bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure-based Classification of Tauopathies
Authors: Shi Yang , Zhang Wenjuan , Yang Yang , Murzin Alexey , Falcon Benjamin , Kotecha Abhay , van Beers Mike , Tarutani Airi , Kametani Fuyuki , Garringer Holly J. , Vidal Ruben , Hallinan Grace I. , Lashley Tammaryn , Saito Yuko , Murayama Shigeo , Yoshida Mari , Tanaka Hidetomo , Kakita Akiyoshi , Ikeuchi Takeshi , Robinson Andrew C. , Mann David M.A. , Kovacs Gabor G. , Revesz Tamas , Ghetti Bernardino , Hasegawa Masato , Goedert Michel , Scheres Sjors H.W. 
Published: May 2021

ABSTRACTOrdered assembly of the tau protein into filaments characterizes multiple neurodegenerative diseases, which are called tauopathies. We previously reported that by electron cryo-microscopy (cryo-EM), tau filament structures from Alzheimer’s disease (1,2), chronic traumatic encephalopathy (CTE) (3), Pick’s disease (4) and corticobasal degeneration (CBD) (5) are distinct. Here we show that the structures of tau filaments from typical and atypical progressive supranuclear palsy (PSP), the most common tauopathy after Alzheimer’s disease, define a previously unknown, three-layered fold. Moreover, the tau filament structures from globular glial tauopathy (GGT, Types I and II) are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs from the above and resembles the four-layered CBD fold. The majority of tau filaments from aging-related tau astrogliopathy (ARTAG) also have the AGD fold. Surprisingly, tau protofilament structures from inherited cases with mutations +3/+16 in intron 10 of MAPT, the microtubule-associated protein tau gene, are identical to those from AGD, suggesting that a relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, tau filament structures from cases of familial British dementia (FBD) and familial Danish dementia (FDD) are the same as those from Alzheimer’s disease and primary age-related tauopathy (PART). These structures provide the basis for a classification of tauopathies that also allows identification of new entities, as we show here for a case diagnosed as PSP, but with abundant spherical 4R tau inclusions in limbic and other brain areas. The structures of the tau fold of this new disease (Limbic-predominant Neuronal inclusion body 4R Tauopathy, LNT) were intermediate between those of GGT and PSP.
Decomposition of the SARS-CoV-2-ACE2 interface reveals a common trend among emerging viral variants
Authors: Socher Eileen , Conrad Marcus , Heger Lukas , Paulsen Friedrich , Sticht Heinrich , Zunke Friederike , Arnold Philipp 
Published: May 2021

AbstractNew viral variants of the SARS-CoV-2 virus show enhanced infectivity compared to wild type, resulting in an altered pandemic situation in affected areas. These variants are the B.1.1.7 (United Kingdom), B.1.1.7 with the additional E484K mutation, the B.1.351 variant (South Africa) and the P.1 variant (Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows depicting changes, but also common motifs of virus-host cell interaction. The trimeric spike protein expressed at the viral surface contains the receptor-binding domain (RBD) that forms the molecular interface with ACE2. All the above-mentioned variants carry between one and three amino acid exchanges within the interface-forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics simulations and decomposition of the interaction energies between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500 and tyrosine 505 as important interface-forming residues across viral variants. We also suggest a reduced binding energy between RBD and ACE2 in viral variants with higher infectivity, attributed to residue-specific differences in electrostatic interaction energy. Importantly, individual amino acid exchanges not only influence the affected position, but also alter the conformation of surrounding residues and affect their interaction potential as well. We demonstrate how computational methods can help to identify changed as well as common motifs across viral variants. These identified motifs might play a crucial role, in the strategical development of therapeutic interventions against the fast mutating SARS-CoV-2 virus.Significance StatementThe COVID-19 pandemic caused by the SARS-CoV-2 virus has significantly changed our lives. To date, there is a lack of neutralizing drugs that specifically target SARS-CoV-2. Hope lies in newly developed vaccines that effectively prevent severe cases of acute respiratory syndrome. However, emerging viral variants escape vaccine-induced immune-protection. Therefore, identification of appropriate molecular targets across viral variants is important for the development of second- and third-generation vaccines and inhibitory antibodies. In this study, we identify residues across viral variants that are important for viral binding to the host cell. As such residues cannot be replaced without diminishing infectivity of the virus, these residues represent primary targets for intervention, for example by neutralizing antibodies.
A universal, open-source, high-performance tool for automated sleep staging
Authors: Vallat Raphael , Walker Matthew P. 
Published: May 2021

AbstractThe creation of a completely automated sleep-scoring system that is highly accurate, flexible, well validated, free and simple to use by anyone has yet to be accomplished. In part, this is due to the difficulty of use of existing algorithms, algorithms having been trained on too small samples, and paywall demotivation. Here we describe a novel algorithm trained and validated on +27,000 hours of polysomnographic sleep recordings across heterogeneous populations around the world. This tool offers high sleep-staging accuracy matching or exceeding human accuracy and interscorer agreement no matter the population kind. The software is easy to use, computationally low-demanding, open source, and free. Such software has the potential to facilitate broad adoption of automated sleep staging with the hope of becoming an industry standard.
Pharmacological activation of PIEZO1 in human red blood cells prevents Plasmodium falciparum invasion
Authors: Lohia Rakhee , Le Guet Jordy , Berry Laurence , Guizouarn Hélène , Bernal Roberto , Cerdan Rachel , Abkarian Manouk , Douguet Dominique , Honoré Eric , Wengelnik Kai 
Published: May 2021

AbstractAn inherited gain-of–function variant (E756 del) in the mechanosensitive cationic channel PIEZO1 was recently shown to confer a significant protection against severe malaria. Here, we demonstrate in vitro that human red blood cell (RBC) infection by Plasmodium falciparum is prevented by the pharmacological activation of PIEZO1. The PIEZO1 activator Yoda1 inhibits RBC invasion, without affecting parasite intraerythrocytic growth, division or egress. RBC dehydration, echinocytosis and intracellular Na+/K+ imbalance are unrelated to the mechanism of protection. Inhibition of invasion is maintained, even after a prolonged wash out of Yoda1. Similarly, the chemically unrelated activators Jedi1 and Jedi2 potently inhibit parasitemia, further indicating a PIEZO1-dependent mechanism. Notably, Yoda1 treatment significantly reduced RBC surface receptors of P. falciparum, and decreased merozoite attachment and subsequent RBC deformation. Altogether these data indicate that the pharmacological activation of Piezo1 in human RBCs inhibits malaria infection by impairing P. falciparum invasion.
The Dual Mechanisms of Cognitive Control dataset, a theoretically-guided within-subject task fMRI battery
Authors: Etzel Joset A. , Brough Rachel E. , Freund Michael C. , Kizhner Alexander , Lin Yanli , Singh Matthew F. , Tang Rongxiang , Tay Allison , Wang Anxu , Braver Todd S. 
Published: May 2021

AbstractCognitive control is a critical higher mental function, which is subject to considerable individual variation, and is impaired in a range of mental health disorders. We describe here the initial release of Dual Mechanisms of Cognitive Control (DMCC) project data, the DMCC55B dataset, with 55 healthy unrelated young adult participants. Each participant performed four well-established cognitive control tasks (AX-CPT, Cued Task-Switching, Sternberg Working Memory, and Stroop) while undergoing functional MRI scanning. The dataset includes a range of state and trait self-report questionnaires, as well as behavioural tasks assessing individual differences in cognitive ability. The DMCC project is on-going and features additional components (e.g., related participants, manipulations of cognitive control mode, resting state fMRI, longitudinal testing) that will be publicly released following study completion. This DMCC55B subset is released early with the aim of encouraging wider use and greater benefit to the scientific community. The DMCC55B dataset is suitable for benchmarking and methods exploration, as well as analyses of task performance and individual differences.
Probing effects of the SARS-CoV-2 E protein on membrane curvature and intracellular calcium
Authors: Mehregan Aujan , Pérez-Conesa Sergio , Zhuang Yuxuan , Elbahnsi Ahmad , Pasini Diletta , Lindahl Erik , Howard Rebecca J , Ulens Chris , Delemotte Lucie 
Published: May 2021

AbstractSARS-CoV-2 contains four structural proteins in its genome. These proteins aid in the assembly and budding of new virions at the ER-Golgi intermediate compartment (ERGIC). Current fundamental research efforts largely focus on one of these proteins – the spike (S) protein. Since successful antiviral therapies are likely to target multiple viral components, there is considerable interest in understanding the biophysical role of its other structural proteins, in particular structural membrane proteins. Here, we have focused our efforts on the characterization of the full-length envelope (E) protein from SARS-CoV-2, combining experimental and computational approaches. Recombinant expression of the full-length E protein from SARS-CoV-2 reveals that this membrane protein is capable of independent multimerization, possibly as a tetrameric or smaller species. Fluorescence microscopy shows that the protein localizes intracellularly, and coarse-grained MD simulations indicate it causes bending of the surrounding lipid bilayer, corroborating a potential role for the E protein in viral budding. Although we did not find robust electrophysiological evidence of ion-channel activity, cells transfected with the E protein exhibited reduced intracellular Ca2+, which may further promote viral replication. However, our atomistic MD simulations revealed that previous NMR structures are relatively unstable, and result in models incapable of ion conduction. Our study highlights the importance of using high-resolution structural data obtained from a full-length protein to gain detailed molecular insights, and eventually permitting virtual drug screening.
Manganese transport by Streptococcus sanguinis in acidic conditions and its impact on growth in vitro and in vivo
Authors: Puccio Tanya , Schultz Alexander C. , Lizarraga Claudia A. , Bryant Ashley S. , Culp David J. , Burne Robert A. , Kitten Todd 
Published: May 2021

SummaryStreptococcus sanguinis is an oral commensal and an etiological agent of infective endocarditis. Previous studies have identified the SsaACB manganese transporter as essential for endocarditis virulence; however, the significance of SsaACB in the oral environment has never been examined. Here we report that a ΔssaACB mutant of strain SK36 exhibits reduced growth and manganese uptake under acidic conditions. Further studies revealed that these deficits resulted from the decreased activity of TmpA, shown in the accompanying paper to function as a ZIP-family manganese transporter. Transcriptomic analysis of fermentor-grown cultures of SK36 WT and ΔssaACB strains identified pH-dependent changes related to carbon catabolite repression in both strains, though their magnitude was generally greater in the mutant. In strain VMC66, which possesses a MntH transporter, loss of SsaACB did not significantly alter growth or cellular manganese levels under the same conditions. Interestingly, there were only modest differences between SK36 and its ΔssaACB mutant in competition with Streptococcus mutans in vitro and in a murine oral colonization model. Our results suggest that the heterogeneity of the oral environment may provide a rationale for the variety of manganese transporters found in S. sanguinis and point to strategies for enhancing the safety of oral probiotics.Graphical AbstractDepiction of methods. Streptococcal strains used are depicted at the top. The four methods illustrated are: 1. S. sanguinis cells were grown in media at pH 7.3 and pH 6.2 and quantified by plating. 2. S. sanguinis cells were grown in a fermentor vessel for RNA-sequencing and metal analysis. 3. S. sanguinis and S. mutans cells were grown in 12-well plates singly or in competition, then plated and the pH of the media measured. 4. S. sanguinis and S. mutans cells were inoculated into the mouths of mice. Oral swabs and dental biofilms from molars were assayed for bacterial composition by qPCR. (Biorender)
The N-terminal and central domains of CoV-2 nsp1 play key functional roles in suppression of cellular gene expression and preservation of viral gene expression
Authors: Mendez Aaron S. , Ly Michael , González-Sánchez Angélica M. , Hartenian Ella , Ingolia Nicholas T. , Cate Jamie H. , Glaunsinger Britt A. 
Published: May 2021

AbstractNonstructural protein 1 (nsp1) is the first viral protein synthesized during coronavirus (CoV) infection and is a key virulence factor that dampens the innate immune response. It restricts cellular gene expression through a combination of inhibiting translation by blocking the mRNA entry channel of the 40S ribosomal subunit and by promoting mRNA degradation. We performed a detailed structure-guided mutational analysis of CoV-2 nsp1 coupled with in vitro and cell-based functional assays, revealing insight into how it coordinates these activities against host but not viral mRNA. We found that residues in the N-terminal and central regions of nsp1 not involved in docking into the 40S mRNA entry channel nonetheless stabilize its association with the ribosome and mRNA, thereby enhancing its restriction of host gene expression. These residues are also critical for the ability of mRNA containing the CoV-2 leader sequence to escape translational repression. Notably, we identify CoV-2 nsp1 mutants that gain the ability to repress translation of viral leader-containing transcripts. These data support a model in which viral mRNA binding functionally alters the association of nsp1 with the ribosome, which has implications for drug targeting and understanding how engineered or emerging mutations in CoV-2 nsp1 could attenuate the virus.
Novel antibodies for the simple and efficient enrichment of native O-GlcNAc modified peptides
Authors: Burt Rajan A. , Dejanovic Borislav , Peckham Hayley J. , Lee Kimberly A. , Li Xiang , Ounadjela Johain R. , Rao Anjana , Malaker Stacy A. , Carr Steven A. , Myers Samuel A. 
Published: May 2021

AbstractAntibodies against post-translational modifications (PTMs) such as lysine acetylation, ubiquitin remnants, or phosphotyrosine have resulted in significant advances in our understanding of the fundamental roles of PTMs in biology. However, the roles of a number of PTMs remain largely unexplored due to the lack of robust enrichment reagents. The addition of N-acetylglucosamine to serine and threonine residues (O-GlcNAc) by the O-GlcNAc transferase (OGT) is a PTM implicated in numerous biological processes and disease states but with limited techniques for its study. Here, we evaluate a new mixture of anti-O-GlcNAc monoclonal antibodies for the immunoprecipitation of native O-GlcNAcylated peptides from cells and tissues. The anti-O-GlcNAc antibodies display good sensitivity and high specificity toward O-GlcNAc-modified peptides, and do not recognize O-GalNAc or GlcNAc in extended glycans. Applying this antibody-based enrichment strategy to synaptosomes from mouse brain tissue samples, we identified over 1,300 unique O-GlcNAc-modified peptides and over 1,000 sites using just a fraction of sample preparation and instrument time required in other landmark investigations of O-GlcNAcylation. Our rapid and robust method greatly simplifies the analysis of O-GlcNAc signaling and will help to elucidate the role of this challenging PTM in health and disease.
Frontal language areas do not emerge in the absence of temporal language areas: A case study of an individual born without a left temporal lobe
Authors: Tuckute Greta , Paunov Alexander , Kean Hope , Small Hannah , Mineroff Zachary , Blank Idan , Fedorenko Evelina 
Published: May 2021

AbstractLanguage relies on a left-lateralized fronto-temporal brain network. How this network emerges ontogenetically remains debated. We asked whether frontal language areas emerge in the absence of temporal language areas through a ‘deep-data’ investigation of an individual (EG) born without her left temporal lobe. Using fMRI methods that have been validated to elicit reliable individual-level responses, we find that—as expected for early left hemisphere damage—EG has a fully functional language network in her right hemisphere (comparable to that in n=145 controls) and performs normally on language assessments. However, we detect no response to language in EG’s left frontal lobe (replicated across two sessions, 3 years apart). Another network—the multiple demand network—is robustly present in frontal lobes bilaterally, suggesting that EG’s left frontal cortex can support non-linguistic cognition. The existence of temporal language areas therefore appears to be a prerequisite for the emergence of the frontal language areas.
Computational genomic analysis of the lung tissue microenvironment in COVID-19 patients
Authors: Bhuvaneshwar Krithika , Madhavan Subha , Gusev Yuriy 
Published: May 2021

ABSTRACTThe coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has affected over 170 million people, and caused over 3.5 million deaths throughout the world as of May 2021. Although over 150 million people around the world have recovered from this disease, the long term effects of the disease are still under study. A year after the start of the pandemic, data from COVID-19 recovered patients shows multiple organs affected with a broad spectrum of manifestations. Long term effects of SARS-CoV-2 infection includes fatigue, chest pain, cellular damage, and robust innate immune response with inflammatory cytokine production. More clinical studies and clinical trials are needed to not only document, but also to understand and determine the factors that predispose certain people to the long term side effects of his infection.In this manuscript, our goal was to explore the multidimensional landscape of infected lung tissue microenvironment to better understand complex interactions between SARS-CoV-2 viral infection, immune response and the lungs microbiome of COVID-19 patients. Each sample was analyzed with several machine learning tools allowing simultaneous detection and quantification of viral RNA amount at genome and gene level; human gene expression and fractions of major types of immune cells, as well as metagenomic analysis of bacterial and viral abundance. To contrast and compare specific viral response to SARS-COV-2 we have analyzed deep sequencing data from additional cohort of patients infected with NL63 strain of corona virus.Our correlation analysis of three types of measurements in patients i.e. fraction of viral RNA (at genome and gene level), Human RNA (transcripts and gene level) and bacterial RNA (metagenomic analysis), showed significant correlation between viral load as well as level of specific viral gene expression with the fractions of immune cells present in lung lavage as well as with abundance of major fractions of lung microbiome in COVID-19 patients.Our exploratory study has provided novel insights into complex regulatory signaling interactions and correlative patterns between the viral infection, inhibition of innate and adaptive immune response as well as microbiome landscape of the lung tissue. These initial findings could provide better understanding of the diverse dynamics of immune response and the side effects of the SARS-CoV-2 infection.
Variomes: a high recall search engine to support the curation of genomic variants
Authors: Pasche Emilie , Mottaz Anaïs , Caucheteur Déborah , Gobeill Julien , Michel Pierre-André , Ruch Patrick 
Published: May 2021

AbstractPrecision oncology relies on the use of treatments targeting specific genetic variants. However, identifying clinically actionable variants as well as relevant information likely to be used to treat a patient with a given cancer is a labor-intensive task, which includes searching the literature for a large set of variants. The lack of universally adopted standard nomenclature for variants requires the development of variant-specific literature search engines. We develop a system to perform triage of publications relevant to support an evidence-based decision. Together with providing a ranked list of articles for a given variant, the system is also able to prioritize variants, as found in a Variant Calling Format, assuming that the clinical actionability of a genetic variant is correlated with the volume of literature published about the variant. Our system searches within three pre-annotated document collections: MEDLINE abstracts, PubMed Central full-text articles andClinicalTrials.govclinical trials. A variant synonym generator is used to increase the comprehensiveness of the set of retrieved documents. We then apply different strategies to rank the publications. We assess the search effectiveness of the system using different experimental settings. Experimental setting 1: The literature retrieval task is tuned and evaluated using the TREC Precision Medicine 2018 and 2019 benchmarks consisting respectively in 50 and 40 topics. Almost two thirds (62%) of the publications returned in the top-5 are relevant for clinical decision-support. Experimental setting 2: The evaluation of the variant prioritization task is based on a manually-created benchmark composed of eight patients for a total of 756 variants. For each patient, we used both their complete set of variants and tumor board reports. Our approach enabled identifying 81.8% of clinically actionable variants in the top-3. Experimental setting 3: A comparison of Variomes with LitVar, a well-known search engine for genetic variants is performed. Variomes was able to retrieve on average 90.8% of the content, while LitVar retrieved on average 58.6%. Out of the 9.2% articles, which are “missed” by Variomes, a per error analysis suggests that they are artefacts. To conclude, we are proposing here a competitive system to facilitate the curation of variants for personalized medicine.