bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated phospho-proteogenomic and single-cell transcriptomic analysis of meningiomas establishes robust subtyping and reveals subtype-specific immune invasion
Authors: Blume Christina , Dogan Helin , Schweizer Lisa , Peyre Matthieu , Doll Sophia , Picard Daniel , Sankowski Roman , Hovestadt Volker , Okonechnikov Konstantin , Sievers Philipp , Patel Areeba , Reuss David , Friedrich Mirco , Stichel Damian , Schrimpf Daniel , Beck Katja , Wirsching Hans-Georg , Jungwirth Gerhard , Hanemann C Oliver , Lamszus Katrin , Westphal Manfred , Etminan Nima , Unterberg Andreas , Mawrin Christian , Remke Marc , Ayrault Olivier , Lichter Peter , Pfister Stefan M , Reifenberger Guido , Platten Michael , Milde Till , Jones David TW , Grossmann Rachel , Ram Zvi , Ratliff Miriam , Herold-Mende Christel , Mallm Jan-Philipp , Neidert Marian C , Wick Wolfgang , Prinz Marco , Weller Michael , Mann Matthias , Kalamarides Michel , von Deimling Andreas , Schlesner Matthias , Sahm Felix 
Published: May 2021

ABSTRACTMeningiomas are the most frequent primary intracranial tumors. They can follow a wide clinical spectrum from benign to highly aggressive clinical course. No specific therapy exists for refractory cases or cases not amenable to resection and radiotherapy. Identification of risk of recurrence and malignant transformation for the individual patients is challenging. However, promising molecular markers and prognostic subgrouping by DNA methylation are emerging. Still, the biological underpinnings of these diagnostic subgroups are elusive, and, consequently, no novel therapeutic options arise thereof. Here we establish robust subgroups across the full landscape of meningiomas, consistent through DNA methylation, mutations, the transcriptomic, proteomic and phospho-proteomic level. Pronounced proliferative stress and DNA damage repair signals in malignant cells and in clusters exclusive to recurrent tumors are in line with their higher mitotic activity, but also provide an explanation for the accumulation of genomic instability in anaplastic meningiomas. Although homozygous deletion of CDKN2A/B is a diagnostic marker of high-grade meningioma, the expression of its gene product increased from low to non-deleted high-grade cases. Differences between subgroups in lymphocyte and myeloid cell infiltration, representing a majority of tumor mass in low-grade NF2 tumors, could be assigned to cluster-specific interaction with tumor cells. Activation to a more proinflammatory phenotype and decreased infiltration of myeloid cells in high-grade cases correlated with lower expression of CSF1, located on chromosome arm 1p, whose deletion is known as prognostic marker, with no proposed mechanism before. Our results demonstrate a robust molecular subclassification of a tumor type across multiple layers, provide insight into heterogeneous growth dynamics despite shared pathognomonic mutations, and highlight immune infiltration modulation as a novel target for meningioma therapy.
Marine biofilms on different fouling control coating types reveal differences in microbial community composition and abundance
Authors: Papadatou Maria , Robson Samuel C. , Dobretsov Sergey , Watts Joy E.M. , Longyear Jennifer , Salta Maria 
Published: May 2021

AbstractMarine biofouling imposes serious environmental and economic impacts on marine applications, especially in the shipping industry. To combat biofouling, protective coatings are applied on vessel hulls which are divided into two major groups: biocidal and non-toxic fouling-release. The aim of the current study was to explore the effect of coating type on microbial biofilm community profiles to better understand the differences between the communities developed on fouling control biocidal antifouling and biocidal-free coatings. Biocidal (Intersmooth® 7460HS SPC), fouling-release (Intersleek® 900), and inert surfaces were deployed in the marine environment for 4 months and the biofilms that developed on these surfaces were investigated using Illumina NGS sequencing, targeting the prokaryotic 16S rRNA gene. The results confirmed differences in the community profiles between coating types. The biocidal coating supported communities dominated by Alphaproteobacteria (Loktanella, Sphingorhabdus, Erythrobacter) and Bacteroidetes (Gilvibacter), whilst other taxa such as Portibacter and Sva0996 marine group, proliferated on the fouling-release surface. Knowledge of these marine biofilm components on fouling control coatings will serve as a guide for future investigations of marine microfouling as well as informing the coatings industry of potential microbial targets for robust coating formulations.
Phase separation of both a plant virus movement protein and cellular factors support virus-host interactions
Authors: Brown Shelby L. , May Jared P. 
Published: May 2021

ABSTRACTPhase separation concentrates biomolecules, which should benefit RNA viruses that must sequester viral and host factors during an infection. Here, the p26 movement protein from Pea enation mosaic virus 2 (PEMV2) was found to phase separate and partition in nucleoli and G3BP stress granules (SGs) in vivo. Electrostatic interactions drive p26 phase separation as mutation of basic (R/K-G) or acidic (D/E-G) residues either blocked or reduced phase separation, respectively. During infection, p26 must partition inside the nucleolus and interact with fibrillarin (Fib2) as a pre-requisite for systemic trafficking of viral RNAs. Partitioning of p26 in pre-formed Fib2 droplets was dependent on p26 phase separation suggesting that phase separation of viral movement proteins supports nucleolar partitioning and virus movement. Furthermore, viral ribonucleoprotein complexes containing p26, Fib2, and PEMV2 RNA were formed via phase separation in vitro and could provide the basis for self-assembly in planta. Interestingly, both R/K-G and D/E-G p26 mutants failed to support systemic trafficking of a Tobacco mosaic virus (TMV) vector in Nicotiana benthamiana suggesting that p26 phase separation, proper nucleolar partitioning, and systemic movement are intertwined. p26 also partitioned in SGs and G3BP over-expression restricted PEMV2 accumulation >20-fold. Expression of phase separation-deficient G3BP only restricted PEMV2 5-fold, demonstrating that G3BP phase separation is critical for maximum antiviral activity.AUTHOR SUMMARYPhase separation of several cellular proteins is associated with forming pathological aggregates and exacerbating neurodegenerative disease progression. In contrast, roles for viral protein phase separation in RNA virus lifecycles are less understood. Here, we demonstrate that the p26 movement protein from Pea enation mosaic virus 2 phase separates and partitions with phase-separated cellular proteins fibrillarin and G3BP. The related orthologue from Groundnut rosette virus has been extensively studied and is known to interact with fibrillarin in the nucleolus as a pre-requisite for virus movement. We determined that basic residues and electrostatic interactions were critical for p26 phase separation. Furthermore, mutation of charged residues prevented the rescue of a movement-deficient Tobacco mosaic virus vector in Nicotiana benthamiana. Stress granules form through phase separation and we found that p26 could partition inside stress granules following heat shock. Phase separation of the stress granule nucleator G3BP was required for maximum antiviral activity and constitutes a host response that is dependent on cellular protein phase separation. Collectively, we demonstrate that phase separation of a plant virus protein facilitates virus-host interactions that are required for virus movement and phase separation of cellular proteins can simultaneously restrict virus replication.
The Aspartyl Protease Ddi1 Is Essential for Erythrocyte Invasion by the Malaria Parasite
Authors: Ridewood Sophie , Dirac-Svejstrup A. Barbara , Howell Stephen , Weston Anne , Lehmann Christine , Patel Asha Parbhu , Collinson Lucy , Bingham Ryan , Powell David , Snijder Ambrosius , Svejstrup Jesper Q. , Deu Edgar 
Published: May 2021

ABSTRACTMalaria pathology is caused by the exponential replication of Plasmodium parasites in the blood stream. The bottleneck of the parasite life cycle is the invasion of erythrocytes immediately after parasites egress from infected red blood cells. DNA damage-inducible protein 1 (Ddi1) is a conserved eukaryotic proteasome shuttle protein containing an internal retroviral-like protease domain. Using conditional genetics, we now show that the proteolytic activity of the P. falciparum homologue, PfDdi1, is critically required for invasion of red blood cells. Furthermore, PfDdi1 disruption results in the accumulation of highly polyubiquitinated proteins that can be processed by purified PfDdi1 or distant eukaryotic homologues. We also show that PfDdi1 interacts with multiple components of the ubiquitin-proteasome system and that parasites lacking PfDdi1 are more sensitive to proteasome inhibition. Overall, this study establishes PfDdi1 as a key component of the eukaryotic ubiquitin-proteasome system and as a promising antimalarial target.
The macrophage reprogramming ability of antifolates reveals soluble CD14 as a potential biomarker for methotrexate response in rheumatoid arthritis
Authors: Fuentelsaz-Romero Sara , Alonso Celia Barrio , Campos Raquel García , Torresano Mónica Torres , Muller Ittai , Triguero-Martínez Ana , Nuño Laura , Villalba Alejandro , García-Vicuña Rosario , Jansen Gerrit , Miranda-Carús María-Eugenia , González-Álvaro Isidoro , Puig-Kröger Amaya 
Published: May 2021

ABSTRACTThe physio-pathological relevance of the one-carbon metabolism (OCM) is illustrated by the chemotherapeutic and anti-inflammatory effects of the antifolates Pemetrexed (PMX) and Methotrexate (MTX) in cancer and rheumatoid arthritis (RA). We report that OCM determines the functional and gene expression profile of human macrophages. PMX induces the acquisition of a p53-dependent proinflammatory gene signature in human monocyte-derived macrophages (GM-MØ). Indeed, OCM blockade reprograms GM-MØ towards a state of LPS-tolerance at the signaling and functional levels, an effect abolished by folinic acid. Importantly, OCM blockade led to reduced expression of membrane-bound and soluble CD14 (sCD14), whose exogenous addition restores LPS sensitivity. The therapeutic relevance of these results was confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. Our results indicate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance, and positions sCD14 as a valuable tool to predict MTX-response in RA patients.
Effect of plant tubulin kinetic diversification on microtubule lengths
Authors: Jain Kunalika , Roy Megha , Athale Chaitanya A. 
Published: May 2021

AbstractMicrotubules (MTs) are dynamic polymers vital for cellular physiology. Bulk tubulin polymerization is nucleation dependent, while individual filaments exhibit ‘dynamic instability’ driven by GTP hydrolysis rates. Although MTs assembled from well-studied animal brain tubulins have very comparable nucleation and GTP-hydrolysis rates, the kinetic rates of evolutionarily more distant species could diverge. Here we focus on a plant tubulin, the legume Vigna sp. (mung bean) to test the effect of kinetic diversification on MT polymerization. We activity purify tubulin from seedlings and find MT filaments are fewer and shorter than animal brain tubulin. We find mung tubulin polymerization kinetics is nucleation dependent with a high rate of GTP hydrolysis and a critical concentration lower than previously reported for tubulins. A computational model of the kinetics based on the relative influence of rates of nucleation and hydrolysis demonstrates increased rates of hydrolysis can affect MT filament numbers and their lengths, as compared to increasing nucleation rates. Our approach provides a framework to compare the effect of evolutionary diversification of MT nucleation and elongation.
Epigenetic Inheritance is Gated by Naïve Pluripotency and Dppa2
Authors: Carlini Valentina , Policarpi Cristina , Hackett Jamie A. 
Published: May 2021

ABSTRACTEnvironmental factors can trigger cellular responses that propagate across mitosis or even generations. Perturbations to the epigenome could underpin such acquired changes, however, the extent and contexts in which modified chromatin states confer heritable memory in mammals is unclear. Here we exploit a modular epigenetic editing strategy to establish de novo heterochromatin domains (epialleles) at endogenous loci and track their inheritance in a developmental model. We find that naïve pluripotent phases systematically erase ectopic domains of heterochromatin via active mechanisms, which acts as an intergenerational safeguard against transmission of epialleles. Upon lineage specification however, acquired chromatin states can be probabilistically inherited under selectively favourable conditions, including propagation of p53 silencing through in vivo development. Using genome-wide CRISPR screening, we identify the mechanisms that block heritable silencing memory in pluripotent cells, and demonstrate removal of Dppa2 unlocks the potential for epigenetic inheritance uncoupled from DNA sequence. Our study outlines a mechanistic basis for how epigenetic inheritance is restricted in mammals, and reveals genomic- and developmental-contexts in which heritable memory is feasible.
Exploiting noise, non-linearity, and feedback for differential control of multiple synthetic cells with a single optogenetic input
Authors: May Michael P , Munsky Brian 
Published: May 2021

AbstractSynthetic biology seeks to develop modular bio-circuits that combine to produce complex, controllable behaviors. These designs are often subject to noisy fluctuations and uncertainties, and most modern synthetic biology design processes have focused to create robust components to mitigate the noise of gene expression and reduce the heterogeneity of single-cell responses. However, deeper understanding of noise can achieve control goals that would otherwise be impossible. We explore how an “Optogenetic Maxwell Demon” could selectively amplify noise to control multiple cells using single-input-multiple-output (SIMO) feedback. Using data-constrained stochastic model simulations and theory, we show how an appropriately selected stochastic SIMO controller can drive multiple different cells to different user-specified configurations irrespective of initial condition. We explore how controllability depends on cells’ regulatory structures, the amount of information available to the controller, and the accuracy of the model used. Our results suggest that gene regulation noise, when combined with optogenetic feedback and non-linear biochemical auto-regulation, can achieve synergy to enable precise control of complex stochastic processes.
O-GlcNAcylation reduces phase separation and aggregation of the EWS
N-terminal low complexity region
Authors: Nosella Michael L. , Tereshchenko Maria , Pritišanac Iva , Chong P. Andrew , Toretsky Jeffrey A. , Lee Hyun O. , Forman-Kay Julie D. 
Published: May 2021

ABSTRACT
Many membraneless organelles are thought to be biomolecular condensates
formed by phase separation of proteins and other biopolymers. Post-translational
modifications (PTMs) can impact protein phase separation behavior, although for
many PTMs this aspect of their function is unknown.
O-linked
β-D-N-acetylglucosaminylation
(O-GlcNAcylation) is an abundant form of
intracellular glycosylation whose roles in regulating biomolecular condensate
assembly and dynamics have not been delineated. Using an in
vitro approach, we found that
O-GlcNAcylation reduces the phase separation
propensity of the EWS N-terminal low complexity
region (LCRN) under different conditions, including in the
presence of the arginine-and glycine-rich RNA-binding domains (RBD).
O-GlcNAcylation enhances fluorescence recovery
after photobleaching (FRAP) within EWS LCRN condensates and
causes the droplets to exhibit more liquid-like relaxation following fusion.
Following extended incubation times, EWS LCRN+RBD
condensates exhibit diminished FRAP, indicating a loss of fluidity, while
condensates containing the O-GlcNAcylated
LCRN do not. In HeLa cells, EWS is less
O-GlcNAcylated following
OGT knockdown and more prone to aggregation based
on a filter retardation assay. Relative to the human proteome,
O-GlcNAcylated proteins are enriched with regions
that are predicted to phase separate, suggesting a general role of
O-GlcNAcylation in regulation of biomolecular
condensates.

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Generation and timing of graded responses to morphogen gradients
Authors: Carmon Shari , Jonas Felix , Barkai Naama , Schejter Eyal D. , Shilo Ben-Zion 
Published: May 2021

AbstractMorphogen gradients are known to subdivide a naïve cell field into distinct zones of gene expression. Here we examine whether morphogens can also induce a graded response within such domains. To this end we explore the role of the Dorsal protein nuclear gradient along the dorso-ventral axis in defining the graded pattern of actomyosin constriction that initiates gastrulation in early Drosophila embryos. Two complementary mechanisms for graded accumulation of mRNAs of critical zygotic target genes were identified. First, activation of target-gene expression expands over time from the ventral-most region of high nuclear Dorsal to lateral regions where the levels are lower, due to a Dorsal-dependent priming probability of transcription sites. Thus, sites that are activated earlier will lead to more mRNA accumulation. Second, once the sites are primed, the rate of Pol II loading is also dependent on Dorsal levels. Morphological restrictions require that translation of the graded mRNA be delayed until completion of embryonic cell formation. Such timing is achieved by large introns, that provide a delay in production of the mature mRNAs.
Bacteriophage adaptation to a mammalian mucosa reveals a trans-domain evolutionary axis
Authors: Chin Wai Hoe , Kett Ciaren , Cooper Oren , Müseler Deike , Zhang Yaqi , Bamert Rebecca , Patwa Ruzeen , Woods Laura C. , Devendran Citsabehsan , Tiralongo Joe , Lithgow Trevor , McDonald Mike J. , Neild Adrian , Barr Jeremy J. 
Published: May 2021

AbstractThe majority of viruses within the human gut are obligate bacterial viruses known as bacteriophages (phages)1. Their bacteriotropism underscores the study of phage ecology in the gut, where they sustain top-down control2–4 and co-evolve5 with gut bacterial communities. Traditionally, these were investigated empirically via in vitro experimental evolution6–8 and more recently, in vivo models were adopted to account for gut niche effects4,9. Here, we probed beyond conventional phage-bacteria co-evolution to investigate the potential evolutionary interactions between phages and the mammalian “host”. To capture the role of the mammalian host, we recapitulated a life-like mammalian gut mucosa using in vitro lab-on-a-chip devices (to wit, the gut-on-a-chip) and showed that the mucosal environment supports stable phage-bacteria co-existence. Next, we experimentally evolved phage populations within the gut-on-a-chip devices and discovered that phages adapt by de novo mutations and genetic recombination. We found that a single mutation in the phage capsid protein Hoc – known to facilitate phage adherence to mucus10 – caused altered phage binding to fucosylated mucin glycans. We demonstrated that the altered glycan-binding phenotype provided the evolved mutant phage a competitive fitness advantage over their ancestral wildtype phage in the gut-on-a-chip mucosal environment. Collectively, our findings revealed that phages – in addition to their evolutionary relationship with bacteria – are also able to engage in evolution with the mammalian host.
How Korean universities portray themselves in the global marketplace: text-mining analysis of university president's messages
Authors: Lee Soo Jeung , Park Soowon 
Published: May 2021

PurposeThis study aims to examine university president's messages (PMs) on Korean university websites to analyze how Korean universities present their image and position themselves in the global marketplace.Design/methodology/approachAssuming that visions, missions and strategies might vary depending on the characteristics of a university, the study analyzed PMs according to university type: research, teaching and technology. The authors applied text analysis to 105 Korean universities' PMs to understand the images they project. The authors also used text mining on the PMs to examine the frequencies of keywords, to create word clouds, to investigate the keywords' degrees of centrality and to conduct sentiment analysis.FindingsThe findings show that Korean universities' PMs project hybrid images, simultaneously portraying the universities as public institutes that produce public goods and as globally competitive strategic actors. In addition, while Korean university PMs explicitly position the universities as education-oriented, they nonetheless reveal that the universities pursue both research-oriented and education-oriented goals.Originality/valueThis is the study to examine PMs using text mining with Python to extract information and reveal hidden meanings regarding how universities portray themselves on their websites. Highlighting current challenges faced by universities, this article argues for continued discussion on their societal roles and their strategies for positioning themselves in today's globalized and marketized higher education environment.
The impact of climate change on the Mpumalanga Provincial Archives and records management activities
Authors: Netshakhuma Nkholedzeni Sidney 
Published: May 2021

Purpose
The purpose of this paper is to investigate the impact of climate change on South Africa’s Mpumalanga Provincial Archives (MPA) and related records management activities.

Design/methodology/approach
A qualitative research approach/method was used to collect data from the source, including purposive sampling and expert knowledge solicited through semi-structured interviews. A review was undertaken to source climate data and related archival sector literature.

Findings
Recent extreme weather events in Mpumalanga seem to bear out climate change projections. The current absence of relevant strategies and plans implies that the MPA and provincial departments are not yet prepared for emergencies. The lack of a plan, an implementation strategy and related training may increase the impact of disasters on the provincial archives’ environment. Without disaster plans and robust preparedness, the question of how the MPA is going to preserve archives for future generations is raised. In addition, due to a lack of guidance for registry staff, appraisal is not allowing for identification and processing of archival materials, so combined with a lack of disaster management strategies and plans contributes to the loss of archives.

Research limitations/implications
This research is limited to the MPA; however, the findings may be extended to other South Africa provincial archives and parts of the world experiencing similar issues. There is a need to conduct similar research on a larger scale so as to explore the impact of climate change in other provincial archives to provide a wider context of the problem within South Africa.

Practical implications
When archivists accept holdings into their repositories, they take the responsibility for their archival custody. But, these efforts may come to nothing if the archives are lost. Disaster management is the key to the protection of the archives.

Originality/value
This paper contributes to the literature on the impact of climate change on archives. The results achieved should be seen as a first step towards identification of the issue.