bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphatidylserine prevents the generation of a protein-free giant plasma membrane domain in yeast
Authors: Mioka Tetsuo , Tian Guo , Shiyao Wang , Tsuji Takuma , Kishimoto Takuma , Fujimoto Toyoshi , Tanaka Kazuma 
Published: August 2020

AbstractMembrane phase separation accompanied with micron-scale domains of lipids and proteins occurs in artificial membranes; however, a similar large phase separation has not been reported in the plasma membrane of the living cells. We demonstrate here that a stable micron-scale protein-free region is generated in the plasma membrane of the yeast mutants lacking phosphatidylserine. We named this region the “void zone”. Transmembrane proteins, peripheral membrane proteins, and certain phospholipids are excluded from the void zone. The void zone is rich in ergosterol and requires ergosterol and sphingolipids for its formation. These characteristics of the void zone are similar to the properties of the cholesterol-enriched domain in phase-separated artificial membranes. We propose that phosphatidylserine prevents the formation of the void zone by preferentially interacting with ergosterol. We also found that void zones were frequently in contact with vacuoles, in which a membrane domain was also formed at the contact site.Summary statementYeast cells lacking phosphatidylserine generate protein-free plasma membrane domains, and vacuoles contact with this domain. This is the first report of micron-scale plasma membrane domains in living cells.
The impact of non-pharmaceutical interventions on SARS-CoV-2 transmission across 130 countries and territories
Authors: Liu Yang , Morgenstern Christian , Kelly James , Lowe Rachel ,   CMMID COVID-19 Working Group, Jit Mark 
Published: August 2020

AbstractIntroductionNon-pharmaceutical interventions (NPIs) are used to reduce transmission of SARS coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). However, empirical evidence of the effectiveness of specific NPIs has been inconsistent. We assessed the effectiveness of NPIs around internal containment and closure, international travel restrictions, economic measures, and health system actions on SARS-CoV-2 transmission in 130 countries and territories.MethodsWe used panel (longitudinal) regression to estimate the effectiveness of 13 categories of NPIs in reducing SARS-CoV-2 transmission with data from January - June 2020. First, we examined the temporal association between NPIs using hierarchical cluster analyses. We then regressed the time-varying reproduction number (Rt) of COVID-19 against different NPIs. We examined different model specifications to account for the temporal lag between NPIs and changes in Rt, levels of NPI intensity, time-varying changes in NPI effect and variable selection criteria. Results were interpreted taking into account both the range of model specifications and temporal clustering of NPIs.ResultsThere was strong evidence for an association between two NPIs (school closure, internal movement restrictions) and reduced Rt. Another three NPIs (workplace closure, income support and debt/contract relief) had strong evidence of effectiveness when ignoring their level of intensity, while two NPIs (public events cancellation, restriction on gatherings) had strong evidence of their effectiveness only when evaluating their implementation at maximum capacity (e.g., restrictions on 1000+ people gathering were not effective, restrictions on <10 people gathering was). Evidence supporting the effectiveness of the remaining NPIs (stay-at-home requirements, public information campaigns, public transport closure, international travel controls, testing, contact tracing) was inconsistent and inconclusive. We found temporal clustering between many of the NPIs.ConclusionUnderstanding the impact that specific NPIs have had on SARS-CoV-2 transmission is complicated by temporal clustering, time-dependent variation in effects and differences in NPI intensity. However, the effectiveness of school closure and internal movement restrictions appears robust across different model specifications taking into account these effects, with some evidence that other NPIs may also be effective under particular conditions. This provides empirical evidence for the potential effectiveness of many although not all the actions policy-makers are taking to respond to the COVID-19 pandemic.
Histopathology of Third Trimester Placenta from SARS-CoV-2-Positive Women
Authors: He Mai , Skaria Priya , Kreutz Kasey , Chen Ling , Hagemann Ian , Carter Ebony B. , Mysorekar Indira U. , Nelson D Michael , Pfeifer John , Dehner Louis P. 
Published: August 2020

BackgroundThis study aims to investigate whether maternal SARS-CoV-2 status affect placental pathology.MethodsA retrospective case-control study was conducted by reviewing charts and slides of placentas between April 1 to July 24, 2020. Clinical history of “COVID-19” were searched in Pathology Database (CoPath). Controls were matched with SARS-CoV-2-negative women with singleton deliveries in the 3rd-trimester. Individual and group, pathological features were extracted from placental pathology reports.ResultsTwenty-one 3rd-trimester, placentas from SARS-CoV-2-positive women were identified and compared to 20 placentas from SARS-CoV-2-negative women. There were no significant differences in individual or group gross or microscopic pathological features between the groups. Within the SARS-CoV-2+ group, there are no differences between symptomatic and asymptomatic women.ConclusionPlacentas from SARS-CoV-2-positive women do not demonstrate a specific pathological pattern. Pregnancy complicated with COVID-19 during the 3rd trimester does not have a demonstrable effect on placental structure and pathology.
Moose or spruce: A systems analysis model for managing conflicts between moose and forestry in Sweden
Authors: Franklin Oskar , Krasovskiy Andrey , Kraxner Florian , Platov Anton , Schepaschenko Dmitry , Leduc Sylvain , Mattsson Brady 
Published: August 2020

AbstractSweden has the world’s highest density of moose (Alces alces). Moose is not only a valuable game species; it also causes forest damages and traffic accidents. To avoid moose browsing, foresters respond by planting spruce (Picea abies) to an extent that reshapes the forest landscape with impacts on both production and biodiversity. To address this problem and maintain a healthy moose population in balance with the other interests, an adaptive management based on the knowledge and experiences of local hunters and landowners is advocated. However, the different stakeholders do not agree on what is an appropriate moose population, which leads to conflicts that are hard to resolve. A key problem is that it is very difficult to encompass and foresee long-term consequences of different options for moose hunting and forest management. This makes it challenging to form coherent strategies that integrate different sectorial interests at a national level. To address this issue, we have developed a systems analysis framework for integrated modeling of the moose population, forestry, and their interactions and consequences for biodiversity. We analyze the short and long-term consequences for multiple scenarios of moose hunting and forest management. Based on the results we elucidate and quantify the trade-offs and possible synergies between moose hunting and forest production. This analysis can be used to support better informed and more constructive discussions among the stakeholders in the Swedish forest sectors, and to support policies for long term sustainable forest and moose management.
A single-cell method to map higher-order 3D genome organization in thousands of individual cells reveals structural heterogeneity in mouse ES cells
Authors: Arrastia Mary V. , Jachowicz Joanna W. , Ollikainen Noah , Curtis Matthew S. , Lai Charlotte , Quinodoz Sofia A. , Selck David A. , Guttman Mitchell , Ismagilov Rustem F. 
Published: August 2020

ABSTRACTIn eukaryotes, the nucleus is organized into a three dimensional structure consisting of both local interactions such as those between enhancers and promoters, and long-range higher-order structures such as nuclear bodies. This organization is central to many aspects of nuclear function, including DNA replication, transcription, and cell cycle progression. Nuclear structure intrinsically occurs within single cells; however, measuring such a broad spectrum of 3D DNA interactions on a genome-wide scale and at the single cell level has been a great challenge. To address this, we developed single-cell split-pool recognition of interactions by tag extension (scSPRITE), a new method that enables measurements of genome-wide maps of 3D DNA structure in thousands of individual nuclei. scSPRITE maximizes the number of DNA contacts detected per cell enabling high-resolution genome structure maps within each cells and is easy-to-use and cost-effective. scSPRITE accurately detects chromosome territories, active and inactive compartments, topologically associating domains (TADs), and higher-order structures within single cells. In addition, scSPRITE measures cell-to-cell heterogeneity in genome structure at different levels of resolution and shows that TADs are dynamic units of genome organization that can vary between different cells within a population. scSPRITE will improve our understanding of nuclear architecture and its relationship to nuclear function within an individual nucleus from complex cell types and tissues containing a diverse population of cells.
Structural basis for VIPP1 oligomerization and maintenance of thylakoid membrane integrity
Authors: Gupta Tilak Kumar , Klumpe Sven , Gries Karin , Heinz Steffen , Wietrzynski Wojciech , Ohnishi Norikazu , Niemeyer Justus , Schaffer Miroslava , Rast Anna , Strauss Mike , Plitzko Jürgen M. , Baumeister Wolfgang , Rudack Till , Sakamoto Wataru , Nickelsen Jörg , Schuller Jan M. , Schroda Michael , Engel Benjamin D. 
Published: August 2020

AbstractVesicle-inducing protein in plastids (VIPP1) is essential for the biogenesis and maintenance of thylakoid membranes, which transform light into life. However, it is unknown how VIPP1 performs its vital membrane-shaping function. Here, we use cryo-electron microscopy to determine structures of cyanobacterial VIPP1 rings, revealing how VIPP1 monomers flex and interweave to form basket-like assemblies of different symmetries. Three VIPP1 monomers together coordinate a non-canonical nucleotide binding pocket that is required for VIPP1 oligomerization. Inside the ring’s lumen, amphipathic helices from each monomer align to form large hydrophobic columns, enabling VIPP1 to bind and curve membranes.In vivopoint mutations in these hydrophobic surfaces cause extreme thylakoid swelling under high light, indicating an essential role of VIPP1 lipid binding in resisting stress-induced damage. Our study provides a structural basis for understanding how the oligomerization of VIPP1 drives the biogenesis of thylakoid membranes and protects these life-giving membranes from environmental stress.
Cryo-EM Structures of the SARS-CoV-2 Endoribonuclease Nsp15
Authors: Pillon Monica C. , Frazier Meredith N. , Dillard Lucas B. , Williams Jason G. , Kocaman Seda , Krahn Juno M. , Perera Lalith , Hayne Cassandra K. , Gordon Jacob , Stewart Zachary D. , Sobhany Mack , Deterding Leesa J. , Hsu Allen L. , Dandey Venkata P. , Borgnia Mario J. , Stanley Robin E. 
Published: August 2020

AbstractNew therapeutics are urgently needed to inhibit SARS-CoV-2, the virus responsible for the on-going Covid-19 pandemic. Nsp15, a uridine-specific endoribonuclease found in all coronaviruses, processes viral RNA to evade detection by RNA-activated host defense systems, making it a promising drug target. Previous work with SARS-CoV-1 established that Nsp15 is active as a hexamer, yet how Nsp15 recognizes and processes viral RNA remains unknown. Here we report a series of cryo-EM reconstructions of SARS-CoV-2 Nsp15. The UTP-bound cryo-EM reconstruction at 3.36 Å resolution provides molecular details into how critical residues within the Nsp15 active site recognize uridine and facilitate catalysis of the phosphodiester bond, whereas the apo-states reveal active site conformational heterogeneity. We further demonstrate the specificity and mechanism of nuclease activity by analyzing Nsp15 products using mass spectrometry. Collectively, these findings advance understanding of how Nsp15 processes viral RNA and provide a structural framework for the development of new therapeutics.
Investigating molecular mechanisms of 2A-stimulated ribosomal pausing and frameshifting inTheilovirus
Authors: Hill Chris H. , Cook Georgia M. , Napthine Sawsan , Kibe Anuja , Brown Katherine , Caliskan Neva , Firth Andrew E. , Graham Stephen C. , Brierley Ian 
Published: August 2020

AbstractThe 2A protein of Theiler’s murine encephalomyelitis virus (TMEV) acts as a switch to stimulate programmed −1 ribosomal frameshifting (PRF) during infection. Here we present the X-ray crystal structure of TMEV 2A and define how it recognises the stimulatory RNA element. We demonstrate a critical role for bases upstream of the originally predicted stem-loop, providing evidence for a pseudoknot-like conformation and suggesting that the recognition of this pseudoknot by beta-shell proteins is a conserved feature in cardioviruses. Through examination of PRF in TMEV-infected cells by ribosome profiling, we identify a series of ribosomal pauses around the site of PRF induced by the 2A-pseudoknot complex. Careful normalisation of ribosomal profiling data with a 2A knockout virus facilitated the identification, through disome analysis, of ribosome stacking at the TMEV frameshifting signal. These experiments provide unparalleled detail of the molecular mechanisms underpinningTheilovirusprotein-stimulated frameshifting.
Discovery of a protein uptake pathway in lysosomes
Authors: Fujiwara Yuuki , Contu Viorica Raluca , Kabuta Chihana , Ogawa Megumu , Fujita Hiromi , Kikuchi Hisae , Sakai Ryohei , Hase Katsunori , Suzuki Mari , Koyama-Honda Ikuko , Inoue Michio , Oya Yasushi , Inoue Yukiko U. , Inoue Takayoshi , Takahashi Ryosuke , Nishino Ichizo , Wada Keiji , Noguchi Satoru , Kabuta Tomohiro 
Published: August 2020

AbstractThe degradation of cellular components plays an essential role in homeostasis. However, the known degradation pathways cannot account for the levels of proteolysis in cells. Here, we demonstrate that cytosolic proteins are imported into lysosomes in an ATP-dependent manner for degradation through a direct uptake mechanism distinct from any known pathway. SIDT2, a lysosomal membrane protein previously reported as an RNA transporter, translocates substrate proteins across the lysosomal membrane. Furthermore, we identify a dominant-negative mutation inSIDT2that causes neuropathy and distal myopathy with rimmed vacuoles, a protein aggregation disease in humans. We generateSidt2knockout mice, recapitulating the characteristic features of this disease. Our results reveal a novel degradation pathway and illustrate its crucial role in cellular proteostasis, physiology, and pathophysiology.One Sentence SummaryDiscovery of a novel proteolytic pathway in cells, the dysfunction of which leads to protein aggregation disease in humans.
Besca, a single-cell transcriptomics analysis toolkit to accelerate translational research
Authors: Mädler Sophia Clara , Julien-Laferriere Alice , Wyss Luis , Phan Miroslav , Kang Albert S. W. , Ulrich Eric , Schmucki Roland , Zhang Jitao David , Ebeling Martin , Badi Laura , Kam-Thong Tony , Schwalie Petra C. , Hatje Klas 
Published: August 2020

AbstractSingle-cell RNA sequencing (scRNA-seq) revolutionised our understanding of disease biology and presented the promise of transforming translational research. We developedBesca, a toolkit that streamlines scRNA-seq analyses according to current best practices. A standard workflow covers quality control, filtering, and clustering. Two complementaryBescamodules, utilizing hierarchical cell signatures or supervised machine learning, automate cell annotation and provide harmonised nomenclatures across studies. Subsequently,Bescaenables estimation of cell type proportions in bulk transcriptomics studies. Using multiple heterogeneous scRNA-seq datasets we show howBescaaids acceleration, interoperability, reusability, and interpretability of scRNA-seq data analysis, crucial aspects in translational research and beyond.
Red deerCervus elaphusblink more in larger groups
Authors: Rowe Zeke W. , Robins Joseph H. , Rands Sean A. 
Published: August 2020

ABSTRACTMost animals need to spend time being vigilant for predators, at the expense of other activities such as foraging. Group-living animals can benefit from the shared vigilance effort of other group members, with individuals reducing personal vigilance effort as group size increases. Behaviours like active scanning or head lifting are usually used to quantify vigilance, but may not be accurate measures as the individual could be conducting them for other purposes. We suggest that measuring an animal’s blinking rate gives a meaningful measure of vigilance: increased blinking implies reduced vigilance, as the animal cannot detect predators when its eyes are closed. We demonstrate that as group size increases in red deer, individuals increase their blink rate, confirming the prediction that vigilance should decrease. Blinking is a simple non-invasive measure, and offers a useful metric for assessing the welfare of animals experiencing an increase in perceived predation risk or other stressors.
Critical Assessment of Protein Intrinsic Disorder Prediction
Authors: Necci Marco , Piovesan Damiano ,   CAID Predictors,   DisProt Curators, Tosatto Silvio C.E. 
Published: August 2020

AbstractIntrinsically disordered proteins defying the traditional protein structure-function paradigm represent a challenge to study experimentally. As a large part of our knowledge rests on computational predictions, it is crucial for their accuracy to be high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in predicting intrinsically disordered regions in proteins and the subset of disordered residues involved in binding other molecules. A total of 43 methods, 32 for disorder and 11 for binding regions, were evaluated on a dataset of 646 novel manually curated proteins from DisProt. The best methods use deep learning techniques and significantly outperform widely used earlier physicochemical methods across different types of targets. Disordered binding regions remain hard to predict correctly. Depending on the definition used, the top disorder predictor has an FMaxof 0.483 (DisProt) or 0.792 (DisProt-PDB). As the top binding predictor only attains an FMaxof 0.231, this suggests significant potential for improvement. Intriguingly, computing times among the top performing methods vary by up to four orders of magnitude.
IGF targeting perturbs global replication through ribonucleotide reductase dysfunction
Authors: Rieunier Guillaume , Wu Xiaoning , Harris Letitia , Mills Jack , Nandakumar Ashwin , Colling Laura , Seraia Elena , Hatch Stephanie B. , Ebner Daniel , Folkes Lisa K. , Weyer-Czernilofsky Ulrike , Bogenrieder Thomas , Ryan Anderson J. , Macaulay Valentine M. 
Published: August 2020

AbstractIGF receptor (IGF-1R) inhibition delays repair of radiation-induced DNA double-strand breaks (DSBs), prompting us to investigate whether IGF-1R influences endogenous DNA damage. We demonstrate that IGF-1R inhibition generates endogenous DNA lesions protected by 53BP1 bodies, indicating under-replicated DNA. We detect delayed replication fork progression in IGF-inhibited or IGF-1R depleted cancer cells, with activation of ATR-CHK1 signaling and the intra-S-phase checkpoint. This phenotype reflects unanticipated regulation of global replication by IGF-1, mediated via AKT, MEK/ERK and JUN to influence expression of ribonucleotide reductase (RNR) subunit RRM2. IGF-1R inhibition or depletion downregulate RRM2, compromising RNR function and dNTP supply. The resulting delay in fork progression and hallmarks of replication stress are rescued by RRM2 overexpression, confirming RRM2 as the critical factor through which IGF-1 regulates replication. Following targeted compound screens, we identify synergy between IGF inhibition and ATM loss, with evidence that IGF inhibition compromises growth of ATM null cells and xenografts. This synthetic lethal effect reflects conversion of single-stranded lesions in IGF-inhibited cells into toxic DSBs upon ATM inhibition. These data implicate IGF-1R in alleviating replication stress, and the identified reciprocal IGF:ATM co-dependence provides an approach to exploit this effect in ATM-deficient cancers.
Cisplatin is more mutagenic than carboplatin or oxaliplatin at equitoxic concentrations
Authors: Szikriszt Bernadett , Póti Ádám , Németh Eszter , Kanu Nnennaya , Swanton Charles , Szüts Dávid 
Published: August 2020

ABSTRACTPlatinum-based drugs are a mainstay of cancer chemotherapy. However, their mutagenic effect can increase tumour heterogeneity, contribute to the evolution of treatment resistance, and also induce secondary malignancies. We coupled whole genome sequencing with phenotypic investigations on two cell line models to compare the magnitude and understand the mechanism of mutagenicity of cisplatin, carboplatin and oxaliplatin. Cisplatin induced significantly more base substitution mutations than carboplatin or oxaliplatin when used at equitoxic concentrations on human TK6 or chicken DT40 cells, and also induced the highest number of short insertions and deletions. Assessment through histone H2AX phosphorylation and single cell agarose gel electrophoresis suggested that cisplatin caused more DNA damage than carboplatin or oxaliplatin. The analysis of base substitution spectra revealed that all three tested platinum drugs elicit both a direct mutagenic effect at purine dinucleotides, and an indirect effect of accelerating endogenous mutagenic processes. Whereas the direct mutagenic effect correlated with the level of DNA damage caused, the indirect mutagenic effects were equal. The different mutagenicity and DNA damaging effect of equitoxic platinum drug treatments suggests that DNA damage independent mechanisms significantly contribute to their cytotoxicity. Thus, the comparatively high mutagenicity of cisplatin should be taken into account in the design of chemotherapeutic regimens.