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At least 55 records · Page 3

Neutrino point source searches for dark matter spikes

Any dark matter spikes surrounding black holes in our Galaxy are sites of significant dark matter annihilation, leading to a potentially detectable neutrino signal. In this paper we examine 10-10 5 M ⊙ black holes associated with dark matter spikes that formed in early minihalos and still exist in our Milky Way Galaxy today, in light of neutrino data from the ANTARES and IceCube detectors. In various regions of the sky, we determine the minimum distance away from the solar system that a dark matter spike must be in order to have not been detected as a neutrino point source for a variety of representative dark matter annihilation channels. Given these constraints on the distribution of dark matter spikes in the Galaxy, we place significant limits on the formation of the first generation of stars in early minihalos — stronger than previous limits from gamma-ray searches in Fermi Gamma-Ray Space Telescope data. The larger black holes considered in this paper may arise as the remnants of Dark Stars after the dark matter fuel is exhausted; thus neutrino observations may be used to constrain the properties of Dark Stars. The limits are particularly strong for heavier WIMPs. For WIMP masses ~ 5TeV, we show that ≲ 10 % of minihalos can host first stars that collapse into BHs larger than 10 3 M ⊙ .

79 ASTRONOMY AND ASTROPHYSICS↗

Explaining Neural Spike Activity for Simulated Bio-plausible Network through Deep Sequence Learning

With significant improvements in large-scale simulations of brain models, there is a growing need to develop tools for rapid analysis and interpreting the simulation results. In this work, we explore the potential of sequential deep learning models to understand and explain the network dynamics among the neurons extracted from a large-scale neural simulation in STACS (Simulation Tool for Asynchronous Cortical Stream). Our method employs a representative neuroscience model that abstracts the cortical dynamics with a reservoir of randomly connected spiking neurons with a low stable spike firing rate throughout the simulation duration. We subsequently analyze the spike dynamics of the simulated spiking neural network through an autoencoder model and an attention-based mechanism.

Kulkarni, Shruti↗

Evolving Ensembles of Spiking Neural Networks for Neuromorphic Systems

Evolutionary algorithms have been proposed as a solution to overcome many of the challenges associated with training spiking neural networks. While evolutionary optimization for spiking neural networks is very flexible, its performance has difficulty scaling to complex tasks and correspondingly complex network structures. Here we propose a method for evolving ensembles of spiking neural networks. By using ensemble learning, the flexibility of evolutionary optimization is fully preserved while scaling to more challenging tasks. We test the performance of the proposed method using handwritten digit classification. We investigate multiple strategies for constructing ensembles of spiking neural networks, and demonstrate that evolving ensembles of SNNs offers significant performance advantages over evolutionary optimization.

Elbrecht, Daniel↗

An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo–electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

60 APPLIED LIFE SCIENCES↗

Effect of natural mutations of SARS-CoV-2 on spike structure, conformation, and antigenicity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike mutations enable increased transmission and antibody resistance. We combined cryo–electron microscopy (cryo-EM), binding, and computational analyses to study variant spikes, including one that was involved in transmission between minks and humans, and others that originated and spread in human populations. All variants showed increased angiotensin-converting enzyme 2 (ACE2) receptor binding and increased propensity for receptor binding domain (RBD)–up states. While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies. Our studies revealed allosteric effects of mutations and mechanistic differences that drive either interspecies transmission or escape from antibody neutralization.

59 BASIC BIOLOGICAL SCIENCES↗

Design of a Robust Memristive Spiking Neuromorphic System with Unsupervised Learning in Hardware

Spiking neural networks (SNN) offer a power efficient, biologically plausible learning paradigm by encoding information into spikes. The discovery of the memristor has accelerated the progress of spiking neuromorphic systems, as the intrinsic plasticity of the device makes it an ideal candidate to mimic a biological synapse. Despite providing a nanoscale form factor, non-volatility, and low-power operation, memristors suffer from device-level non-idealities, which impact system-level performance. To address these issues, this article presents a memristive crossbar-based neuromorphic system using unsupervised learning with twin-memristor synapses, fully digital pulse width modulated spike-timing-dependent plasticity, and homeostasis neurons. Additionally, the implemented single-layer SNN was applied to a pattern-recognition task of classifying handwritten-digits. The performance of the system was analyzed by varying design parameters such as number of training epochs, neurons, and capacitors. Furthermore, the impact of memristor device non-idealities, such as device-switching mismatch, aging, failure, and process variations, were investigated and the resilience of the proposed system was demonstrated.

97 MATHEMATICS AND COMPUTING↗

The Promise of Mutation Resistant Drugs for SARS-CoV-2 That Interdict in the Folding of the Spike Protein Receptor Binding Domain

In recent work, we proposed that effective therapeutic drugs aimed at treating the SARS-CoV-2 infection could be developed based on interdicting in the early steps of the folding pathway of key viral proteins, including the receptor binding domain (RBD) of the spike protein. In order to provide for a drug target on the protein, the earliest contact-formation event along the dominant folding pathway of the RBD spike protein was predicted employing the Sequential Collapse Model (SCM). The segments involved in the predicted earliest contact were suggested to provide optimal folding interdiction target regions (FITRs) for potential therapeutic drugs, with a focus on folding interdicting peptides (FIPs). In this paper, we extend our analysis to include 13 known single mutations of the RBD spike protein as well as the triple mutation B1.351 and the recent double mutation B1.617.2. The results show that the location of the FITR does not change in any of the 15 studied mutations, providing for a mutation-resistant drug design strategy for the RBD-spike protein.

Bergasa-Caceres, Fernando↗

Gravitational Waves from Primordial Black Hole Dark Matter Spikes

The origin of the binary black hole mergers observed by LIGO–Virgo–KAGRA remains an open question. We calculate the merger rate from primordial black holes (PBHs) within the density spike around supermassive black holes (SMBHs) at the centers of galaxies. We show that the merger rate within the spike is comparable to that within the wider dark matter halo. We also calculate the extreme mass ratio inspiral (EMRI) signal from PBHs hosted within the density spike spiralling into their host SMBHs due to gravitational-wave emission. We predict that LISA may detect ∼10 4 of these EMRIs with a signal-to-noise ratio threshold of 20 within a 4 yr observation run, if all dark matter is made up of ∼30 M ⊙ PBHs. Uncertainties in our rates come from the uncertain mass fraction of PBHs within the dark matter spike, relative to the host central SMBHs, which defines the parameter space LISA can constrain.

dark matter↗

Combustion control using spiking neural networks

A system that controls a combustion engine stores network vectors in a memory that represent diverse and distinct spiking neural networks. The system decodes the network vectors and trains and evaluates the spiking neural networks. The system duplicates selected network vectors and crosses-over the duplicated network vectors that represent modified spiking neural networks. The system mutates the crossed-over duplicated network vectors by randomly modifying one or more portions of the crossing-over duplicated network vectors. The system meter exhaust gas into an intake manifold when an engine temperature exceeds a threshold, an engine load exceeds a threshold, an engine's rotation-per-minute rate exceeds a threshold, and a fuel flow exceeds a threshold. The system modifies fuel flow into an engine's combustion chamber on a cycle-to-cycle basis by the trained spiking neural network.

Puente, Brian P. Maldonado↗

Formation and Redshift Evolution of Dark Matter Spikes

Dark matter density spikes forming around adiabatically growing black holes can dramatically enhance indirect and direct detection signals. Canonical predictions, however, assume a zero-mass seed in a purely dark matter environment and do not track the long-term dynamical impact of surrounding stars. We present a semi-analytic framework that first generalizes adiabatic spike formation to include finite seed masses, stellar cusps, and non-circular orbits, and then studies the subsequent cosmic evolution by solving coupled Fokker-Planck equations for the dark matter and stellar phase-space distributions, with a heating rate modulated by the cosmic star formation rate. Starting conservatively from canonical Gondolo-Silk spikes and marginalizing over astrophysical uncertainties, we find that stellar gravitational heating drives the inner slope towards $γ_χ\simeq 1.5$ within a few Gyrs (e.g by $z \lesssim 2$ for spikes formed at $z\simeq 10$), yielding overdensities two to four orders of magnitude below canonical expectations but still well above an NFW-like cusp. We provide redshift-dependent benchmarks for the column density and $J$-factor relevant to scattering, decay and annihilation signatures. Any robust interpretation of indirect dark matter signals from galactic nuclei must account for this evolution.

Herrera, Gonzalo [MIT, LNS; MIT, MKI; Harvard U.]↗

Analysis of the molecular determinants for furin cleavage of the spike protein S1/S2 site in defined strains of the prototype coronavirus murine hepatitis virus (MHV)

We analyzed the spike protein S1/S2 cleavage of selected strains of a prototype coronavirus, mouse hepatitis virus (MHV) by the cellular protease furin, in order to understand the structural requirements underlying the sequence selectivity of the scissile segment. The probability of cleavage of selected MHV strains was first evaluated from furin cleavage scores predicted by the ProP computer software, and then cleavage was measured experimentally with a fluorogenic peptide cleavage assay consisting of S1/S2 peptide mimics and purified furin. We found that in vitro cleavability varied across MHV strains in line with predicted results—but with the notable exception of MHV-A59, which was not cleaved despite a high score predicted for its sequence. Using the known X-Ray structure of furin in complex with a substrate-like inhibitor as an initial structural reference, we carried out molecular dynamics (MD) simulations to learn the modes of binding of the peptides in the furin active site, and the suitability of the complex for initiation of the enzymatic cleavage. We identified the 3D structural requirements of the furin active site configuration that enable bound peptides to undergo cleavage, and the way in which the various strains tested experimentally are fulfilling these requirements. We find that despite some flexibility in the organization of the peptide bound to the active site of the enzyme, the presence of a histidine at P2 of MHV-A59 fails to properly orient the sidechain of His194 of the furin catalytic triad and therefore produces a distortion that renders the peptide/complex structural configuration in the active site incompatible with requirements for cleavage initiation. The Ser/Thr in P1 of MHV-2 and MHV-S has a similar effect of distorting the conformation of the furin active site residues produced by the elimination of the canonical salt-bridge formed by arginine in P1 position. This work informs a study of coronavirus infection and pathogenesis with respect to the function of the viral spike protein, and suggests an important process of viral adaptation and evolution within the spike S1/S2 structural loop.

60 APPLIED LIFE SCIENCES↗

Skip-Connected Self-Recurrent Spiking Neural Networks with Joint Intrinsic Parameter and Synaptic Weight Training

As an important class of spiking neural networks (SNNs), recurrent spiking neural networks (RSNNs) possess great computational power and have been widely used for processing sequential data like audio and text. However, most RSNNs suffer from two problems. 1. Due to the lack of architectural guidance, random recurrent connectivity is often adopted, which does not guarantee good performance. 2. Training of RSNNs is in general challenging, bottlenecking achievable model accuracy. To address these problems, we propose a new type of RSNNs called Skip-Connected Self-Recurrent SNNs (ScSr-SNNs). Recurrence in ScSr-SNNs is introduced in a stereotyped manner by adding self-recurrent connections to spiking neurons. The SNNs with self-recurrent connections can realize recurrent behaviors similar to those of more complex RSNNs while the error gradients can be more straightforwardly calculated due to the mostly feedforward nature of the network. The network dynamics is enriched by skip connections between nonadjacent layers. Moreover, we propose a new backpropagation (BP) method called backpropagated intrinsic plasticity (BIP) to further boost the performance of ScSr-SNNs by training intrinsic model parameters. Unlike standard intrinsic plasticity rules that adjust the neuron's intrinsic parameters according to neuronal activity, the proposed BIP method optimizes intrinsic parameters based on the backpropagated error gradient of a well-defined global loss function in addition to synaptic weight training. Here, based on challenging speech, neuromorphic speech, and neuromorphic image datasets, the proposed ScSr-SNNs can boost performance by up to 2.85% compared with other types of RSNNs trained by state-of-the-art BP methods.

97 MATHEMATICS AND COMPUTING↗

Atomic Force Microscopy and Infrared Nanospectroscopy of COVID-19 Spike Protein for the Quantification of Adhesion to Common Surfaces

The COVID-19 pandemic has claimed millions of lives worldwide, sickened many more, and has resulted in severe socio-economic consequences. As society returns to normal, understanding the spread and persistence of SARS CoV-2 on commonplace surfaces can help to mitigate future outbreaks of coronaviruses and other pathogens. We hypothesize that such an understanding can be aided from studying the binding and interaction of viral proteins with non-biological surfaces. Here, we propose a methodology for investigating the adhesion of the SARS CoV-2 spike glycoprotein on common inorganic surfaces such as aluminum-, copper-, iron-, silica-, and ceria-oxides as well as metallic gold. Quantitative adhesion was obtained from the analysis of measured forces at the nanoscale using an atomic force microscope operated under ambient conditions. Without imposing further constraints on the measurement conditions, our preliminary findings suggest that spike glycoproteins interact with similar adhesion forces across the majority of the metal oxides tested with the exception to gold, for which attraction forces ~10 times stronger than all other materials studied were observed. Ferritin, which was used as a reference protein, was found to exhibit similar adhesion forces as SARS CoV-2 spike protein. Further, this study results show that glycoprotein adhesion forces for similar ambient humidity, tip shape, and contact surface are non-specific to the properties of metal oxide surfaces, which are expected to be covered by a thin water film. The findings suggest that at ambient conditions glycoprotein adhesion to metal oxides is primarily controlled by the water capillary forces and they depend on the surface tension of the liquid (water). We discuss further strategies warranted to decipher the intricate nanoscale forces for improved quantification of the adhesion.

59 BASIC BIOLOGICAL SCIENCES↗

Efficient human activity recognition with spatio-temporal spiking neural networks

In this study, we explore Human Activity Recognition (HAR), a task that aims to predict individuals' daily activities utilizing time series data obtained from wearable sensors for health-related applications. Although recent research has predominantly employed end-to-end Artificial Neural Networks (ANNs) for feature extraction and classification in HAR, these approaches impose a substantial computational load on wearable devices and exhibit limitations in temporal feature extraction due to their activation functions. To address these challenges, we propose the application of Spiking Neural Networks (SNNs), an architecture inspired by the characteristics of biological neurons, to HAR tasks. SNNs accumulate input activation as presynaptic potential charges and generate a binary spike upon surpassing a predetermined threshold. This unique property facilitates spatio-temporal feature extraction and confers the advantage of low-power computation attributable to binary spikes. We conduct rigorous experiments on three distinct HAR datasets using SNNs, demonstrating that our approach attains competitive or superior performance relative to ANNs, while concurrently reducing energy consumption by up to 94%.

60 APPLIED LIFE SCIENCES↗

De novo design and Rosetta-based assessment of high-affinity antibody variable regions (Fv) against the SARS-CoV -2 spike receptor binding domain ( RBD )

The continued emergence of new SARS-CoV-2 variants has accentuated the growing need for fast and reliable methods for the design of potentially neutralizing antibodies (Abs) to counter immune evasion by the virus. Here, we report on the de novo computational design of high-affinity Ab variable regions (Fv) through the recombination of VDJ genes targeting the most solvent-exposed hACE2-binding residues of the SARS-CoV-2 spike receptor binding domain (RBD) protein using the software tool OptMAVEn-2.0. Subsequently, we carried out computational affinity maturation of the designed variable regions through amino acid substitutions for improved binding with the target epitope. Immunogenicity of designs was restricted by preferring designs that match sequences from a 9-mer library of “human Abs” based on a human string content score. We generated 106 different antibody designs and reported in detail on the top five that trade-off the greatest computational binding affinity for the RBD with human string content scores. We further describe computational evaluation of the top five designs produced by OptMAVEn-2.0 using a Rosetta-based approach. We used Rosetta SnugDock for local docking of the designs to evaluate their potential to bind the spike RBD and performed “forward folding” with DeepAb to assess their potential to fold into the designed structures. Ultimately, our results identified one designed Ab variable region, P1.D1, as a particularly promising candidate for experimental testing. This effort puts forth a computational workflow for the de novo design and evaluation of Abs that can quickly be adapted to target spike epitopes of emerging SARS-CoV-2 variants or other antigenic targets.

59 BASIC BIOLOGICAL SCIENCES↗

Stochasticity and robustness in spiking neural networks

Despite drawing inspiration from biological systems which are inherently noisy and variable, artificial neural networks have been shown to require precise weights to carry out the task which they are trained to accomplish. This creates a challenge when adapting these artificial networks to specialized execution platforms which may encode weights in a manner which restricts their accuracy and/or precision.Reflecting back on the non-idealities which are observed in biological systems, we investigated the effect these properties have on the robustness of spiking neural networks under perturbations to weights. First, we examined techniques extant in conventional neural networks which resemble noisy processes, and postulated they may produce similar beneficial effects in spiking neural networks. Second, we evolved a set of spiking neural networks utilizing biological non-idealities to solve a pole-balancing task, and estimated their robustness. We showed it is higher in networks using noisy neurons, and demonstrated that one of these networks can perform well under the variance expected when a hafnium-oxide based resistive memory is used to encode synaptic weights. Lastly, we trained a series of networks using a surrogate gradient method on the MNIST classification task. We confirmed that these networks demonstrate similar trends in robustness to the evolved networks. We discuss these results and argue that they display empirical evidence supporting the role of noise as a regularizer which can increase network robustness.

97 MATHEMATICS AND COMPUTING↗

Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques

The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants.

59 BASIC BIOLOGICAL SCIENCES↗

Osmosensor-mediated control of Ca 2+ spiking in pollen germination

Higher plants survive terrestrial water deficiency and fluctuation by arresting cellular activities (dehydration) and resuscitating processes (rehydration). However, how plants monitor water availability during rehydration is unknown. Although increases in hypo-osmolarity-induced cytosolic Ca 2+ concentration (HOSCA) have long been postulated to be the mechanism for sensing hypo-osmolarity in rehydration, the molecular basis remains unknown. Because osmolarity triggers membrane tension and the osmosensing specificity of osmosensing channels can only be determined in vivo, these channels have been classified as a subtype of mechanosensors. Here we identify bona fide cell surface hypo-osmosensors in Arabidopsis and find that pollen Ca 2+ spiking is controlled directly by water through these hypo-osmosensors—that is, Ca 2+ spiking is the second messenger for water status. We developed a functional expression screen in Escherichia coli for hypo-osmosensitive channels and identified OSCA2.1, a member of the hyperosmolarity-gated calcium-permeable channel (OSCA) family of proteins. We screened single and high-order OSCA mutants, and observed that the osca2.1/osca2.2 double-knockout mutant was impaired in pollen germination and HOSCA. OSCA2.1 and OSCA2.2 function as hypo-osmosensitive Ca 2+ -permeable channels in planta and in HEK293 cells. Decreasing osmolarity of the medium enhanced pollen Ca 2+ oscillations, which were mediated by OSCA2.1 and OSCA2.2 and required for germination. OSCA2.1 and OSCA2.2 convert extracellular water status into Ca 2+ spiking in pollen and may serve as essential hypo-osmosensors for tracking rehydration in plants.

59 BASIC BIOLOGICAL SCIENCES↗