bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amyloidogenic proteins in the SARS-CoV and SARS-CoV-2 proteomes
Authors: Bhardwaj Taniya , Gadhave Kundlik , Kapuganti Shivani K , Kumar Prateek , Brotzakis Zacharias Faidon , Saumya Kumar Udit , Nayak Namyashree , Kumar Ankur , Garg Neha , Vendruscolo Michele , Giri Rajanish 
Published: May 2021

AbstractThe phenomenon of protein aggregation is associated with a wide range of human diseases. Our knowledge on the aggregation behaviour of viral proteins, however, is still rather limited. Here, we investigated this behaviour in the the SARS-CoV and SARS-CoV-2 proteomes. An initial analysis using a panel of sequence-based predictors suggested the presence of multiple aggregation-prone regions in these proteomes, and revealed an enhanced aggregation propensity in some SARS-CoV-2 proteins. We then studied the in vitro aggregation of predicted aggregation-prone SARS-CoV-2 proteins, including the signal sequence peptide and fusion peptide 1 of the spike protein, a peptide from the NSP6 protein (NSP6-p), the ORF10 protein, and the NSP11 protein. Our results show that these peptides and proteins form aggregates via a nucleation-dependent mechanism. Moreover, we demonstrated that the aggregates of NSP11 are toxic to mammalian cell cultures. These findings provide evidence about the aggregation of proteins in the SARS-CoV-2 proteome.SignificanceThe aggregation of proteins is linked with human disease in a variety of ways. In the case of viral infections, one could expect that the aberrant aggregation of viral proteins may damage the host cells, and also that viral particles may trigger the misfolding and aggregation of host proteins, resulting in damage to the host organism. Here we investigate the aggregation propensity of SARS-CoV-2 proteins and show that many of them can form aggregates that are potentially cytotoxic. In perspective, these results suggest that a better understanding of the effects of viruses on the human protein homeostasis system could help future therapeutic efforts.
Transposable elements drive the evolution of genome streamlining
Authors: van Dijk Bram , Bertels Frederic , Stolk Lianne , Takeuchi Nobuto , Rainey Paul B. 
Published: May 2021

AbstractEukaryotes and prokaryotes have distinct genome architectures, with marked differences in genome size, the ratio of coding/non-coding DNA, and the abundance of transposable elements (TEs). As TEs replicate independently of their hosts, the proliferation of TEs is thought to have driven genome expansion in eukaryotes. However, prokaryotes also have TEs in intergenic spaces, so why do prokaryotes have small, streamlined genomes? Using an in silico model describing the genomes of single-celled asexual organisms that co-evolve with TEs, we show that TEs acquired from the environment by horizontal gene transfer can drive the evolution of genome streamlining. The process depends on local interactions and is underpinned by rock-paper-scissor dynamics in which populations of cells with streamlined genomes beat TEs, which beat non-streamlined genomes, in continuous and repeating cycles. Streamlining is maladaptive to individual cells, but delivers lineage-level benefits. Streamlining does not evolve in sexually reproducing populations because recombination partially frees TEs from the deleterious effects they cause.
Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation
Authors: Biechele Gloria , Blume Tanja , Deussing Maximilian , Zott Benedikt , Shi Yuan , Xiang Xianyuan , Franzmeier Nicolai , Kleinberger Gernot , Peters Finn , Ochs Katharina , Focke Carola , Sacher Christian , Wind Karin , Schmidt Claudio , Lindner Simon , Gildehaus Franz-Josef , Eckenweber Florian , Beyer Leonie , von Ungern-Sternberg Barbara , Bartenstein Peter , Baumann Karlheinz , Dorostkar Mario M. , Rominger Axel , Cumming Paul , Willem Michael , Adelsberger Helmuth , Herms Jochen , Brendel Matthias 
Published: May 2021

AbstractModulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer’s disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP,AppNL-G-F). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Pioglitazone-treated female PS2APP andAppNL-G-Fmice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated maleAppNL-G-Fmice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R=−0.874, p<0.0001) but not in vehicle controls (R=−0.356, p=0.081). Reduced TSPO-PET signal upon treatment was associated with better spatial learning and higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R=0.952, p<0.0001). TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Pre-therapeutic assessment of baseline microglial activation and sex are strong predictors of individual immunomodulation effects and could serve for responder stratification.
Distinct regulation of tonic GABAergic inhibition by NMDA receptor subtypes
Authors: Wu Kunwei , Castellano David , Tian Qingjun , Lu Wei 
Published: May 2021

SUMMARYTonic inhibition mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABAARs) play important roles in the regulation of various brain functions. However, the regulatory mechanisms for tonic inhibition remain largely unknown. Here we report distinct actions of GluN2A- and GluN2B-containing subtypes of NMDA receptors (NMDARs) on tonic inhibition in hippocampal neurons. Mechanistically, GluN2A- and GluN2B-containing NMDARs play differential roles in α5-GABAAR internalization. Additionally, GluN2A-, but not GluN2B-, containing receptors are required for the homeostatic potentiation of tonic inhibition. In an acute seizure model induced by kainic acid, tonic inhibition is decreased during acute seizures, while it is increased 24 h later, and these alterations are dependent on the distinct GluN2-containing NMDARs. Collectively, these data reveal a critical link between NMDARs and extrasynaptic GABAARs in both physiological and pathological conditions.
Arthropods and the evolution of RNA viruses
Authors: Chang Tianyi , Hirai Junya , Hunt Brian P. V. , Suttle Curtis A. 
Published: May 2021

AbstractMany viruses of arthropods also infect other organisms including humans, sometimes with devastating consequences. Yet, for the vast diversity of arthropods, their associated viruses remain unexplored. Here, we mined meta-transcriptomes from 711 arthropod species, including insects, arachnids, myriapods, and crustaceans, and uncovered more than 1400 previously unknown RNA viruses, representing 822 novel evolutionary groups at a level between species and genus. These newly found viral groups fill major evolutionary gaps within the five branches of RNA viruses, bridging the evolution of viruses infecting early and later diverging eukaryotes. Additionally, co-phylogenetic analysis implies that RNA viruses of arthropods commonly co-evolved with their hosts. Our analyses indicate that arthropods have played a central role in the macroevolution of RNA viruses by serving as reservoirs in which viruses co-evolved with arthropods while being exchanged with a vast diversity of organisms.
Efficient biallelic knock-in in mouse embryonic stem cells by in vivo-linearization of donor and transient inhibition of DNA Polymerase θ/DNA-PK
Authors: Arai Daisuke , Nakao Yoichi 
Published: May 2021

AbstractCRISPR/Cas9-mediated homology-directed repair (HDR) is used for error-free targeted knock-in of foreign donor DNA. However, the low efficiency of HDR-mediated knock-in hinders establishment of knock-in clones. Double-strand breaks (DSBs) induced by CRISPR/Cas9 are preferentially repaired by non-homologous end joining (NHEJ) or microhomology-mediated end joining (MMEJ) before HDR can occur, thereby preventing HDR-mediated knock-in. NHEJ/MMEJ also cause random integrations, which give rise to false-positive knock-in events, or silently disrupt the genome. In this study, we optimized an HDR-mediated knock-in method for mouse embryonic stem cells (mESCs). We succeeded in improving efficiency of HDR-mediated knock-in of a plasmid donor while almost completely suppressing NHEJ/MMEJ-based integration by combining in vivo-linearization of the donor plasmid, transient knockdown of DNA Polymerase θ, and chemical inhibition of DNA-dependent protein kinase (DNA-PK) by M3814. This method also dramatically improved the efficiency of biallelic knock-in; at the Rosa26a locus, 95% of HDR-mediated knock-in clones were biallelic. We designate this method BiPoD (Biallelic knock-in assisted by Pol θ and DNA-PK inhibition). BiPoD achieved simultaneous efficient biallelic knock-in into two loci. BiPoD, therefore, enables rapid and easy establishment of biallelic knock-in mESC lines.
Epigenetic regulation of innate immune memory in microglia
Authors: Zhang Xiaoming , Kracht Laura , Lerario Antonio M. , Dubbelaar Marissa L. , Brouwer Nieske , Wesseling Evelyn M. , Boddeke Erik W.G.M. , Eggen Bart J.L. , Kooistra Susanne M. 
Published: May 2021

AbstractMicroglia are the tissue-resident macrophages of the CNS. They originate in the yolk sac, colonize the CNS during embryonic development and form a self-sustaining population with limited turnover. A consequence of their relative slow turnover is that microglia can serve as a long-term memory for inflammatory or neurodegenerative events. We characterized the epigenomes and transcriptomes of microglia exposed to different stimuli; an endotoxin challenge (LPS) and genotoxic stress (DNA repair deficiency-induced accelerated aging). Whereas the enrichment of permissive epigenetic marks at enhancer regions explains training (hyperresponsiveness) of primed microglia to LPS challenge, the tolerized response of microglia seems to be regulated by loss of permissive epigenetic marks. Here, we identify that inflammatory stimuli and accelerated aging because of genotoxic stress activate distinct gene networks. These gene networks and associated biological processes are partially overlapping, which is likely driven by specific transcription factor networks, resulting in altered epigenetic signatures and distinct functional (desensitized vs. primed) microglia phenotypes.
A generative nonparametric Bayesian model for whole genomes
Authors: Amin Alan N. , Weinstein Eli N. , Marks Debora S. 
Published: May 2021

AbstractGenerative probabilistic modeling of biological sequences has widespread existing and potential use across biology and biomedicine, particularly given advances in high-throughput sequencing, synthesis and editing. However, we still lack methods with nucleotide resolution that are tractable at the scale of whole genomes and that can achieve high predictive accuracy either in theory or practice. In this article we propose a new generative sequence model, the Bayesian embedded autoregressive (BEAR) model, which uses a parametric autoregressive model to specify a conjugate prior over a nonparametric Bayesian Markov model. We explore, theoretically and empirically, applications of BEAR models to a variety of statistical problems including density estimation, robust parameter estimation, goodness-of-fit tests, and two-sample tests. We prove rigorous asymptotic consistency results including nonparametric posterior concentration rates. We scale inference in BEAR models to datasets containing tens of billions of nucleotides. On genomic, transcriptomic, and metagenomic sequence data we show that BEAR models provide large increases in predictive performance as compared to parametric autoregressive models, among other results. BEAR models offer a flexible and scalable framework, with theoretical guarantees, for building and critiquing generative models at the whole genome scale.
EP400NL is required for cMyc-mediated PD-L1 gene activation by forming a transcriptional coactivator complex
Authors: Li Zidong , Fitzsimons Helen L , Hale Tracy K , Park Jeong Hyeon 
Published: May 2021

ABSTRACTEP400 is an ATP-dependent chromatin remodeling enzyme that has been implicated in DNA double-strand break repair and transcription regulation including Myc-dependent gene expression. We previously showed that the N-terminal domain of EP400 increases the efficacy of chemotherapeutic drugs against cancer cells. As the EP400 N-terminal-Like (EP400NL) gene resides next to the EP400 gene locus prompted us to investigate whether EP400NL also plays a similar role in epigenetic transcriptional regulation to the full-length EP400 protein. We found that EP400NL forms a human NuA4-like chromatin remodelling complex that lacks both the TIP60 histone acetyltransferase and EP400 ATPase. However, this EP400NL complex displays H2A.Z deposition activity on a chromatin template comparable to the human NuA4 complex, suggesting another associated ATPase such as BRG1 or RuvBL1/RuvBL2 catalyses the reaction. We also demonstrated that the transcriptional coactivator function of EP400NL is required for cMyc and IFNγ-mediated PD-L1 gene activation. Collectively, our studies show that EP400NL plays a role as a transcription coactivator for cMyc-mediated gene expression and provides a potential target to modulate PD-L1 expression in cancer immunotherapy.
findere: fast and precise approximate membership query
Authors: Robidou Lucas , Peterlongo Pierre 
Published: May 2021

AbstractMotivationApproximate membership query (AMQ) structures as Cuckoo filters or Bloom filters are widely used for representing large sets of elements. Their lightweight space usage explains their success, mainly as they are the only way to scale hundreds of billions or trillions of elements. However, they suffer by nature from non-avoidable false-positive calls that bias downstream analyses of methods using these data structures.ResultsIn this work we propose a simple strategy and its implementation for reducing the false-positive rate of any AMQ data structure indexing k-mers (words of length k). The method we propose, called findere, enables to speed-up the queries by a factor two and to decrease the false-positive rate by two order of magnitudes. This achievement is done one the fly at query time, without modifying the original indexing data-structure, without generating false-negative calls and with no memory overhead. With no drawback, this method, as simple as it is effective, reduces either the false-positive rate or the space required to represent a set given a user-defined false-positive rate.Availabilityhttps://github.com/lrobidou/findere
Micro-Meta App: an interactive software tool to facilitate the collection of microscopy metadata based on community-driven specifications
Authors: Rigano Alex , Ehmsen Shannon , Ozturk Serkan Utku , Ryan Joel , Balashov Alexander , Hammer Mathias , Kirli Koray , Bellve Karl , Boehm Ulrike , Brown Claire M. , Chambers James J. , Coleman Robert A. , Cosolo Andrea , Faklaris Orestis , Fogarty Kevin , Guilbert Thomas , Hamacher Anna B. , Itano Michelle S. , Keeley Daniel P. , Kunis Susanne , Lacoste Judith , Laude Alex , Ma Willa , Marcello Marco , Montero-Llopis Paula , Nelson Glyn , Nitschke Roland , Pimentel Jaime A. , Weidtkamp-Peters Stefanie , Park Peter J. , Alver Burak , Grunwald David , Strambio-De-Castillia Caterina 
Published: May 2021

AbstractFor the information content of microscopy images to be appropriately interpreted, reproduced, and meet FAIR (Findable Accessible Interoperable and Reusable) principles, they should be accompanied by detailed descriptions of microscope hardware, image acquisition settings, image pixel and dimensional structure, and instrument performance. Nonetheless, the thorough documentation of imaging experiments is significantly impaired by the lack of community-sanctioned easy-to-use software tools to facilitate the extraction and collection of relevant microscopy metadata. Here we presentMicro-Meta App, an intuitive open-source software designed to tackle these issues that was developed in the context of nascent global bioimaging community organizations, includingBioImagingNorthAmerica (BINA) andQUAlity Assessment andREProducibility inLightMicroscopy (QUAREP-LiMi), whose goal is to improve reproducibility, data quality and sharing value for imaging experiments. The App provides a user-friendly interface for building comprehensive descriptions of the conditions utilized to produce individual microscopy datasets as specified by the recently proposed 4DN-BINA-OME tiered-system of Microscopy Metadata model. To achieve this goal the App provides a visual guide for a microscope-user to: 1) interactively build diagrammatic representations of hardware configurations of given microscopes that can be easily reused and shared with colleagues needing to document similar instruments. 2) Automatically extracts relevant metadata from image files and facilitates the collection of missing image acquisition settings and calibration metrics associated with a given experiment. 3) Output all collected Microscopy Metadata to interoperable files that can be used for documenting imaging experiments and shared with the community. In addition to significantly lowering the burden of quality assurance, the visual nature of Micro-Meta App makes it particularly suited for training users that have limited knowledge of the intricacies of light microscopy experiments. To ensure wide-adoption by microscope-users with different needs Micro-Meta App closely interoperates withMethodsJ2andOMERO.mde, two complementary tools described in parallel manuscripts.
Identification of Pex34p as a component of the peroxisomal de novo biogenesis machinery in yeast
Authors: Radke Juliane , Nagotu Shirisha , Girzalsky Wolfgang , Chakraborty Anirban , Deckers Markus , Schuldiner Maya , Zalckvar Einat , Erdmann Ralf 
Published: May 2021

SummaryCells can regulate the abundance and composition of peroxisomes to adapt to environmental changes. In the baker’s yeast,S. cerevisiae, peroxisomes represent the only site for degradation of fatty acids. Hence, it is not surprising that growth of yeast cells on oleic acid results in a massive proliferation of peroxisomes. New peroxisomes can form either by division of pre-existing peroxisomes or de novo in a Pex25p-dependent process with the involvement of the Endoplasmic Reticulum (ER). In search for further factors involved in de novo formation of peroxisomes, we screened ~6,000 yeast mutants that were depleted of peroxisomes by conditional inhibition ofPEX19expression. Screening the mutants for the reappearance of peroxisomes upon expression ofPEX19identified Pex34p, in addition to the well-known component Pex25p, as crucial determinants for de novo biogenesis. Pex34p interacts with Pex19p and with different Peroxisomal Membrane Proteins (PMPs) in aPEX19-dependent manner. Depletion of Pex34p results in reduced numbers of import-competent peroxisomes formed de novo and Pex3p is partly retained and distributed in ER-like structures. We suggest that Pex25p and Pex34p are both required to maintain peroxisome number in a cell and that they perform non-redundant roles in the de novo formation of peroxisomes.
PIF7 controls leaf cell proliferation through an AN3 substitution-repression mechanism
Authors: Hussain Ejaz , Romanowski Andrés , Halliday Karen J. 
Published: May 2021

AbstractPlants are agile, plastic organisms, able to adapt to ever-changing circumstances. Responding to far-red (FR) wavelengths from nearby vegetation, shade-intolerant species elicit the adaptive Shade Avoidance Syndrome (SAS), characterised by elongated petioles, leaf hyponasty and smaller leaves. We utilised end-of-day FR (EODFR) treatments to interrogate molecular processes that underlie the SAS leaf response. Genetic analysis establishes PHYTOCHROME INTERACTING FACTOR 7 (PIF7) is required for EODFR-mediated constraint of leaf blade cell division, while EODFR mRNAseq data identified ANGUSTIFOLIA3 (AN3) as a potential PIF7 target. We show PIF7 can suppress AN3 transcription through a sequestering mechanism that prevents AN3 activation of its own expression. We also establish PIF7 and AN3 impose antagonistic control of gene expression via common cis-acting promoter motifs in several cell cycle regulator genes. EODFR triggers the molecular substitution of AN3 to PIF7 at G-box/PBE-box promoter regions, and a switch from promotion to repression of gene expression.
A hybrid approach for investigating impacts of leadership dynamics on project performance
Authors: Luo Lan , Zhang Limao , Zheng Xian , Wu Guangdong 
Published: May 2021

PurposeThis paper proposes a novel hybrid simulation approach that incorporates the structural equation model (SEM) and system dynamics (SD) to investigate the impacts of leadership dynamics on project performance under different scenarios.Design/methodology/approachSEM is used to identify and validate a correlation between leadership variables and project performance statically. On this basis, the SD model is constructed to depict a system model connecting the leadership and project performance. Different scenarios are simulated to dynamically model the variation in leadership on the evolution of project performance.FindingsResults indicate that (1) leadership can be divided into personal ability, relationship atmosphere and organizational strategy in complex construction projects; (2) personal ability, relationship atmosphere and organizational strategy positively correlate with project performance over time; and (3) L1 (stress management ability), L7 (team building) and L17 (institution support) are the leading factors influencing project performance and should be paid more attention under limited resources.Originality/valueThis research contributes to (1) the state of the knowledge by proposing a hybrid methodology that can systematically model the impacts of leadership dynamics on project performance over time and (2) the state of the practice by gaining a better understanding of the strategy of resource distribution for enhancing project performance in complex construction projects.
The homotopy perturbation method for fractional differential equations: part 2, two-scale transform
Authors: Nadeem Muhammad , He Ji-Huan 
Published: May 2021

PurposeThe purpose of this paper is to find an approximate solution of a fractional differential equation. The fractional Newell–Whitehead–Segel equation (FNWSE) is used to elucidate the solution process, which is one of the nonlinear amplitude equation, and it enhances a significant role in the modeling of various physical phenomena arising in fluid mechanics, solid-state physics, optics, plasma physics, dispersion and convection systems.Design/methodology/approachIn Part 1, the authors adopted Mohand transform to find the analytical solution of FNWSE. In this part, the authors apply the fractional complex transform (the two-scale transform) to convert the problem into its differential partner, and then they introduce the homotopy perturbation method (HPM) to bring down the nonlinear terms for the approximate solution.FindingsThe HPM makes numerical simulation for the fractional differential equations easy, and the two-scale transform is a strong tool for fractal models.Originality/valueThe HPM with the two-scale transform sheds a bright light on numerical approach to fractional calculus.