bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational modelling unveils how epiblast remodelling and positioning rely on trophectoderm morphogenesis during mouse implantation
Authors: Dokmegang Joel , Yap Moi Hoon , Han Liangxiu , Cavaliere Matteo , Doursat René 
Published: June 2020

AbstractUnderstanding the processes by which the mammalian embryo implants in the maternal uterus is a long-standing challenge in embryology. New insights into this morphogenetic event could be of great importance in helping, for example, to reduce human infertility. During implantation the blastocyst, composed of epiblast and trophectoderm, undergoes significant remodelling from an oval ball to an egg cylinder. A main feature of this transformation is symmetry breaking and reshaping of the epiblast into a “cup”. Based on previous studies, we hypothesise that this event is the result of mechanical constraints originating from the trophectoderm, which is also significantly transformed during this process. In order to investigate this hypothesis we propose MG#, an original computational model of biomechanics able to reproduce key cell shape changes and tissue level behavioursin silico. With this model, we simulate epiblast and trophectoderm morphogenesis during implantation. First, our results uphold experimental findings that repulsion at the apical surface of the epiblast is sufficient to drive lumenogenesis. Then, we provide new theoretical evidence that trophectoderm morphogenesis indeed dictates the cup shape of the epiblast and fosters its movement towards the uterine tissue. Together, these results offer mechanical insights into mouse implantation and highlight the usefulness of agent-based modelling methods in the study of embryogenesis.Author summaryComputational modelling is increasingly used in the context of biological development. Here we propose a novel agent-based model of biological cell and tissue mechanics to investigate important morphological changes during mouse embryo implantation. Our model is able to replicate key biological cell shape changes and tissue-level behaviour. Simulating mouse implantation with this model, we bring theoretical support to previous experimental observations that lumenogenesis in the epiblast is driven by repulsion, and provide theoretical evidence that changes in epiblast shape during implantation are regulated by trophectoderm development.
On the evolution of chaperones and co-chaperones and the expansion of proteomes across the Tree of Life
Authors: Rebeaud Mathieu E. , Mallik Saurav , Goloubinoff Pierre , Tawfik Dan S. 
Published: June 2020

ABSTRACTAcross the Tree of Life (ToL), the complexity of proteomes varies widely. Our systematic analysis depicts that from the simplest archaea to mammals, the total number of proteins per proteome expanded ~200-fold. Individual proteins also became larger, and multi-domain proteins expanded ~50-fold. Apart from duplication and divergence of existing proteins, completely new proteins were born. Along the ToL, the number of different folds expanded ~5-fold and fold-combinations ~20-fold. Proteins prone to misfolding and aggregation, such as repeat and beta-rich proteins, proliferated ~600-fold, and accordingly, proteins predicted as aggregation-prone became 6-fold more frequent in mammalian compared to bacterial proteomes. To control the quality of these expanding proteomes, core-chaperones, ranging from HSP20s that prevent aggregation to HSP60, HSP70, HSP90, and HSP100 acting as ATP-fueled unfolding and refolding machines, also evolved. However, these core-chaperones were already available in prokaryotes, and they comprise ~0.3% of all genes from archaea to mammals. This challenge—roughly the same number of core-chaperones supporting a massive expansion of proteomes, was met by (i) higher cellular abundances of the ancient generalist core-chaperones, and (ii) continuous emergence of new substrate-binding and nucleotide-exchange factor co-chaperones that function cooperatively with core-chaperones, as a network.
A novel epitope tagging system to visualize and monitor antigens in live cells with chromobodies
Authors: Traenkle Bjoern , Segan Sören , Kaiser Philipp D. , Rothbauer Ulrich 
Published: June 2020

SummaryEpitope tagging is a versatile approach to study different proteins using a well-defined and established methodology. To date, most epitope tags such as myc, HA, V5 and FLAG tags are recognized by antibodies which limits their application to fixed cells, tissues or protein samples. Here we introduce a broadly applicable tagging strategy utilizing a short peptide tag/chromobody (PepTag/PepCB) system. The addition of the small PepTag does not interfere with the examined structures in different cellular compartments and its detection with the fluorescently labeled Pep-chromobody (PepCB) enables optical antigen tracing in real time. By employing the phenomenon of antigen-mediated chromobody stabilization (AMCBS) using a turnover-accelerated PepCB we demonstrated that the system is suitable to visualize and quantify changes in Pep-tagged antigen concentration by quantitative live-cell imaging. We expect that this novel tagging strategy offers new opportunities to study the dynamic regulation of proteins, e.g. during cellular signaling, cell differentiation, or upon drug action.
Cross-subunit Interactions that Stabilize Open States Mediate Gating in NMDA Receptors
Authors: Iacobucci Gary J , Wen Han , Helou Matthew B , Zheng Wenjun , Popescu Gabriela K 
Published: June 2020

ABSTRACTNMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are of current interest. Very likely, the earliest steps in the activation reaction include glutamate binding to and compression of the ligand-binding domain. Later, three short linkers transduce this movement to open the gate by mechanical coupling with transmembrane helices. Here, we used double-mutant cycle analyses to demonstrate that a direct chemical interaction between GluN1-I642 (on M3) and GluN2A-L550 (on L1-M1) stabilizes receptors after they have opened, and therefore represents one of the structural changes that occur late in the activation reaction. This native interaction extends the current decay, and its absence predicts deficits in charge transfer by GluN1-I642L, a pathogenic human variant.SIGNIFICANCE STATEMENTNMDA receptors are glutamatergic channels whose activations control the strength of excitatory synapses in the central nervous system. Agonist binding initiates a complex activation reaction that consists of a stepwise sequence of reversible isomerizations. In addition to previously identified steps in this series, which include agonist-induced closure of the ligand-binding lobes, and the subsequent mechanical pulling by the ligand-binding domain on the gate-forming transmembrane helix, we identify a new cross-subunit interaction, which stabilizes open receptors and slows the rate of the current decay. Naturally occurring NMDA receptor variants lacking this interaction are pathogenic.
treeclimbR pinpoints the data-dependent resolution of hierarchical hypotheses
Authors: Huang Ruizhu , Soneson Charlotte , Germain Pierre-Luc , Schmidt Thomas S.B. , Von Mering Christian , Robinson Mark D. 
Published: June 2020

AbstractThe arrangement of hypotheses in a hierarchical structure (e.g., phylogenies, cell types) appears in many research fields and indicates different resolutions at which data can be interpreted. A common goal is to find a representative resolution that gives high sensitivity to identify relevant entities (e.g., microbial taxa or cell subpopulations) that are related to a phenotypic outcome (e.g. disease status) while controlling false detections, therefore providing a more compact view of detected entities and summarizing characteristics shared among them. Current methods, either performing hypothesis tests at an arbitrary resolution or testing hypotheses at all possible resolutions leading to nested results, are suboptimal. Moreover, they are not flexible enough to work in situations where each entity has multiple features to consider and different resolutions might be required for different features. For example, in single cell RNA-seq data, an increasing focus is to find differential state genes that change expression within a cell subpopulation in response to an external stimulus. Such differential expression might occur at different resolutions (e.g., all cells or a small set of cells) for different genes. Our new algorithmtreeclimbRis designed to fill this gap by exploiting a hierarchical tree of entities, proposing multiple candidates that capture the latent signal and pinpointing branches or leaves that contain features of interest, in a data-driven way. It outperforms currently available methods on synthetic data, and we highlight the approach on various applications, including microbiome and microRNA surveys as well as single cell cytometry and RNA-seq datasets. With the emergence of various multi-resolution genomic datasets,treeclimbRprovides a thorough inspection on entities across resolutions and gives additional flexibility to uncover biological associations.
Tools for Visualizing and Analyzing Fourier Space Sampling in Cryo-EM
Authors: Baldwin Philip R. , Lyumkis Dmitry 
Published: June 2020

AbstractA complete understanding of how an orientation distribution contributes to a cryo-EM reconstruction remains lacking. It is necessary to begin critically assessing the set of views to gain an understanding of its effect on experimental reconstructions. Toward that end, we recently suggested that the type of orientation distribution may alter resolution measures in a systematic manner. We introduced the sampling compensation factor (SCF), which incorporates how the collection geometry might change the spectral signal-to-noise ratio (SSNR), irrespective of the other experimental aspects. We show here that knowledge of the sampling restricted to spherical surfaces of sufficiently large radii in Fourier space is equivalent to knowledge of the set of projection views. Moreover, the SCF geometrical factor may be calculated from one such surface. To aid cryo-EM researchers, we developed a graphical user interface (GUI) tool that evaluates experimental orientation distributions. The GUI returns plots of projection directions, sampling constrained to the surface of a sphere, the SCF value, the fraction of the empty region of Fourier space, and a histogram of the sampling values over the points on a sphere. Finally, a fixed tilt angle may be incorporated to determine how tilting the grid during collection may improve the distribution of views and Fourier space sampling. We advocate this simple conception of sampling and the use of such tools as a complement to the distribution of views to capture the different aspects of the effect of projection directions on cryo-EM reconstructions.
Combinatorial Library Designing and Virtual Screening of Cryptolepine Derivatives against Topoisomerase II by Molecular Docking
Authors: Maria  , Khan Zahid 
Published: June 2020

AbstractComputational approaches have emerging role for designing potential inhibitors against topoisomerase 2 for treatment of cancer. TOP2A plays a key role in DNA replication before cell division and thus facilitates the growth of cells. This function of TOP2A can be suppressed by targeting with potential inhibitors in cancer cells to stop the uncontrolled cell division. Among potential inhibitors cryptolepine is more selective and has the ability to intercalate into DNA, effectively block TOP2A and cease cell division in cancer cells. However, cryptolepine is non-specific and have low affinity, therefore, a combinatorial library was designed and virtually screened for identification of its derivatives with greater TOP2A binding affinities.A combinatorial library of 31114 derivatives of cryptolepine was formed and the library was virtually screened by molecular docking to predict the molecular interactions between cryptolepine derivatives and TOP2A taking cryptolepine as standard. The overall screening and docking approach explored all the binding poses of cryptolepine for TOP2A to calculate binding energy. The compounds are given database number 8618, 907, 147, 16755, and 8186 scored lowest binding energies of −9.88kcal/mol, −9.76kcal/mol, −9.75kcal/mol, −9.73kcal/mol, and −9.72kcal/mol respectively and highest binding affinity while cryptolepine binding energy is −6.09kcal/mol. The good binding interactions of the derivatives showed that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of derivatives with different amino acid residues were also observed. A comprehensive understanding of the interactions of proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This Computational study suggests useful references to understand inhibition mechanisms that will help in the modification of TOP2A inhibitors.
Attention differentially affects acoustic and phonetic feature encoding in a multispeaker environment
Authors: Teoh Emily S. , Lalor Edmund C. 
Published: June 2020

AbstractHumans have the remarkable ability to selectively focus on a single talker in the midst of other competing talkers. The neural mechanisms that underlie this phenomenon remain incompletely understood. In particular, there has been longstanding debate over whether attention operates at an early or late stage in the speech processing hierarchy. One way to better understand this is to examine how attention might differentially affect neurophysiological indices of hierarchical acoustic and linguistic speech representations. In this study, we do this by using encoding models to identify neural correlates of speech processing at various levels of representation. Specifically, using EEG recorded during a “cocktail party” attention experiment, we show that phonetic feature processing is evident for attended, but not unattended speech. Furthermore, we show that attention specifically enhances isolated indices of phonetic feature processing, but that such attention effects are not apparent for isolated measures of acoustic processing. These results provide new insights into the effects of attention on different pre-lexical representations of speech, insights that complement recent anatomical accounts of the hierarchical encoding of attended speech. Furthermore, our findings support the notion that – for attended speech – phonetic features are processed as a distinct stage, separate from the processing of the speech acoustics.
Influenza-induced activation of recruited alveolar macrophages during the early inflammatory phase drives lung injury and lethality
Authors: Koch Clarissa M , Anekalla Kishore R , Hu Yuan-Shih , Davis Jennifer M. , Ciesielski Mark , Gadhvi Gaurav , Chen Shang-Yang , Turner Margaret , Cheng Yuan , Coates Bria M , Abdala-Valencia Hiam , Reyfman Paul A , Misharin Alexander V , Budinger GR Scott , Winter Deborah R , Ridge Karen M 
Published: June 2020

AbstractSevere respiratory virus infections initiate a robust host immune response that contributes to disease severity. Immunomodulatory strategies that limit virus-initiated inflammation are of critical importance. In this study, we compared the host response to influenza A virus (IAV) infection in susceptible animals (wild-type, WT) to resilient mice (Vimentin-/-mice). We identified distinct gene expression patterns in recruited monocyte-derived alveolar macrophages (MoAMs) associated with three phases (Infiltrating, Early Inflammatory, Late Inflammatory) that evolve in sequence over the course of IAV infection. We report a core set of pro-inflammatory genes involved in the WT MoAM Early Inflammatory response that is suppressed inVim-/-MoAMs. Moreover, we identify CEBPB, Jun-AP1, and IRF transcriptions factors as regulators of this attenuated inflammatory response. We performed causal experiments using bone-marrow chimeras to credential thatVim-/-MoAMs with suppressed pro-inflammatory genes confer protection from influenza-induced mortality in WT susceptible mice. Taken together, these data support the notion that vimentin plays a causal role in determining the pro-inflammatory function of recruited MoAMs and drives IAV-induced lung injury.
Effect of organic zinc supplementation in hens on fertility from cryopreserved semen
Authors: Murugesan Shanmugam , Kannan Alagarsamy , Mahapatra Ramkrishna 
Published: June 2020

AbstractOrganic zinc supplementation in hen has been reported to improve fertility. The current study evaluated the effect of organic zinc supplementation in hens on fertility after insemination with cryopreserved semen. White Leghorn rooster semen was cryopreserved using 4% dimethylsulfoxide (DMSO) in 0.5ml French straws. Different semen parameters and fertility were assessed in post-thaw samples. White Leghorn hens were divided into 5 groups with 30 birds in each group. Each group was further divided into six replicates of five birds each. The control group was fed basal diet, other groups were fed with basal diet supplemented with 40, 60, 120 and 160 mg/kg organic zinc (zinc proteinate). After two weeks of feeding insemination was done in hens per vagina using thawed semen (200 million sperm/0.1 ml). Basal group hens were inseminated with fresh or cryopreserved semen and served as control groups. Sperm motility, live sperm, and acrosome intact sperm parameters were significantly (p< 0.05) lower in post-thaw semen samples. Fertility from cryopreserved semen was significantly (p< 0.05) lower and organic zinc supplemented hens had fertility similar to that of cryopreserved semen inseminated into basal diet group hens. In conclusion, organic zinc supplementation in hens does not improve fertility after insemination with 4% DMSO cryopreserved semen.
Serological Assays Estimate Highly Variable SARS-CoV-2 Neutralizing Antibody Activity in Recovered COVID19 Patients
Authors: Luchsinger Larry L. , Ransegnola Brett , Jin Daniel , Muecksch Frauke , Weisblum Yiska , Bao Weili , George Parakkal Jovvian , Rodriguez Marilis , Tricoche Nancy , Schmidt Fabian , Gao Chengjie , Jawahar Shabnam , Pal Mouli , Schnall Emily , Zhang Huan , Strauss Donna , Yazdanbakhsh Karina , Hillyer Christopher D. , Bieniasz Paul D. , Hatziioannou Theodora 
Published: June 2020

AbstractThe development of neutralizing antibodies (nAb) against SARS-CoV-2, following infection or vaccination, is likely to be critical for the development of sufficient population immunity to drive cessation of the COVID19 pandemic. A large number of serologic tests, platforms and methodologies are being employed to determine seroprevalence in populations to select convalescent plasmas for therapeutic trials, and to guide policies about reopening. However, tests have substantial variability in sensitivity and specificity, and their ability to quantitatively predict levels of nAb is unknown. We collected 370 unique donors enrolled in the New York Blood Center Convalescent Plasma Program between April and May of 2020. We measured levels of antibodies in convalescent plasma using commercially available SARS-CoV-2 detection tests and in-house ELISA assays and correlated serological measurements with nAb activity measured using pseudotyped virus particles, which offer the most informative assessment of antiviral activity of patient sera against viral infection. Our data show that a large proportion of convalescent plasma samples have modest antibody levels and that commercially available tests have varying degrees of accuracy in predicting nAb activity. We found the Ortho Anti-SARS-CoV-2 Total Ig and IgG high throughput serological assays (HTSAs), as well as the Abbott SARS-CoV-2 IgG assay, quantify levels of antibodies that strongly correlate with nAb assays and are consistent with gold-standard ELISA assay results. These findings provide immediate clinical relevance to serology results that can be equated to nAb activity and could serve as a valuable ‘roadmap’ to guide the choice and interpretation of serological tests for SARS-CoV-2.
A consensus Covid-19 immune signature combines immuno-protection with discrete sepsis-like traits associated with poor prognosis
Authors: Laing Adam G. , Lorenc Anna , Del Molino Del Barrio Irene , Das Abhishek , Fish Matthew , Monin Leticia , Muñoz-Ruiz Miguel , McKenzie Duncan R. , Hayday Thomas S. , Francos-Quijorna Isaac , Kamdar Shraddha , Joseph Magdalene , Davies Daniel , Davis Richard , Jennings Aislinn , Zlatareva Iva , Vantourout Pierre , Wu Yin , Sofra Vasiliki , Cano Florencia , Greco Maria , Theodoridis Efstathios , Freedman Joshua , Gee Sarah , En Chan Julie Nuo , Ryan Sarah , Bugallo-Blanco Eva , Peterson Pärt , Kisand Kai , Haljasmägi Liis , Martinez Lauren , Merrick Blair , Bisnauthsing Karen , Brooks Kate , Ibrahim Mohammad , Mason Jeremy , Gomez Federico Lopez , Babalola Kola , Abdul- Jawad Sultan , Cason John , Mant Christine , Doores Katie J , Seow Jeffrey , Graham Carl , Rosa Francesca Di , Edgeworth Jonathan , Shankar-Hari Manu , Hayday Adrian C. 
Published: June 2020

AbstractPerson-to-person transmission of SARS-CoV-2 virus has triggered a global emergency because of its potential to cause life-threatening Covid-19 disease. By comparison to paucisymptomatic virus clearance by most individuals, Covid-19 has been proposed to reflect insufficient and/or pathologically exaggerated immune responses. Here we identify a consensus peripheral blood immune signature across 63 hospital-treated Covid-19 patients who were otherwise highly heterogeneous. The core signature conspicuously blended adaptive B cell responses typical of virus infection or vaccination with discrete traits hitherto associated with sepsis, including monocyte and dendritic cell dampening, and hyperactivation and depletion of discrete T cell subsets. This blending of immuno-protective and immuno-pathogenic potentials was exemplified by near-universal CXCL10/IP10 upregulation, as occurred in SARS1 and MERS. Moreover, specific parameters including CXCL10/IP10 over-expression, T cell proliferation, and basophil and plasmacytoid dendritic cell depletion correlated, often prognostically, with Covid-19 progression, collectively composing a resource to inform SARS-CoV-2 pathobiology and risk-based patient stratification.