Efficient simulation of plasmas in various contexts often involves the use of meshes that conform to the intrinsic geometry of the system under consideration. We present here a description of a new ...magnetohydrodynamic code, GAMERA (Grid Agnostic MHD for Extended Research Applications), designed to combine geometric flexibility with high-order spatial reconstruction and constrained transport to maintain the divergence-free magnetic field. GAMERA carries on the legacy of its predecessor, the LFM (Lyon-Fedder-Mobarry), a research code whose use in space physics has spanned three decades. At the time of its initial development, the LFM code had a number of novel features: eighth-order centered spatial differencing, the Partial Donor Cell Method limiter for shock capturing, a non-orthogonal staggered mesh with constrained transport, and conservative averaging-reconstruction for axis singularities. The capability to handle multiple ion species was also added later. GAMERA preserves the core numerical philosophy of LFM while also incorporating numerous algorithmic and computational improvements. The upgrades in the numerical schemes include accurate grid metric calculations using high-order Gaussian quadrature techniques, high-order upwind reconstruction, non-clipping options for interface values, and improved treatment of axis singularities. The improvements in the code implementation include the use of data structures and memory access patterns conducive to aligned vector operations and the implementation of hybrid parallelism, using MPI and OMP. GAMERA is designed to be a portable and easy-to-use code that implements multidimensional MHD simulations in arbitrary non-orthogonal curvilinear geometries on modern supercomputer architectures.
Seasonal influenza vaccines offer little protection against pandemic influenza virus strains. It is difficult to create effective prepandemic vaccines because it is uncertain which influenza virus ...subtype will cause the next pandemic. In this work, we developed a nucleoside-modified messenger RNA (mRNA)-lipid nanoparticle vaccine encoding hemagglutinin antigens from all 20 known influenza A virus subtypes and influenza B virus lineages. This multivalent vaccine elicited high levels of cross-reactive and subtype-specific antibodies in mice and ferrets that reacted to all 20 encoded antigens. Vaccination protected mice and ferrets challenged with matched and mismatched viral strains, and this protection was at least partially dependent on antibodies. Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses by simultaneously inducing antibodies against multiple antigens.
Neuroscientists are actively pursuing high-precision maps, or
consisting of networks of neurons and connecting synapses in mammalian and non-mammalian brains. Such graphs, when coupled with ...physiological and behavioral data, are likely to facilitate greater understanding of how circuits in these networks give rise to complex information processing capabilities. Given that the automated or semi-automated methods required to achieve the acquisition of these graphs are still evolving, we developed a metric for measuring the performance of such methods by comparing their output with those generated by human annotators ("ground truth" data). Whereas classic metrics for comparing annotated neural tissue reconstructions generally do so at the voxel level, the metric proposed here measures the "integrity" of neurons based on the degree to which a collection of synaptic terminals belonging to a single neuron of the reconstruction can be matched to those of a single neuron in the ground truth data. The metric is largely insensitive to small errors in segmentation and more directly measures accuracy of the generated brain graph. It is our hope that use of the metric will facilitate the broader community's efforts to improve upon existing methods for acquiring brain graphs. Herein we describe the metric in detail, provide demonstrative examples of the intuitive scores it generates, and apply it to a synthesized neural network with simulated reconstruction errors. Demonstration code is available.
In analyzing the stability of DNA replication origins in Saccharomyces cerevisiae we faced the question whether one set of sequences is significantly enriched in the number and/or the quality of the ...matches of a particular position weight matrix relative to another set.
We present SADMAMA, a computational solution to a address this problem. SADMAMA implements two types of statistical tests to answer this question: one type is based on simplified models, while the other relies on bootstrapping, and as such might be preferable to users who are averse to such models. The bootstrap approach incorporates a novel "site-protected" resampling procedure which solves a problem we identify with naive resampling.
SADMAMA's utility is demonstrated here by offering a plausible explanation to the differential ARS activity observed in our previous mcm1-1 mutant experiments 1, by suggesting the relevance of multiple weak ACS matches to efficient replication origin function in Saccharomyces cerevisiae, and by suggesting an explanation to the observed negative effect FKH2 has on chromatin silencing 2. SADMAMA is available for download from http://www.cs.cornell.edu/~keich/.
Efficient simulation of plasmas in various contexts often involves the use of meshes that conform to the intrinsic geometry of the system under consideration. We present here a description of a new ...magnetohydrodynamic code, Gamera (Grid Agnostic MHD for Extended Research Applications), designed to combine geometric flexibility with high-order spatial reconstruction and constrained transport to maintain the divergence-free magnetic field. Gamera carries on the legacy of its predecessor, the LFM (Lyon-Fedder-Mobarry), a research code whose use in space physics has spanned three decades. At the time of its initial development the LFM code had a number of novel features: eighth-order centered spatial differencing, the Partial Donor Cell Method limiter for shock capturing, a non-orthogonal staggered mesh with constrained transport, and conservative averaging-reconstruction for axis singularities. A capability to handle multiple ion species was also added later. Gamera preserves the core numerical philosophy of LFM while also incorporating numerous algorithmic and computational improvements. The upgrades in the numerical schemes include accurate grid metric calculations using high-order Gaussian quadrature techniques, high-order upwind reconstruction, non-clipping options for interface values, and improved treatment of axis singularities. The improvements in the code implementation include the use of data structures and memory access patterns conducive to aligned vector operations and the implementation of hybrid parallelism, using MPI and OMP. Gamera is designed to be a portable and easy-to-use code that implements multi-dimensional MHD simulations in arbitrary non-orthogonal curvilinear geometries on modern supercomputer architectures.
We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a ...heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.
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•SARS-CoV-2 spike protein interacts with heparan sulfate and ACE2 through the RBD•Heparan sulfate promotes Spike-ACE2 interaction•SARS-CoV-2 infection is co-dependent on heparan sulfate and ACE2•Heparin and non-anticoagulant derivatives block SARS-CoV-2 binding and infection
Clausen et al. provide evidence that heparan sulfate is a necessary co-factor for SARS-CoV-2 infection. They show that heparan sulfate interacts with the receptor-binding domain of the SARS-CoV-2 spike glycoprotein, adjacent to ACE2, shifting the spike structure to an open conformation to facilitate ACE2 binding.
Neuroscientists are actively pursuing high-precision maps, or graphs, consisting of networks of neurons and connecting synapses in mammalian and non-mammalian brains. Such graphs, when coupled with ...physiological and behavioral data, are likely to facilitate greater understanding of how circuits in these networks give rise to complex information processing capabilities. Given that the automated or semi-automated methods required to achieve the acquisition of these graphs are still evolving, we develop a metric for measuring the performance of such methods by comparing their output with those generated by human annotators ("ground truth" data). Whereas classic metrics for comparing annotated neural tissue reconstructions generally do so at the voxel level, the metric proposed here measures the "integrity" of neurons based on the degree to which a collection of synaptic terminals belonging to a single neuron of the reconstruction can be matched to those of a single neuron in the ground truth data. The metric is largely insensitive to small errors in segmentation and more directly measures accuracy of the generated brain graph. It is our hope that use of the metric will facilitate the broader community's efforts to improve upon existing methods for acquiring brain graphs. Herein we describe the metric in detail, provide demonstrative examples of the intuitive scores it generates, and apply it to a synthesized neural network with simulated reconstruction errors.
Small molecule inhibitors of glycosylation enzymes are valuable tools for dissecting glycan functions and potential drug candidates. Screening for inhibitors of glycosyltransferases are mainly ...performed by in vitro enzyme assays with difficulties moving candidates to cells and animals. Here, we circumvent this by employing a cell-based screening assay using glycoengineered cells expressing tailored reporter glycoproteins. We focused on GalNAc-type O-glycosylation and selected the GalNAc-T11 isoenzyme that selectively glycosylates endocytic low-density lipoprotein receptor (LDLR)-related proteins as targets. Our screen of a limited small molecule compound library did not identify selective inhibitors of GalNAc-T11, however, we identify two compounds that broadly inhibited Golgi-localized glycosylation processes. These compounds mediate the reversible fragmentation of the Golgi system without affecting secretion. We demonstrate how these inhibitors can be used to manipulate glycosylation in cells to induce expression of truncated O-glycans and augment binding of cancer-specific Tn-glycoprotein antibodies and to inhibit expression of heparan sulfate and binding and infection of SARS-CoV-2.
The role of diffuse electron precipitation in the formation of subauroral polarization streams (SAPS) is investigated with the Multiscale Atmosphere‐Geospace Environment (MAGE) model. Diffuse ...precipitation is derived from the distribution of drifting electrons. SAPS manifest themselves as a separate mesoscale flow channel in the duskside ionosphere, which gradually merges with the primary auroral convection toward dayside as the equatorward auroral boundary approaches the poleward Region‐2 field‐aligned currents (FACs) boundary. SAPS expand to lower latitudes and toward the nightside during the main phase of a geomagnetic storm, associated with magnetotail earthward plasma flows building up the ring current and intensifying Region‐2 FACs and electron precipitation. SAPS shrink poleward and sunward as the interplanetary magnetic field turns northward. When diffuse precipitation is turned off in a controlled MAGE simulation, ring current and duskside Region‐2 FACs become weaker, but subauroral zonal ion drifts are still comparable to auroral convection. However, subauroral and auroral convection manifest as a single broad flow channel without showing any mesoscale structure. SAPS overlap with the downward Region‐2 FACs equatorward of diffuse precipitation, where poleward electric fields are strong due to a low conductance in the subauroral ionosphere. The Region‐2 FACs extend to latitudes lower than the diffuse precipitation because the ring current protons penetrate closer to the Earth than the electrons do. This study reproduces the key physics of SAPS formation and their evolution in the coupled magnetosphere‐ionosphere during a geomagnetic storm. Diffuse electron precipitation is demonstrated to play a critical role in determining SAPS location and structure.
Plain Language Summary
Subauroral polarization streams (SAPS) are a mesoscale (∼100–500 km) plasma flow channel frequently observed in the duskside subauroral ionosphere. This study investigates how diffuse electron precipitation affects the location and structure of SAPS, using the newly developed, state‐of‐the‐art geospace model of Multiscale Atmosphere‐Geospace Environment (MAGE). The MAGE model has the capability to directly simulate diffuse precipitation using particle drift physics. MAGE numerical experiments show that SAPS exhibit as a separate flow channel when diffuse precipitation is included in the simulation, but subauroral and auroral convections become one broad channel when diffuse precipitation is turned off. SAPS are produced in the gap region between the low latitude boundaries of electron aurora and downward field‐aligned current (FAC) on the duskside, where the ionospheric conductance is low due to lack of ionization while downward region‐2 FAC closes through this low conductance region. Strong poleward electric fields are generated to drive large westward ion drifts in the SAPS channel. Tracing back to the magnetosphere, the gap between the inner boundaries is formed because the ring current protons, whose distribution primarily determines the downward FAC, penetrate deeper than the electrons. Thus diffuse aurora, with plasma sheet as the source population, occurs poleward of the lower boundary of the downward Region‐2 current. This study demonstrates the importance of including diffuse precipitation in coupled geospace models to understand the dynamics of SAPS.
Key Points
A fully coupled geospace model captures the key physical mechanism and distinct spatial structure of subauroral polarization streams
The separation of the flow channel from the main auroral convection is determined by diffuse electron precipitation boundary
The evolution of the SAPS in the ionosphere and magnetosphere is reproduced by the simulation in accordance with observations
DNA and RNA oligomers are used in a myriad of diverse biological and biochemical experiments. These oligonucleotides are designed to have unique biophysical, chemical and hybridization properties. We ...have created an integrated set of bioinformatics tools that predict the properties of native and chemically modified nucleic acids and assist in their design. Researchers can select PCR primers, probes and antisense oligonucleotides, find the most suitable sequences for RNA interference, calculate stable secondary structures, and evaluate the potential for two sequences to interact. The latest, most accurate thermodynamic algorithms and models are implemented. This free software is available at http://www.idtdna.com/SciTools/SciTools.aspx.
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