bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of force function formulations on the numerical simulation of centre-based models
Authors: Mathias Sonja , Coulier Adrien , Bouchnita Anass , Hellander Andreas 
Published: March 2020

AbstractCentre-based, or cell-centre models are a framework for the computational study of multicellular systems with widespread use in cancer modelling and computational developmental biology. At the core of these models are the numerical method used to update cell positions and the force functions that encode the pairwise mechanical interactions of cells. For the latter there are multiple choices that could potentially affect both the biological behaviour captured, and the robustness and efficiency of simulation. For example, available open-source software implementations of centre-based models rely on different force functions for their default behaviour and it is not straightforward for a modeler to know if these are interchangeable. Our study addresses this problem and contributes to the understanding of the potential and limitations of three popular force functions from a numerical perspective. We show empirically that choosing the force parameters such that the relaxation time for two cells after cell division is consistent between different force functions results in good agreement of the population radius of a growing monolayer. Furthermore, we report that numerical stability is not sufficient to prevent unphysical cell trajectories following cell division, and consequently, that too large time steps can cause geometrical differences at the population level.
Secondary structural characterization of the nucleic acids from circular dichroism spectra using extreme gradient boosting decision-tree algorithm
Authors: Sathyaseelan Chakkarai , Vinothini V , Rathinavelan Thenmalarchelvi 
Published: March 2020

AbstractNucleic acids exhibit a repertoire of conformational preference depending on the sequence and environment. Circular dichroism (CD) is an important and valuable tool for monitoring such secondary structural conformations of nucleic acids. Nonetheless, the CD spectral diversity associated with these structures poses a challenge in obtaining the quantitative information about the secondary structural content of a given CD spectrum. To this end, the competence of extreme gradient boosting decision-tree algorithm has been exploited here to predict the diverse secondary structures of nucleic acids. A curated library of 610 CD spectra corresponding to 16 different secondary structures of nucleic acids has been developed and used as a training dataset. For a test dataset of 242 CD spectra, the algorithm exhibited the prediction accuracy of 99%. For the sake of accessibility, the entire process is automated and implemented as a webserver, called CD-NuSS (CD to nucleic acids secondary structure) and is freely accessible athttps://www.iith.ac.in/cdnuss/. The XGBoost algorithm presented here may also be extended to identify the hybrid nucleic acid topologies in future.
Polymorphic SNPs, short tandem repeats and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains
Authors: Mortazavi Milad , Ren Yangsu , Saini Shubham , Antaki Danny , Pierre Celine St. , Williams April , Sohni Abhishek , Wilkinson Miles , Gymrek Melissa , Sebat Jonathan , Palmer Abraham A. 
Published: March 2020

SummaryMouse substrains are an invaluable model for understanding disease. We compared C57BL/6J, which is the most commonly used inbred mouse strain, with 8 C57BL/6 and 5 C57BL/10 closely related inbred substrains. Whole genome sequencing and RNA-sequencing analysis yielded 352,631 SNPs, 109,096 INDELs, 150,344 short tandem repeats (STRs), 3,425 structural variants (SVs) and 2,826 differentially expressed genes (DEGenes) among these 14 strains. 312,981 SNPs (89%) distinguished the B6 and B10 lineages. These SNPs were clustered into 28 short segments that are likely due to introgressed haplotypes rather than new mutations. Outside of these introgressed regions, we identified 53 SVs, protein-truncating SNPs and frameshifting INDELs that were associated with DEGenes. Our results can be used for both forward and reverse genetic approaches, and illustrate how introgression and mutational processes give rise to differences among these widely used inbred substrains.
Formation of polarized contractile interfaces by self-organized Toll-8/Cirl GPCR asymmetry
Authors: Lavalou Jules , Mao Qiyan , Harmansa Stefan , Kerridge Stephen , Lellouch Annemarie C. , Philippe Jean-Marc , Audebert Stephane , Camoin Luc , Lecuit Thomas 
Published: March 2020

SummaryDuring development, interfaces between cells with distinct genetic identities elicit signals to organize local cell behaviors driving tissue morphogenesis. TheDrosophilaembryonic axis extension requires planar polarized enrichment of Myosin-II powering oriented cell intercalations. Myosin-II levels are quantitatively controlled by G protein-coupled receptor (GPCR) signaling whereas Myosin-II polarity requires patterned expression of several Toll receptors. How Toll receptors polarizes Myosin-II, and how this involves GPCRs, remain unknown. Here we report that differential expression of a single Toll receptor, Toll-8, polarizes Myosin-II via a novel binding partner, the adhesion GPCR Cirl/Latrophilin. Asymmetric expression of Cirl is sufficient to enrich Myosin-II and Cirl localization is asymmetric at Toll-8 expression boundaries. Exploring the process dynamically, we reveal that Toll-8 and Cirl exhibit mutually dependent planar polarity in response to quantitative differences in Toll-8 expression between neighboring cells. Collectively, we propose that a novel cell surface protein complex Toll-8/Cirl self-organizes to generate local asymmetric interfaces essential for planar polarization of contractile interfaces.
Amyloid-β oligomers are captured by the DNAJB6 chaperone: Direct detection of interactions that can prevent primary nucleation
Authors: Österlund Nicklas , Lundquist Martin , Ilag Leopold L. , Gräslund Astrid , Emanuelsson Cecilia 
Published: March 2020

AbstractA human molecular chaperone protein, DNAJB6, is an efficient inhibitor of amyloid aggregation owing to a unique motif with conserved S/T-residues with high capacity for hydrogen bonding. Global analysis of kinetics data previously showed that especially the primary nucleation rate is inhibited. It was concluded that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-β (Aβ) peptide but with aggregated species. The pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here we employed an approach to directly detect oligomeric forms of Aβ formed in solution by subsequent analysis with native mass spectrometry (native MS). Results show that the signals from the various forms of Aβ (1-40) oligomers were reduced considerably in the presence of DNAJB6, but not with a mutational variant of DNAJB6 in which the S/T-residues were substituted. With focus on DNAJB6 we could also detect signals that appear to represent DNAJB6 dimers and trimers to which varying amounts of Aβ is bound. These data provide direct experimental evidence that it is the oligomeric forms of Aβ that are captured by DNAJB6 in a manner which is dependent on the S/T residues. Strong binding of Aβ oligomers to DNAJB6 should indeed inhibit the formation of amyloid nuclei, in agreement with the previously observed decrease in primary nucleation rate.
Evidence of the Recombinant Origin and Ongoing Mutations in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Authors: Huang Jiao-Mei , Jan Syed Sajid , Wei Xiaobin , Wan Yi , Ouyang Songying 
Published: March 2020

SUMMARYThe recent global outbreak of viral pneumonia designated as Coronavirus Disease 2019 (COVID-19) by coronavirus (SARS-CoV-2) has threatened global public health and urged to investigate its source. Whole genome analysis of SARS-CoV-2 revealed ~96% genomic similarity with bat CoV (RaTG13) and clustered together in phylogenetic tree. Furthermore, RaTGl3 also showed 97.43% spike protein similarity with SARS-CoV-2 suggesting that RaTGl3 is the closest strain. However, RBD and key amino acid residues supposed to be crucial for human-to-human and cross-species transmission are homologues between SARS-CoV-2 and pangolin CoVs. These results from our analysis suggest that SARS-CoV-2 is a recombinant virus of bat and pangolin CoVs. Moreover, this study also reports mutations in coding regions of 125 SARS-CoV-2 genomes signifying its aptitude for evolution. In short, our findings propose that homologous recombination has been occurred between bat and pangolin CoVs that triggered cross-species transmission and emergence of SARS-CoV-2, and, during the ongoing outbreak, SARS-CoV-2 is still evolving for its adaptability.
A tissue- and organ-based cell biological atlas of obesity-related human genes and cellular pathways
Authors: Tavassoly Iman , Barbieri Valentina , van Hasselt Coen , Martinez Pedro , Sobie Eric A. , Hansen Jens , Azeloglu Evren , Goldfarb Joseph , Sanseau Philippe , Rajpal Deepak K , Iyengar Ravi 
Published: March 2020

AbstractOver the last decades, several features of obesity have been identified at behavioral, physiological, endocrine and genomic levels, and they have revealed the complexity of the disease; obesity results from a combination of genetic predisposition, endocrine disorders, and dysregulation of both food intake and energy expenditure. This complexity makes the development of new therapeutic regimens challenging and bariatric surgery is still the treatment of choice for many obese patients. Given the need for noninvasive therapeutic intervention strategies, we sought to systematically study the biological manifestations of obesity in peripheral organs. We analyzed publicly available datasets of genes, genomic determinants, and levels of obesity-related hormones in the blood, using a combination of methodologies, including graph theory and dynamical modeling, that allow for the integration of different types of datasets. The analysis revealed tissue- and organ-specific metabolic impairments and potential new drug targets. All the data are organized into a tissue/organ-based subcellular-function atlas for human obesity. The data show that the complexity of the obesity arises due to the multiplicity of subcellular processes in different peripheral organs.
Low-frequency vibrational modes in G-quadruplexes reveal the mechanical properties of nucleic acids
Authors: González-Jiménez M. , Ramakrishnan G. , Wynne K. 
Published: March 2020

AbstractLow-frequency vibrations play an essential role in biomolecular processes involving DNA such as gene expression, charge transfer, drug intercalation, and DNA–protein recognition. However, understanding of the vibrational basis of these mechanisms relies on theoretical models due to the lack of experimental evidence. Here we present the low-frequency vibrational spectra of G-quadruplexes (structures formed by four strands of DNA) and B-DNA characterized using femtosecond optical Kerr-effect spectroscopy. Contrary to expectation, we found that G-quadruplexes show several strongly underdamped delocalized phonon-like modes that have the potential to contribute to the biology of the DNA at the atomic level. In addition, G-quadruplexes present modes at a higher frequency than B-DNA demonstrating that changes in the stiffness of the molecule alter its gigahertz to terahertz vibrational profile. These results demonstrate that current theoretical models fail to predict basic properties of the vibrational modes of DNA.Statement of significanceA number of recent studies have identified thermally excited low-frequency vibrational modes as a key deciding factor in the biological function of DNA. However, the nature of these vibrational modes has never been established. Here, vibrational spectroscopy with unrivalled signal-to-noise in the gigahertz to terahertz range is used to determine the low-frequency Raman spectra of nucleotides and oligomeric DNAs carefully chosen to form G-quadruplexes, structures formed by four strands of DNA common in the genome. These G-quadruplexes exhibit an unusual group of highly-underdamped delocalized vibrational modes—not reproduced by any of the theoretical models in use—which are expected to be the thermally excited. This provides a new perspective on the role of low-frequency vibrational modes in protein interactions and allostery.
Insulin dissociates by diverse mechanisms of coupled unfolding and unbinding
Authors: Antoszewski Adam , Feng Chi-Jui , Vani Bodhi P. , Thiede Erik H. , Hong Lu , Weare Jonathan , Tokmakoff Andrei , Dinner Aaron R. 
Published: March 2020

AbstractThe protein hormone insulin exists in various oligomeric forms, and a key step in binding its cellular receptor is dissociation of the dimer. This dissociation process and its corresponding association process have come to serve as a paradigms of coupled (un)folding and (un)binding more generally. Despite its fundamental and practical importance, the mechanism of insulin dimer dissociation remains poorly understood. Here, we use molecular dynamics simulations, leveraging recent developments in umbrella sampling, to characterize the energetic and structural features of dissociation in unprecedented detail. We find that the dissociation is inherently multipathway with limiting behaviors corresponding to conformational selection and induced fit, the two prototypical mechanisms of coupled folding and binding. Along one limiting path, the dissociation leads to detachment of the C-terminal segment of the insulin B chain from the protein core, a feature believed to be essential for receptor binding. We simulate IR spectroscopy experiments to aid in interpreting current experiments and identify sites where isotopic labeling can be most effective for distinguishing the contributions of the limiting mechanisms.
The Role of Ion Transition from the Pore Cavity to the Selectivity Filter in the Mechanism of Selectivity and Rectification in the Kv1.2 Potassium Channel: Transfer of Ion Solvation from Cavity Water to the Protein and Water of the Selectivity Filter
Authors: Kariev Alisher M , Green Michael E 
Published: March 2020

AbstractPotassium channels generally have a selectivity filter that includes the sequence threonine-threonine-valine-glycine-tyrosine-glycine (TTVGYG). The last five amino acids are conserved over practically the entire range of evolution, so the sequence obviously is necessary to the function of the channel. Here we show by quantum calculations on the upper part of the channel “cavity” (aqueous compartment between the gate and selectivity filter) and lower part of the selectivity filter (SF) how the channel with two sets of four threonines (the channel is fourfold symmetric) effects rectification and selectivity. The threonines are at the location in which the ion transfers from the cavity into the SF; in this calculation they play a key role in selectivity. The channel is also a rectifier. The wild type channel with K+and three other cases are considered: 1) the upper set of four threonines is replaced by serines. 2) and 3) Related computations with the Na+and NH4+ions help to clarify the important factors in moving the ion from the cavity to the SF. In particular, one set of angles (not bond angles,O(T373–C=O) –O(T374–OH) –H(T374–OH)) flips a hydrogen into and out of the ion path, allowing the K+to go forward but not back. This is essentially a ratchet and pawl mechanism, with the ratchet driven by electrostatics. This also allows a clear path forward for K+but not for Na+or NH4+, nor for K+in a T→S mutant. Atomic charges in the lowest positions in the SF are the driving force moving the ion forward, but the O - O - H angle just specified is key to making the “knock-on” mechanism move the ions forward only, using the ratchet with the pawl formed by the hydrogen in the bonds that flip. A water interacts with threonine hydroxyls to allow ion passage, and another water moves together with the K+.
Mechanism of Dynamic Binding of Replication Protein A to ssDNA
Authors: Mondal Anupam , Bhattacherjee Arnab 
Published: March 2020

AbstractReplication protein A (RPA) serves as hub protein inside eukaryotic cells, where it coordinates crucial DNA metabolic processes and activates the DNA-damage response system. A characteristic feature of its action is to associate with ssDNA intermediates before handing over them to downstream proteins. The length of ssDNA intermediates differs for different pathways. This means RPA must have mechanisms for selective processing of ssDNA intermediates based on their length, the knowledge of which is fundamental to elucidate when and how DNA repair and replication processes are symphonized. By employing extensive molecular simulations, we investigated the mechanism of binding of RPA to ssDNA of different lengths. We show that the binding involves dynamic equilibrium with a stable intermediate, the population of which increases with the length of ssDNA. The vital underlying factors are decoded through collective variable principal component analysis. It suggests a differently orchestrated set of interactions that define the action of RPA based on the sizes of ssDNA intermediates. We further estimated the association kinetics and probed the diffusion mechanism of RPA to ssDNA. RPA diffuses on short ssDNA through progressive ‘bulge’ formation. With long ssDNA, we observed a conformational change in ssDNA coupled with its binding to RPA in a cooperative fashion. Our analysis explains how the ‘short-lived,’ long ssDNA intermediates are processed quickly in vivo. The study thus reveals the molecular basis of several recent experimental observations related to RPA binding to ssDNA and provides novel insights into the RPA functioning in DNA repair and replication.Significance StatementDespite ssDNA be the common intermediate to all pathways involving RPA, how does the latter function differently in the DNA processing events such as DNA repair, replication, and recombination just based on the length of ssDNA intermediates remains unknown. The major hindrance is the difficulty in capturing the transient interactions between the molecules. Even attempts to crystallize RPA complexes with 32nt and 62nt ssDNA have yielded a resolved structure of only 25nt ssDNA wrapped with RPA. Here, we used a state-of-the-art coarse-grained protein-ssDNA model to unravel the detailed mechanism of binding of RPA to ssDNA. Our study illustrates the molecular origin of variations in RPA action during various DNA processing events depending on the length of ssDNA intermediates.
A serological assay to detect SARS-CoV-2 seroconversion in humans
Authors: Amanat Fatima , Stadlbauer Daniel , Strohmeier Shirin , Nguyen Thi H.O. , Chromikova Veronika , McMahon Meagan , Jiang Kaijun , Arunkumar Guha Asthagiri , Jurczyszak Denise , Polanco Jose , Bermudez-Gonzalez Maria , Kleiner Giulio , Aydillo Teresa , Miorin Lisa , Fierer Daniel , Lugo Luz Amarilis , Kojic Erna Milunka , Stoever Jonathan , Liu Sean T. H. , Cunningham-Rundles Charlotte , Felgner Philip L. , Moran Thomas , Garcia-Sastre Adolfo , Caplivski Daniel , Cheng Allen , Kedzierska Katherine , Vapalahti Olli , Hepojoki Jussi M. , Simon Viviana , Krammer Florian 
Published: March 2020

AbstractSARS-Cov-2 (severe acute respiratory disease coronavirus 2), which causes Coronavirus Disease 2019 (COVID19) was first detected in China in late 2019 and has since then caused a global pandemic. While molecular assays to directly detect the viral genetic material are available for the diagnosis of acute infection, we currently lack serological assays suitable to specifically detect SARS-CoV-2 antibodies. Here we describe serological enzyme-linked immunosorbent assays (ELISA) that we developed using recombinant antigens derived from the spike protein of SARS-CoV-2. Using negative control samples representing pre-COVID 19 background immunity in the general adult population as well as samples from COVID19 patients, we demonstrate that these assays are sensitive and specific, allowing for screening and identification of COVID19 seroconverters using human plasma/serum as early as two days post COVID19 symptoms onset. Importantly, these assays do not require handling of infectious virus, can be adjusted to detect different antibody types and are amendable to scaling. Such serological assays are of critical importance to determine seroprevalence in a given population, define previous exposure and identify highly reactive human donors for the generation of convalescent serum as therapeutic. Sensitive and specific identification of coronavirus SARS-Cov-2 antibody titers may, in the future, also support screening of health care workers to identify those who are already immune and can be deployed to care for infected patients minimizing the risk of viral spread to colleagues and other patients.
Estimating Assembly Base Errors Using K-mer Abundance Difference (KAD) Between Short Reads and Genome Assembled Sequences
Authors: He Cheng , Lin Guifang , Wei Hairong , Tang Haibao , White Frank F , Valent Barbara , Liu Sanzhen 
Published: March 2020

ABSTRACTGenome sequences provide genomic maps with a single-base resolution for exploring genetic contents. Sequencing technologies, particularly long reads, have revolutionized genome assemblies for producing highly continuous genome sequences. However, current long-read sequencing technologies generate inaccurate reads that contain many errors. Some errors are retained in assembled sequences, which are typically not completely corrected by using either long reads or more accurate short reads. The issue commonly exists but few tools are dedicated for computing error rates or determining error locations. In this study, we developed a novel approach, referred to as K-mer Abundance Difference (KAD), to compare the inferred copy number of each k-mer indicated by short reads and the observed copy number in the assembly. Simple KAD metrics enable to classify k-mers into categories that reflect the quality of the assembly. Specifically, the KAD method can be used to identify base errors and estimate the overall error rate. In addition, sequence insertion and deletion as well as sequence redundancy can also be detected. Therefore, KAD is valuable for quality evaluation of genome assemblies and, potentially, provides a diagnostic tool to aid in precise error correction. KAD software has been developed to facilitate public uses.