML primary cells, which was unaffected by physiological uridine concentrations. Preliminary analyses show that the toxicity of this treatment should be limited to proliferating cells.ConclusionsThe combination of a DHODH inhibitor and dipyridamole is characterized by differentiating and pro-apoptotic features and induces metabolic lethality on a wide variety of AMLs with different genetic backgrounds.
Animal chromosome counts reveal similar range of chromosome numbers but with less polyploidy in animals compared to flowering plants
Authors: Román-Palacios Cristian , Medina Cesar A. , Zhan Shing H. , Barker Michael S. 
Published: October 2020

AbstractUnderstanding the mechanisms that underlie chromosome evolution may provide insights into the processes underpinning the origin, persistence, and evolutionary tempo of lineages. Here we present the first database of chromosome counts for animals (the Animal Chromosome Count database, ACC) summarizing chromosome numbers for ∼18,000 species. We found remarkable similarity in the distribution of chromosome counts between animals and flowering plants. At larger timescales, selection towards a specific range might explain the similar distribution of chromosome counts between these two groups. Nevertheless, changes in chromosome number are still potential drivers of divergence among species at shorter timescales. We also found that while animals and plants exhibit similar frequencies of speciation-related changes in chromosome number, plant speciation is more often related to changes in ploidy. Based on the ACC, our analyses suggest that changes in chromosome number alone could help explain patterns of diversity within animal clades.
Brain aging-dependent glioma traits reversible by NAD+/BDNF-mediated neuronal reactivation
Authors: Yamashita Daisuke , Flanary Victoria L , Munk Rachel B , Sonomura Kazuhiro , Ozaki Saya , Kawaguchi Riki , Suehiro Satoshi , Bastola Soniya , Pavlyukov Marat S , Yamaguchi Shinobu , Nakano Mayu A , Kunieda Takeharu , Hambardzumyan Dolores , Kondo Toru , Kornblum Harley I , Crossman David K , Hackney James R , Sato Taka-aki , Gorospe Myriam , Nakano Ichiro 
Published: October 2020

SummaryThe rise in aging population worldwide is increasing death from cancer, including glioblastoma. Here, we explore the impact of brain aging on glioma tumorigenesis. We find that glioblastoma in older patients and older mice displayed reduced neuronal signaling, including a decline of NTRK-like family member 6 (SLITRK6), a receptor for neurotrophic factor BDNF. This reduction was linked to the systemic decline of nicotinamide adenine dinucleotide (NAD+) with aging, as old mice exposed to young bloodviaparabiosis or supplemented with the NAD+precursor NMN (nicotinamide mononucleotide) reverted phenotypically to young-brain responses to glioma, with reactivated neuronal signaling and reduced death from tumor burden. Interestingly, the phenotypic reversal by NMN was largely absent in old mice undergoing parabiosis with BDNF+/-young mice and in BDNF+/-mice undergoing tumor challenge, supporting the notion that the lower NAD+-BDNF signaling in the aging brain aggravated glioma tumorigenesis. We propose that the aging-associated decline in brain NAD+worsens glioma outcomes at least in part by decreasing neuronal/synaptic activity and increasing neuroinflammation.
Flexible and transparent silver nanowire structures for multifunctional electrical and optical biointerfacing
Authors: Chen Zhiyuan , Boyajian Nicolas , Lin Zexu , Yin Rose T. , Obaid Sofian N. , Tian Jinbi , Brennan Jaclyn A. , Chen Sheena W. , Miniovich Alana N. , Lin Leqi , Qi Yarong , Liu Xitong , Efimov Igor R. , Lu Luyao 
Published: October 2020

AbstractTransparent microelectrodes have recently emerged as a promising approach to combine electrophysiology with optophysiology for multifunctional biointerfacing. High-performance flexible platforms that allow seamless integration with soft tissue systems for such applications are urgently needed. Here, silver nanowires (Ag NWs)-based transparent microelectrodes and interconnects are designed to meet this demand. The Ag NWs percolating networks are patterned on flexible polymer substrates using an innovative photolithography-based solution-processing technique. The resulting nanowire networks exhibit a high average optical transparency of 76.1-90.0% over the visible spectrum, low normalized electrochemical impedance of 3.4-15 Ω cm2at 1 kHz which is even better than those of opaque solid Ag films, superior sheet resistance of 11-25 Ω sq−1, excellent mechanical stability up to 10,000 bending cycles, good biocompatibility and chemical stability. Studies on Langendorff-perfused mouse and rat hearts demonstrate that the Ag NWs microelectrodes enable high-fidelity real-time monitoring of heart rhythm during co-localized optogenetic pacing and optical mapping with negligible light-induced electrical artifacts. This proof-of-concept work illustrates that the solution-processed, transparent, and flexible Ag NWs networks are a promising candidate for the next-generation of large-area multifunctional biointerfaces for interrogating complex biological systems in basic and translational research.
Structural Perturbations of Exon Skipping Edits within the Dystrophin D20:24 Region
Authors: Niu Xin , Menhart Nick 
Published: October 2020

AbstractExon skipping is a disease modifying therapy that operates at the RNA level. In this strategy, oligonucleotide analog drugs are used to specifically mask specific exons and prevent them from inclusion in the mature mRNA. Of course, this also results in loss of the corresponding region from the cognate protein, which is one possible therapeutic aim. Exon skipping can also be used to restore protein expression in cases where a genetic frameshift mutation has occurred, and this how it is applied to Duchenne muscular dystrophy, DMD. DMD most commonly arises as a result of large exonic deletions that juxtapose flanking exons of incompatible reading frame in the dystrophin gene, creating a frameshift and abolishing protein expression. Loss of dystrophin protein leads to the pathology of the disease, which is severe, causing death generally in the second or third decade of life. Here, the primary aim of exon skipping is the restoration of the reading frame by skipping an exon adjacent to the patient’s original defect. However, the therapeutically expressed protein is of course edited, and missing both the region of the underlying genetic defect, as well as the therapeutically skipped exon. While restoring some protein expression is good, how removing some region from the middle of a protein effects its structure and function is unclear. Complicating this in the case of DMD is the fact that the dystrophin gene is very large, containing 79 exons. Many different underlying deletions are known, and exon skipping can be applied in many ways. It has previously been shown that many exon-skip edits result in structural perturbations of varying degrees. What has been unclear is whether and how exon editing can be done to minimize these perturbations. In this study we examine a systematic and comprehensive panel of possible exon edits in a region of the dystrophin protein, and identify for the first time, exon edits that appear to maintain structural stability similar to wildtype protein. We also identify factors that appear to be correlated with the degree of structural perturbation, such as the number of cooperative protein domains, as well as how the underlying exon structure interacts with the protein domain structure.
Colitis is associated with loss of LHPP and up-regulation of histidine phosphorylation in intestinal epithelial cells
Authors: Linder Markus , Liko Dritan , Kancherla Venkatesh , Piscuoglio Salvatore , Hall Michael N. 
Published: October 2020

AbstractProtein histidine phosphorylation (pHis) is a posttranslational modification involved in cell cycle regulation, ion channel activity and phagocytosis (1). Using novel monoclonal antibodies to detect pHis (2), we recently reported that loss of the histidine phosphatase LHPP results in elevated pHis levels in hepatocellular carcinoma (3). Here, we show that intestinal inflammation correlates with loss of LHPP, in DSS-treated mice and in inflammatory bowel disease (IBD) patients. Increased histidine phosphorylation was observed in intestinal epithelial cells (IECs), as determined by pHis immunofluorescence staining of colon samples from a colitis mouse model. However, ablation ofLhppdid not cause increased pHis or promote intestinal inflammation in physiological conditions or after DSS treatment. Our observations suggest that increased histidine phosphorylation plays a role in colitis, but loss of LHPP is not sufficient to increase pHis or to cause inflammation in the intestine.
3D reconstruction of genomic regions from sparse interaction data
Authors: Mendieta-Esteban Julen , Di Stefano Marco , Castillo David , Farabella Irene , Marti-Renom Marc A 
Published: October 2020

AbstractChromosome Conformation Capture (3C) technologies measure the interaction frequency between pairs of chromatin regions within the nucleus in a cell or a population of cells. Some of these 3C technologies retrieve interactions involving non-contiguous sets of loci, resulting in sparse interaction matrices. One of such 3C technologies is Promoter Capture Hi-C (pcHi-C) that is tailored to probe only interactions involving gene promoters. As such, pcHi-C provides sparse interaction matrices that are suitable to characterise short- and long-range enhancer-promoter interactions. Here, we introduce a new method to reconstruct the chromatin structural (3D) organisation from sparse 3C-based datasets such as pcHi-C. Our method allows for data normalisation, detection of significant interactions, and reconstruction of the full 3D organisation of the genomic region despite of the data sparseness. Specifically, it produces reliable reconstructions, in line with the ones obtained from dense interaction matrices, with as low as the 2-3% of the data from the matrix. Furthermore, the method is sensitive enough to detect cell-type-specific 3D organisational features such as the formation of different networks of active gene communities.