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At least 19 records

Deducing the N- and O-glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2

The current emergence of the novel coronavirus pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demands the development of new therapeutic strategies to prevent rapid progress of mortalities. The coronavirus spike (S) protein, which facilitates viral attachment, entry and membrane fusion is heavily glycosylated and plays a critical role in the elicitation of the host immune response. The spike protein is comprised of two protein subunits (S1 and S2), which together possess 22 potential N-glycosylation sites. Herein, we report the glycosylation mapping on spike protein subunits S1 and S2 expressed on human cells through high-resolution mass spectrometry. We have characterized the quantitative N-glycosylation profile on spike protein and interestingly, observed unexpected O-glycosylation modifications on the receptor-binding domain of spike protein subunit S1. Even though O-glycosylation has been predicted on the spike protein of SARS-CoV-2, this is the first report of experimental data for both the site of O-glycosylation and identity of the O-glycans attached on the subunit S1. Our data on the N- and O-glycosylation are strengthened by extensive manual interpretation of each glycopeptide spectra in addition to using bioinformatics tools to confirm the complexity of glycosylation in the spike protein. Here, the elucidation of the glycan repertoire on the spike protein provides insights into the viral binding studies and more importantly, propels research toward the development of a suitable vaccine candidate.

59 BASIC BIOLOGICAL SCIENCES↗

SPIKE-Dx : A Low-Power High-Throughput Fault Diagnostics Tool using Spiking Neural Networks for Constrained Systems

Diagnostic systems are important for many aerospace systems, which are severely limited in available power, like cubesats or UAVs. Therefore, traditional diagnostics systems cannot be used due to their substantial footprint and constraints. In this paper, we present our very low power diagnostic tool SPIKE-DX to monitor critical systems with constrained computational and energy resources. This is made possible through spiking neural networks (SNNs), which are executable within optimized simulation environments and further implemented on on cutting-edge neuromorphic hardware. Based upon FMEA (Failure Mode and Effect Analysis) framework, Diagnostic Bayesian Networks (DBNs) can be constructed that provide powerful means for diagnostic reasoning. In this paper, we describe such DBNs and a method to automatically translate the DBN into highly structured networks of spiking neurons for execution in SPIKE-DX.

Spiking Neural Networks↗

Rethinking skip connections in Spiking Neural Networks with Time-To-First-Spike coding

Time-To-First-Spike (TTFS) coding in Spiking Neural Networks (SNNs) offers significant advantages in terms of energy efficiency, closely mimicking the behavior of biological neurons. In this work, we delve into the role of skip connections, a widely used concept in Artificial Neural Networks (ANNs), within the domain of SNNs with TTFS coding. Our focus is on two distinct types of skip connection architectures: (1) addition-based skip connections, and (2) concatenation-based skip connections. We find that addition-based skip connections introduce an additional delay in terms of spike timing. On the other hand, concatenation-based skip connections circumvent this delay but produce time gaps between after-convolution and skip connection paths, thereby restricting the effective mixing of information from these two paths. To mitigate these issues, we propose a novel approach involving a learnable delay for skip connections in the concatenation-based skip connection architecture. This approach successfully bridges the time gap between the convolutional and skip branches, facilitating improved information mixing. We conduct experiments on public datasets including MNIST and Fashion-MNIST, illustrating the advantage of the skip connection in TTFS coding architectures. Additionally, we demonstrate the applicability of TTFS coding on beyond image recognition tasks and extend it to scientific machine-learning tasks, broadening the potential uses of SNNs.

97 MATHEMATICS AND COMPUTING↗

Electromechanical memcapacitor model offering biologically plausible spiking.

In this article, we introduce a new nanoscale electromechanical device - a leaky memcapacitor - and show that it may be useful for the hardware implementation of spiking neurons. The leaky memcapacitor is a movableplate capacitor that becomes quite conductive when the plates come close to each other. The equivalent circuit of the leaky memcapacitor involves a memcapacitive and memristive system connected in parallel. In the leaky memcapacitor, resistance and capacitance depend on the same internal state variable, which is the displacement of the movable plate. We have performed a comprehensive analysis showing that several types of spiking observed in biological neurons can be implemented with the leaky memcapacitor. Significant attention is paid to the dynamic properties of the model. As in leaky memcapacitors the capacitive, leaking resistive, and reset functionalities are implemented naturally within the same device structure, their use will simplify the creation of spiking neural networks.

Zhang, Zixi↗

Combining Spike Time Dependent Plasticity (STDP) and Backpropagation (BP) for Robust and Data Efficient Spiking Neural Networks (SNN)

National security applications require artificial neural networks (ANNs) that consume less power, are fast and dynamic online learners, are fault tolerant, and can learn from unlabeled and imbalanced data. We explore whether two fundamentally different, traditional learning algorithms from artificial intelligence and the biological brain can be merged. We tackle this problem from two directions. First, we start from a theoretical point of view and show that the spike time dependent plasticity (STDP) learning curve observed in biological networks can be derived using the mathematical framework of backpropagation through time. Second, we show that transmission delays, as observed in biological networks, improve the ability of spiking networks to perform classification when trained using a backpropagation of error (BP) method. These results provide evidence that STDP could be compatible with a BP learning rule. Combining these learning algorithms will likely lead to networks more capable of meeting our national security missions.

97 MATHEMATICS AND COMPUTING↗

Investigation of shock-boundary-layer interaction on the spike of a conical-spike nose inlet

Measurements were made of the height of the shock-induced boundary-layer thickening and separation over a Mach number range of 1.6 to 2.0. The behavior of the interaction depended on longitudinal spike position as well as on cone surface Mach number. The cone position affected the interaction by changing the rate of subsonic diffusion and thereby changing the pressure aft of the terminal shock. When the pressure rise due to the interaction exceeded about 1.9, the boundary layer was separated.

Wise, George A↗

Spiking Neurons for Analysis of Patterns

Artificial neural networks comprising spiking neurons of a novel type have been conceived as improved pattern-analysis and pattern-recognition computational systems. These neurons are represented by a mathematical model denoted the state-variable model (SVM), which among other things, exploits a computational parallelism inherent in spiking-neuron geometry. Networks of SVM neurons offer advantages of speed and computational efficiency, relative to traditional artificial neural networks. The SVM also overcomes some of the limitations of prior spiking-neuron models. There are numerous potential pattern-recognition, tracking, and data-reduction (data preprocessing) applications for these SVM neural networks on Earth and in exploration of remote planets. Spiking neurons imitate biological neurons more closely than do the neurons of traditional artificial neural networks. A spiking neuron includes a central cell body (soma) surrounded by a tree-like interconnection network (dendrites). Spiking neurons are so named because they generate trains of output pulses (spikes) in response to inputs received from sensors or from other neurons. They gain their speed advantage over traditional neural networks by using the timing of individual spikes for computation, whereas traditional artificial neurons use averages of activity levels over time. Moreover, spiking neurons use the delays inherent in dendritic processing in order to efficiently encode the information content of incoming signals. Because traditional artificial neurons fail to capture this encoding, they have less processing capability, and so it is necessary to use more gates when implementing traditional artificial neurons in electronic circuitry. Such higher-order functions as dynamic tasking are effected by use of pools (collections) of spiking neurons interconnected by spike-transmitting fibers. The SVM includes adaptive thresholds and submodels of transport of ions (in imitation of such transport in biological neurons). These features enable the neurons to adapt their responses to high-rate inputs from sensors, and to adapt their firing thresholds to mitigate noise or effects of potential sensor failure. The mathematical derivation of the SVM starts from a prior model, known in the art as the point soma model, which captures all of the salient properties of neuronal response while keeping the computational cost low. The point-soma latency time is modified to be an exponentially decaying function of the strength of the applied potential. Choosing computational efficiency over biological fidelity, the dendrites surrounding a neuron are represented by simplified compartmental submodels and there are no dendritic spines. Updates to the dendritic potential, calcium-ion concentrations and conductances, and potassium-ion conductances are done by use of equations similar to those of the point soma. Diffusion processes in dendrites are modeled by averaging among nearest-neighbor compartments. Inputs to each of the dendritic compartments come from sensors. Alternatively or in addition, when an affected neuron is part of a pool, inputs can come from other spiking neurons. At present, SVM neural networks are implemented by computational simulation, using algorithms that encode the SVM and its submodels. However, it should be possible to implement these neural networks in hardware: The differential equations for the dendritic and cellular processes in the SVM model of spiking neurons map to equivalent circuits that can be implemented directly in analog very-large-scale integrated (VLSI) circuits.

Huntsberger, Terrance↗

Production of novel SARS-CoV-2 Spike truncations in Chinese hamster ovary cells leads to high expression and binding to antibodies

SARS-CoV-2 Spike is a key protein that mediates viral entry into cells and elicits antibody responses. Its importance in infection, diagnostics, and vaccinations has created a large demand for purified Spike for clinical and research applications. Spike is difficult to express, prompting modifications to the protein and expression platforms to improve yields. Alternatively, the Spike receptor-binding domain (RBD) is commonly expressed with higher titers, though it has lower sensitivity in serological assays. Here, we improve transient Spike expression in Chinese hamster ovary (CHO) cells. We demonstrate that Spike titers increase significantly over the expression period, maximizing at 14 mg L -1 on day 7. In comparison, RBD titers peak at 54 mg L -1 on day 3. Next, we develop eight Spike truncations (T1–T8) in pursuit of truncation with high expression and antibody binding. The truncations T1 and T4 express at 130 and 73 mg L -1 , respectively, which are higher than our RBD titers. Purified proteins were evaluated for binding to antibodies raised against full-length Spike. T1 has similar sensitivity as Spike against a monoclonal antibody and even outperforms Spike for a polyclonal antibody. These results suggest that T1 is a promising Spike alternative for use in various applications.

59 BASIC BIOLOGICAL SCIENCES↗

Distinct Conformations of SARS-CoV-2 Omicron Spike Protein and Its Interaction with ACE2 and Antibody

Since November 2021, Omicron has been the dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant that causes the coronavirus disease 2019 (COVID-19) and has continuously impacted human health. Omicron sublineages are still increasing and cause increased transmission and infection rates. The additional 15 mutations on the receptor binding domain (RBD) of Omicron spike proteins change the protein conformation, enabling the Omicron variant to evade neutralizing antibodies. For this reason, many efforts have been made to design new antigenic variants to induce effective antibodies in SARS-CoV-2 vaccine development. However, understanding the different states of Omicron spike proteins with and without external molecules has not yet been addressed. In this review, we analyze the structures of the spike protein in the presence and absence of angiotensin-converting enzyme 2 (ACE2) and antibodies. Compared to previously determined structures for the wildtype spike protein and other variants such as alpha, beta, delta, and gamma, the Omicron spike protein adopts a partially open form. The open-form spike protein with one RBD up is dominant, followed by the open-form spike protein with two RBD up, and the closed-form spike protein with the RBD down. It is suggested that the competition between antibodies and ACE2 induces interactions between adjacent RBDs of the spike protein, which lead to a partially open form of the Omicron spike protein. The comprehensive structural information of Omicron spike proteins could be helpful for the efficient design of vaccines against the Omicron variant.

60 APPLIED LIFE SCIENCES↗

High-energy electron spikes at high latitudes.

Observation of over 750 spikes of precipitating electrons with E greater than or equal to 425 keV aboard the low-altitude polar orbiter Ogo 4 between July 30 and Dec. 31, 1967. The spikes may be divided into three distinct populations, depending on whether they occur at latitudes below, at, or above the local limit of trapping. These spikes are designated type 1, 2, and 3, respectively. Type 3 spikes occur in a narrow latitude band about 3 deg wide, centered at invariant latitude Lambda approximately equal to 78 deg at 1000 MLT (magnetic local time) and 68 deg at 2000 MLT. Type 3 spikes appear to be associated with spikes observed near the magnetopause and the neutral sheet. Type 2 spikes also occur in a latitude band about 3 deg wide, centered at about 71 deg at 1000 MLT and 67 deg at 2200 MLG. Type 2 spikes appear to be related to island fluxes in the neutral sheet, although they occur on closed field lines and may persist for many hours. Type 1 spikes occur in a wider band of latitudes, from about 62 deg to 68 deg near midnight and 66 deg to 68 deg near noon. Although they are observed on closed field lines, type 1 spikes do not persist for periods longer than about 1 hour, and it is concluded that they are produced by strong pitch-angle scattering from the stably trapped population.

Brown, J. W.↗

Structural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans

Abstract Coronavirus spike glycoproteins presented on the virion surface mediate receptor binding, and membrane fusion during virus entry and constitute the primary target for vaccine and drug development. How the structure dynamics of the full-length spikes incorporated in viral lipid envelope correlates with the virus infectivity remains poorly understood. Here we present structures and distributions of native spike conformations on vitrified human coronavirus NL63 (HCoV-NL63) virions without chemical fixation by cryogenic electron tomography (cryoET) and subtomogram averaging, along with site-specific glycan composition and occupancy determined by mass spectrometry. The higher oligomannose glycan shield on HCoV-NL63 spikes than on SARS-CoV-2 spikes correlates with stronger immune evasion of HCoV-NL63. Incorporation of cryoET-derived native spike conformations into all-atom molecular dynamic simulations elucidate the conformational landscape of the glycosylated, full-length spike that reveals a role of hinge glycans in modulating spike bending. We show that glycosylation at N1242 at the upper portion of the stalk is responsible for the extensive orientational freedom of the spike crown. Subsequent infectivity assays implicated involvement of N1242-glyan in virus entry. Our results suggest a potential therapeutic target site for HCoV-NL63.

59 BASIC BIOLOGICAL SCIENCES↗

A Suppression-based STDP Rule Resilient to Jitter Noise in Spike Patterns for Neuromorphic Computing

Multi-spike models of synaptic plasticity, such as the triplet and suppression spike-timing-dependent plasticity (STDP) rules, exhibit better alignment with neurophysiological data in the brain compared to the pair-based STDP rule. Previous studies have empirically shown that the pair-based STDP rule can detect spatiotemporal spike patterns hidden in equally dense distractor spike trains in an unsupervised manner. However, it fails to detect spike patterns influenced by jitter noise. Given that spiking neural networks (SNNs) exhibit variability in generated spike trains in response to the same inputs, it becomes imperative to have learning rules capable of detecting spike patterns even in the presence of jitter noise. In this study, we introduce a simplified suppression-based STDP rule that demonstrates significantly enhanced tolerance to jitter in spike patterns compared to the pair-based STDP rule. Unlike the ideal suppression STDP rule, characterized by an exponential learning window and requiring high-resolution synapses, the simplified rule limits the synaptic efficacy update to a single bit at any given instant. Moreover, it employs 4-bit fixed-point synapses, facilitating straightforward implementation in neuromorphic hardware.

Gautam, Ashish [ORNL]↗

Flight Testing of the Gulfstream Quiet Spike(TradeMark) on a NASA F-15B

Gulfstream Aerospace has long been interested in the development of an economically viable supersonic business jet (SBJ). A design requirement for such an aircraft is the ability for unrestricted supersonic flight over land. Although independent studies continue to substantiate that a market for a SBJ exists, regulatory and public acceptance challenges still remain for supersonic operation over land. The largest technical barrier to achieving this goal is sonic boom attenuation. Gulfstream's attention has been focused on fundamental research into sonic boom suppression for several years. This research was conducted in partnership with the NASA Aeronautics Research Mission Directorate (ARMD) supersonic airframe cruise efficiency technical challenge. The Quiet Spike, a multi-stage telescopic nose boom and a Gulfstream-patented design (references 1 and 2), was developed to address the sonic boom attenuation challenge and validate the technical feasibility of a morphing fuselage. The Quiet Spike Flight Test Program represents a major step into supersonic technology development for sonic boom suppression. The Gulfstream Aerospace Quiet Spike was designed to reduce the sonic boom signature of the forward fuselage for an aircraft flying at supersonic speeds. In 2004, the Quiet Spike Flight Test Program was conceived by Gulfstream and NASA to demonstrate the feasibility of sonic boom mitigation and centered on the structural and mechanical viability of the translating test article design. Research testing of the Quiet Spike consisted of numerous ground and flight operations. Each step in the process had unique objectives, and involved numerous test team members from the NASA Dryden Flight Research Center (DFRC) and Gulfstream Aerospace. Flight testing of the Quiet Spike was conducted at the NASA Dryden Flight Research Center on an F-15B aircraft from August, 2006, to February, 2007. During this period, the Quiet Spike was flown at supersonic speeds up to Mach 1.8 at the maximum design dynamic pressure of 685 pounds per square foot. Extension and retraction tests were conducted at speeds up to Mach 1.4. The design of the Quiet Spike to shape the forward shock wave environment of the aircraft was confirmed during near-field shock wave probing at Mach 1.4. Thirty-two flights were performed without incident and all project objectives were achieved. The success of the Quiet Spike Flight Test Program represents an important step towards developing commercial aircraft capable of supersonic flight over land within the continental United States and in international airspace.

Smolka, James W.↗

Photospheric Current Spikes and Their Possible Association with Flares - Results from an HMI Data Driven Model

A data driven, near photospheric magnetohydrodynamic model predicts spikes in the horizontal current density, and associated resistive heating rate per unit volume Q. The spikes appear as increases by orders of magnitude above background values in neutral line regions (NLRs) of active regions (ARs). The largest spikes typically occur a few hours to a few days prior to M or X flares. The spikes correspond to large vertical derivatives of the horizontal magnetic field. The model takes as input the photospheric magnetic field observed by the Helioseismic & Magnetic Imager (HMI) on the Solar Dynamics Observatory (SDO) satellite. This 2.5 D field is used to determine an analytic expression for a 3 D magnetic field, from which the current density, vector potential, and electric field are computed in every AR pixel for 14 ARs. The field is not assumed to be force-free. The spurious 6, 12, and 24 hour Doppler periods due to SDO orbital motion are filtered out of the time series of the HMI magnetic field for each pixel using a band pass filter. The subset of spikes analyzed at the pixel level are found to occur on HMI and granulation scales of 1 arcsec and 12 minutes. Spikes are found in ARs with and without M or X flares, and outside as well as inside NLRs, but the largest spikes are localized in the NLRs of ARs with M or X flares. The energy to drive the heating associated with the largest current spikes comes from bulk flow kinetic energy, not the electromagnetic field, and the current density is highly non-force free. The results suggest that, in combination with the model, HMI is revealing strong, convection driven, non-force free heating events on granulation scales, and that it is plausible these events are correlated with subsequent M or X flares. More and longer time series need to be analyzed to determine if such a correlation exists. Above an AR dependent threshold value of Q, the number of events N(Q) with heating rates greater than or equal to Q obeys a scale invariant power law distribution for each AR given by N(Q) varies Q(sup -s), where 0.40 less than or equal to S less than or equal to 0.53, with a mean and standard deviation across the 14 ARs of 0.47 and 0.045, showing there is little variation of S from one AR to another. These properties of N(Q) are in close agreement with those of the distribution N(E) for the total energy E of solar flares, determined from observations to be N(E) = constant x E(sup -alpha). From observations of nanoflares in the 0.7 to 4 MK range, and from observations of flares in hard X-rays, it is found that 0.51 less than or equal to alpha less than or equal to 0.57, and 0.4 less than or equal to alpha less than or equal to 0.6, respectively (Crosby et al. 1993, Sol. Phys., 143, 275; Aschwanden & Parnell 2002, ApJ, 572, 1048). Observations also show that, as is found here for the exponent S, there is little variation of alpha with AR (Wheatland 2000, ApJ, 532, 1209), indicating N(E) and N(Q) are largely independent of individual properties of ARs such as area, total magnetic flux, and distribution of current density (i.e. non-potentiality). Therefore the power law scaling of the photospheric heating rate Q computed here on granulation scales is essentially identical to that found for coronal observations of flare energies on scales 1-2 orders of magnitude larger. This suggests the physical mechanisms that cause Q and coronal flares are closely related. It seems likely that Q is the signature of a magnetic reconnection process in an energy range and volume orders of magnitude smaller than those of flares. In this context, at least the larger spikes in Q might be signatures of UV photospheric or lower chromospheric bombs in which plasma is heated to temperatures approximately 10(exp -5) K (Peter et al. 2014, Science 346, 1255726; Judge 2015, ApJ, 808, 116). In addition, lattice based avalanche simulations of flare energy release predict 0.4 less than or equal to alpha less than or equal to 0.5, while analytic, fractal-diffusive self-organized criticality models predict 0.4 less than or equal to alpha less than or equal to 0.67, in excellent agreement with observations, and the results presented here (Aschwanden & Parnell 2002, ApJ, 572, 1048; Aschwanden 2012, A&A, 539, A2; Aschwanden 2013, in "Self Organized Criticality Systems"; Aschwanden et al. 2016, SSR, 198, 47).

Goodman, Michael↗