Individual Spikes Research Articles

Routing states transition during oscillatory bursts and attentional selection

Brain-wide information routing relies on the spatio-temporal dynamics of neural activity, but it remains unclear how routing states emerge at fast spiking timescales and relate to slower activity dynamics during cognitive processes. Here, we show that localized spiking events participate in directional routing states with spiking activity in distant brain areas that dynamically switch or amplify states during oscillatory bursts, attentional selection, and decision-making. Modeling and neural recordings from lateral prefrontal cortex (LPFC), anterior cingulate cortex (ACC), and striatum of nonhuman primates revealed that cross-regional routing states arise within 20ms following individual neuron spikes, with LPFC spikes leading the activity in ACC and striatum. The baseline routing state amplified during LPFC beta bursts between LPFC and striatum and switched direction during ACC theta/alpha bursts between ACC and LPFC. Selective attention amplified theta-/alpha-band-specific lead ensembles in ACC, while decision-making increased the lead of ACC and LPFC spikes to the striatum.

Cholera toxin B scaffolded, focused SIV V2 epitope elicits antibodies that influence the risk of SIVmac251 acquisition in macaques.

An efficacious HIV vaccine will need to elicit a complex package of innate, humoral, and cellular immune responses. This complex package of responses to vaccine candidates has been studied and yielded important results, yet it has been a recurring challenge to determine the magnitude and protective effect of specific in vivo immune responses in isolation. We therefore designed a single, viral-spike-apical, epitope-focused V2 loop immunogen to reveal individual vaccine-elicited immune factors that contribute to protection against HIV/SIV. We generated a novel vaccine by incorporating the V2 loop B-cell epitope in the cholera toxin B (CTB) scaffold and compared two new immunization regimens to a historically protective 'standard' vaccine regimen (SVR) consisting of 2xDNA prime boosted with 2xALVAC-SIV and 1xΔV1gp120. We immunized a cohort of macaques with 5xCTB-V2c vaccine+alum intramuscularly simultaneously with topical intrarectal vaccination of CTB-V2c vaccine without alum (5xCTB-V2/alum). In a second group, we tested a modified version of the SVR consisting of 2xDNA prime and boosted with 1xALVAC-SIV and 2xALVAC-SIV+CTB-V2/alum, (DA/CTB-V2c/alum). In the absence of any other anti-viral antibodies, V2c epitope was highly immunogenic when incorporated in the CTB scaffold and generated highly functional anti-V2c antibodies in the vaccinated animals. 5xCTB-V2c/alum vaccination mediated non-neutralizing ADCC activity and efferocytosis, but produced low avidity, trogocytosis, and no neutralization of tier 1 virus. Furthermore, DA/CTB-V2c/alum vaccination also generated lower total ADCC activity, avidity, and neutralization compared to the SVR. These data suggest that the ΔV1gp120 boost in the SVR yielded more favorable immune responses than its CTB-V2c counterpart. Vaccination with the SVR generates CCR5- α4β7+CD4+ Th1, Th2, and Th17 cells, which are less likely to be infected by SIV/HIV and likely contributed to the protection afforded in this regimen. The 5xCTB-V2c/alum regimen likewise elicited higher circulating CCR5- α4β7+ CD4+ T cells and mucosal α4β7+ CD4+ T cells compared to the DA/CTB-V2c/alum regimen, whereas the first cell type was associated with reduced risk of viral acquisition. Taken together, these data suggest that individual viral spike B-cell epitopes can be highly immunogenic and functional as isolated immunogens, although they might not be sufficient on their own to provide full protection against HIV/SIV infection.

Spike-microstates correlate with interictal epileptogenic discharges: a marker for hidden epileptic activity.

Objectively estimating disease severity and treatment success is a main problem in outpatient managing of epilepsy. Self-reported seizures diaries are well-known to underestimate the actual seizure count, and repeated EEGs might not show interictal epileptiform discharges (IEDs), although patients suffer from seizures. In this prospective study, we investigate the potential of microstate analysis to monitor epilepsy patients independently of their IED count. From our databank of candidates for epilepsy surgery, we included 18 patients who underwent controlled resting EEG sessions (with eyes closed, 30 min), at around the same time of the day, during at least four days (range: 4-8 days; mean: 5). Nine patients with temporal foci, six with extratemporal foci, and three with generalized epilepsy were included. Each patient's IEDs were marked and the topographic voltage maps of the IED peaks were averaged, and an individual average spike topography (AST) was created. The AST was then backfitted to each timepoint of the whole EEG resulting in the Spike-Microstate (SMS). The presence of the SMS in the residual EEG outside of the short IEDs epochs was determined for each recording session in each patient and correlated with the occurrence of the IEDs across all recording session, as well as with the drug charge of each day. Overall, SMS was much more represented in the routine EEG than the IEDs: they were identified 262 times more often than IEDs. The SMS time coverage correlated significantly with the IED occurrence rate (rho = 0.56; P < 0.001). If only patients with focal epilepsy were considered, this correlation was even higher rho = 0.69 (P < 0.001). Drug charge per day did not correlate with SMS. In this proof-of-concept study, the time coverage of SMS correlated strongly with the occurrence rate of the IEDs, they can be retrieved in the scalp EEG at a much higher occurrence rate. We conclude that SMS, once obtained for a given patient, are a more abundant marker of hidden epileptic activity than IEDs, in particular in focal epilepsy, and can be used also in absence of IEDs. Future larger studies are needed to verify its potential as monitoring tool and to determine cut-off values when drug protection becomes imperfect.

Abstract 5929: Individual organoid level analyses reveal hidden tumor molecular heterogeneity

Abstract Introduction: Tumor heterogeneity is a major cause of resistance to therapies in cancer patients occurring during disease progression or secondary to therapeutic intervention due to clonal selection. Mapping tumor heterogeneity is crucial for developing therapeutics for cancer patients. Currently there are no reliable models for identifying heterogeneity in vitro. Patient-derived cancer organoids (PDCOs) from tissue samples of patients capture clonal and subclonal mutations. Here we use PDCOs from colorectal cancer (CRC) patients to study molecular heterogeneity across individual organoids and how the heterogeneity changes with passages. Methods: Fresh CRC tissues from 4 patients undergoing endoscopy were obtained following consent on an IRB-approved protocol. PDCOs were cultured using Matrigel and previously published CRC organoid media. Following maturation, individual organoids (spikes) were separated into Matrigel domes and expanded. Parent cultures from high/low passage numbers and expanded spikes were collected for next generation sequencing (NGS). A variant allele frequency (VAF) was determined for each nonsynonymous variant and considered subclonal if the VAF was between 10%-30%. Variants were annotated pathogenic or not using ClinVar. Results: A total of 49 spikes were collected from 4 CRC PDCO lines and compared to the parent cultures using NGS. For low passage parent cultures, a median of 4 (range 3-8) subclonal alterations were identified. At high passages the number of subclonal variants decreased (median: 2 (range 2-4)). The individual organoid spikes maintained the founder (clonal) alterations and most also contained subclonal alterations, though at a lower frequency. Of those subclonal variants in the parent cultures, 31% were found in the spikes and an additional 54% found in the spikes were not identified in the parent. In a high tumor mutation burden line (MTB111), 12/17 spikes showed subclonal alterations in APCA896V, F1515C, Q1544* that were not present in the parent culture. Two PDCO lines (RC46A and RC46B) obtained from distinct sites of the same tumor were generated. One contained a subclonal mutation in MYCN26S in the high passage parent culture and 7/9 spikes. This mutation was not present in any RC46A samples. The high passage RC46A parent culture and 2/7 spikes showed an alteration in ARID1AG1037fs while it was present only in a single spike of RC46B. Conclusion: PDCOs identified subclonal alterations at the single-organoid level and are an exciting tool to study tumor heterogeneity. The spikes presented less subclonal variants than the parent but were largely not clonal. Future implications of using heterogeneity data from single organoids in therapeutic decisions are warranted. Citation Format: Shirsa Udgata, Aishwarya Sunil, Katherine A. Johnson, Cheri A. Pasch, Dustin A. Deming. Individual organoid level analyses reveal hidden tumor molecular heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5929.

Solar Radio Spikes and Type IIIb Striae Manifestations of Subsecond Electron Acceleration Triggered by a Coronal Mass Ejection

Understanding electron acceleration associated with magnetic energy release at subsecond scales presents major challenges in solar physics. Solar radio spikes observed as subsecond, narrow-bandwidth bursts with Δf/f ∼ 10−3–10−2 are indicative of a subsecond evolution of the electron distribution. We present a statistical analysis of frequency- and time-resolved imaging of individual spikes and Type IIIb striae associated with a coronal mass ejection (CME). LOFAR imaging reveals that the cotemporal (<2 s) spike and striae intensity contours almost completely overlap. On average, both burst types have a similar source size with a fast expansion at millisecond scales. The radio source centroid velocities are often superluminal and independent of frequency over 30–45 MHz. The CME perturbs the field geometry, leading to increased spike emission likely due to frequent magnetic reconnection. As the field restores itself toward the prior configuration, the observed sky-plane emission locations drift to increased heights over tens of minutes. Combined with previous observations above 1 GHz, the average decay time and source size estimates follow a ∼1/f dependence over three decades in frequency, similar to radio-wave scattering predictions. Both time and spatial characteristics of the bursts between 30 and 70 MHz are consistent with radio-wave scattering with a strong anisotropy of the density fluctuation spectrum. Consequently, the site of the radio-wave emission does not correspond to the observed burst locations and implies acceleration and emission near the CME flank. The bandwidths suggest intrinsic emission source sizes <1″ at 30 MHz and magnetic field strengths a factor of two larger than average in events that produce decameter spikes.

Single spikes drive sequential propagation and routing of activity in a cortical network.

Single spikes can trigger repeatable firing sequences in cortical networks. The mechanisms that support reliable propagation of activity from such small events and their functional consequences remain unclear. By constraining a recurrent network model with experimental statistics from turtle cortex, we generate reliable and temporally precise sequences from single spike triggers. We find that rare strong connections support sequence propagation, while dense weak connections modulate propagation reliability. We identify sections of sequences corresponding to divergent branches of strongly connected neurons which can be selectively gated. Applying external inputs to specific neurons in the sparse backbone of strong connections can effectively control propagation and route activity within the network. Finally, we demonstrate that concurrent sequences interact reliably, generating a highly combinatorial space of sequence activations. Our results reveal the impact of individual spikes in cortical circuits, detailing how repeatable sequences of activity can be triggered, sustained, and controlled during cortical computations.

Streamlined alpha‐amylase assays for wheat preharvest sprouting and late maturity alpha‐amylase detection

AbstractLate maturity alpha‐amylase (LMA) and preharvest sprouting (PHS) lead to elevated alpha‐amylase in wheat (Triticum aestivum L.) grain. Risk of poor end‐product quality due to elevated alpha‐amylase is detected in the wheat industry using the Hagberg–Perten falling number (FN) method. In breeding programs, selection for PHS and LMA tolerance requires higher throughput methods requiring a smaller sample size than the 7 g required for the FN method. Specifically, LMA can only be screened only using detection of alpha‐amylase activity or protein after cold treatment of individual wheat spikes at a specific stage of grain development resulting in very small samples (≤1 g). This study developed and evaluated a high throughput 96‐well method for the Phadebas alpha‐amylase enzyme assay for small wheat grain samples and compared this method to FN and the Megazyme Alpha‐Amylase SD (Sprout Damage) Assay Kit performed on the automated Awareness Technology ChemWell‐T Analyzer. In parallel, the efficacy of low‐cost small‐scale milling methods was evaluated relative to traditional larger scale mills. The Phadebas enzyme activity was highly reproducible and showed a strong correlation to the SD enzyme assay and FN method regardless of which mill was used to process the grain. The SD assay offers simpler standardization and calculation of enzyme activity, whereas the Phadebas assay offers higher sensitivity and lower expense. Both the 96‐well Phadebas and automated Megazyme SD assays are suitable for alpha‐amylase detection from small samples, and the use of low‐cost coffee grinders to process small samples did not significantly impact assay performance.

Electromyography as a Method for Distinguishing Dystonia in Mice.

Electromyography (EMG) methods allow quantitative analyses of motor function. The techniques include intramuscular recordings that are performed in vivo. However, recording muscle activity in freely moving mice, particularly in models of motor disease, often creates challenges that prevent the acquisition of clean signals. Recording preparations must be stable enough for the experimenter to collect an adequate number of signals for statistical analyses. Instability results in a low signal-to-noise ratio that prohibits proper isolation of EMG signals from the target muscle during the behavior of interest. Such insufficient isolation prevents the analysis of full electrical potential waveforms. In this case, resolving the shape of a waveform to differentiate individual spikes and bursts of muscle activity can be difficult. A common source of instability is an inadequate surgery. Poor surgical techniques cause blood loss, tissue damage, poor healing, encumbered movement, and unstable implantation of the electrodes. Here, we describe an optimized surgical procedure that ensures electrode stability for in vivo muscle recordings. We implement our technique to obtain recordings from agonist and antagonist muscle pairs in the hindlimbs of freely moving adult mice. We validate the stability of our method by holding EMG recordings during dystonic behavior. Our approach is ideal for studying normal and abnormal motor function in actively behaving mice and valuable for recording intramuscular activity when considerable motion is expected.

A Deep Neural Network-Based Spike Sorting With Improved Channel Selection and Artefact Removal

In order to implement highly efficient brain-machine interface (BMI) systems, high-channel count sensing is often used to record extracellular action potentials. However, the extracellular recordings are typically severely contaminated by artefacts and various noise sources, rendering the separation of multi-unit neural recordings an immensely challenging task. Removing artefact and noise from neural events can improve the spike sorting performance and classification accuracy. This paper presents a deep learning technique called deep spike detection (DSD) with a strong learning ability of high-dimensional vectors for neural channel selection and artefacts removal from the selected neural channel. The proposed method significantly improves spike detection compared to the conventional methods by sequentially diminishing the noise level and discarding the active artefacts in the recording channels. The simulated and experimental results show that there is considerably better performance when the extracellular raw recordings are cleaned prior to assigning individual spikes to the neurons that generated them. The DSD achieves an overall classification accuracy of 91.53% and outperformes Wave_clus by 3.38% on the simulated dataset with various noise levels and artefacts.

Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants

The BQ and XBB subvariants of SARS-CoV-2 Omicron are now rapidly expanding, possibly due to altered antibody evasion properties deriving from their additional spike mutations. Here, we report that neutralization of BQ.1, BQ.1.1, XBB, and XBB.1 by sera from vaccinees and infected persons was markedly impaired, including sera from individuals boosted with a WA1/BA.5 bivalent mRNA vaccine. Titers against BQ and XBB subvariants were lower by 13- to 81-fold and 66- to 155-fold, respectively, far beyond what had been observed to date. Monoclonal antibodies capable of neutralizing the original Omicron variant were largely inactive against these new subvariants, and the responsible individual spike mutations were identified. These subvariants were found to have similar ACE2-binding affinities as their predecessors. Together, our findings indicate that BQ and XBB subvariants present serious threats to current COVID-19 vaccines, render inactive all authorized antibodies, and may have gained dominance in the population because of their advantage in evading antibodies.

Common synaptic input between motor units from the lateral and medial posterior soleus compartments does not differ from that within each compartment.

The human soleus muscle is anatomically divided into four separate anatomical compartments. The functional role of this compartmentalization remains unclear. Here, we tested the hypothesis that the common synaptic input to motor units between the medial and lateral posterior compartments is less than within each compartment. Fourteen male participants performed three different heel-raise tasks that were considered to place a different mechanical demand on the medial and lateral soleus compartments. High-density electromyography (EMG) signals from the medial and lateral soleus compartments and the medial gastrocnemius of the right leg were decomposed into individual motor unit spike trains. The coherence between cumulative spike trains of the motor units was estimated. The coherence analysis was also repeated for motor units that were matched across all three tasks. Furthermore, we calculated the ratio of significant correlations between the spike trains of pairs of motor units. We observed that the coherence between motor units of the two soleus compartments was similar as the coherence between motor units within each compartment, regardless of the task. The correlation analysis performed on pairs of motor units confirmed these results. We conclude that the level of common synaptic input between the motor units innervating the medial and lateral posterior soleus compartment is not different than the common synaptic input between motor units innervating each of these compartments, which contrasts with findings from previous studies on finger muscles. This suggests that there is no independent neural control for the individual posterior soleus compartments.NEW & NOTEWORTHY The human soleus muscle is anatomically subdivided into four compartments. The functional role for this compartmentalization remains unknown. Here, we showed that, contrary to previous findings in finger muscles, the common synaptic input between motor units innervating the medial and lateral posterior soleus compartment was similar as that between motor units within the individual compartments. We suggest that the contradictory findings with other compartmentalized muscles may be explained by differences in muscle-tendon anatomy and function.

Acute Intermittent Hypoxia Increases Motor Unit Discharge Rates And Strength in Persons with SCI

<h3>Research Objectives</h3> To determine whether changes in motor unit discharge rates contribute to acute intermittent hypoxia (AIH)-induced improvements in volitional strength in persons with chronic incomplete spinal cord injury (iSCI) at the cervical level. <h3>Design</h3> Repeated-measures crossover study. <h3>Setting</h3> Rehabilitation hospital. <h3>Participants</h3> Seven individuals with iSCI completed two different sessions (AIH and SHAM) in a randomized order. <h3>Interventions</h3> AIH consisted of breathing 15 brief (∼60s) periods of low oxygen (9% O2) interspersed with 60s of normoxia (21% O2), whereas SHAM consisted of repeated exposures to normoxia. <h3>Main Outcome Measures</h3> We recorded high-density surface electromyograms from biceps and triceps brachii during maximal elbow flexion and extension torques, and decomposed these signals into individual motor unit spike trains before and 60 minutes after the interventions. <h3>Results</h3> After AIH, elbow flexion and extension torque increased by 54% (p = 0.0078; g = 0.58) and 59% (p = 0.04, g = 0.63) from baseline, respectively, whereas there was no change (i.e. < 10% change and p > 0.2 in both cases) after SHAM. Across muscles, motor unit discharge rates increased by 3.96 pulses per second (∼38%; p = 0.0015; G = 0.86) during maximal efforts, from pre to post AIH. Using generalized linear mixed models, we found that changes in motor unit discharge rates explained 54% (p = 0.0033) of the variance of changes in volitional torque. <h3>Conclusions</h3> These findings suggest that excitability and/or the activation of spinal motoneurons are augmented after AIH, providing a mechanism to explain AIH-induced increases in voluntary strength. Pending validation, AIH could potentially be used in conjunction with other therapies to enhance rehabilitation outcomes due to these enhancements in motor unit function and strength. <h3>Author(s) Disclosures</h3> The authors have nothing to disclose.

Physiological bases of cultivar differences in average grain weight in wheat: Scaling down from plot to individual grain in elite material

In recent decades, increases in wheat yield have been achieved mainly through increases in grain number per m 2 (GNM2) rather than through increases in average grain weight (AGW). Using AGW as a lever to increase yield would require avoidance of the negative relationship between GNM2 and AGW. It is usually supposed that this trade-off arises from an increase in the proportion of small grains as GNM2 rises. The proportional increase in small grains being the result either of (1) an increase in the proportion of secondary tillers in the spike population or (2) of an increase in the proportion of grains located in distal positions within each spike. Either or both of these two populational effects would tend to mask any true genotypic differences in AGW. The existence of these constitutive differences has already been proposed, but without considering the full extent of the populational confounding effects. Identification of a component of the constitutive genetic determinism of AGW - one that is truly independent of GNM2 - could contribute to cultivar developments that would lead to further increases in grain yield under future target environments. To address this question, we analysed populational effects on AGW in four, modern, well-adapted bread-wheat cultivars. The four chosen cultivars show similar grain yields but contrasting AGWs. The analysis of populational effects was carried out at three hierarchical levels (the plot, the spike and the single grain) and under two contrasting environmental conditions (well-watered vs water-deficit conditions). Regardless of the environment, no (or only slight) differences in individual spike size were observed between cultivars. Furthermore the weak relationship between spike size and AGWdemonstrates that AGW differences between cultivars cannot be attributed to spike-level populational effects. Meanwhile, the analysis of individual grain mass distributions, showed that the differences in AGW between cultivars, originated from shifts in the whole grain-mass distribution, rather than from shape changes in the grain-mass distribution. This clearly indicates that AGW differences between cultivars cannot be attributed to populational effects at the individual grain level. The analysis carried out at both spike and individual grain levels indicates that the AGW differences between cultivars are largely constitutive, so that increases in grain yield through AGW may be considered independently of the GNM2: AGW trade-off. Taken together, these findings offer a new perspective for the genetic improvement of wheat, and one that should lead to further increases in yield. • The trade-off between grain number (GNM2) and average grain weight (AGW) may limit wheat yield. • AGW differences between cultivars are not driven only by this trade-off. • AGW differences between cultivars have a constitutive nature. • Increasing AGW should be possible without negative effects on GNM2. • Increasing grain yield through AGW may be relevant to future target environments.

Dynamic control of eye-head gaze shifts by a spiking neural network model of the superior colliculus.

To reorient gaze (the eye's direction in space) towards a target is an overdetermined problem, as infinitely many combinations of eye- and head movements can specify the same gaze-displacement vector. Yet, behavioral measurements show that the primate gaze-control system selects a specific contribution of eye- and head movements to the saccade, which depends on the initial eye-in-head orientation. Single-unit recordings in the primate superior colliculus (SC) during head-unrestrained gaze shifts have further suggested that cells may encode the instantaneous trajectory of a desired straight gaze path in a feedforward way by the total cumulative number of spikes in the neural population, and that the instantaneous gaze kinematics are thus determined by the neural firing rates. The recordings also indicated that the latter is modulated by the initial eye position. We recently proposed a conceptual model that accounts for many of the observed properties of eye-head gaze shifts and on the potential role of the SC in gaze control. Here, we extend and test the model by incorporating a spiking neural network of the SC motor map, the output of which drives the eye-head motor control circuitry by linear cumulative summation of individual spike effects of each recruited SC neuron. We propose a simple neural mechanism on SC cells that explains the modulatory influence of feedback from an initial eye-in-head position signal on their spiking activity. The same signal also determines the onset delay of the head movement with respect to the eye. Moreover, the downstream eye- and head burst generators were taken to be linear, as our earlier work had indicated that much of the non-linear main-sequence kinematics of saccadic eye movements may be due to neural encoding at the collicular level, rather than at the brainstem. We investigate how the spiking activity of the SC population drives gaze to the intended target location within a dynamic local gaze-velocity feedback circuit that yields realistic eye- and head-movement kinematics and dynamic SC gaze-movement fields.

Multimodal Neural Probes with Small Form Factor Based on Dual‐Side Fabrication

AbstractMonitoring both individual neuronal spikes and neurotransmitters released from a specific brain region plays a significant role in understanding neuronal circuits and brain functionalities. While polymer neural probe offers distinctive advantages of flexibility, optical transparency, and biocompatibility, achieving high‐density recording with multifunctionalities and multimodality is still a challenge due to limited microfabrication techniques. Here, a multimodal polymer neural probe array based on a dual‐side fabrication process with the potential for high‐density neural recording and electrochemical neurotransmitter detection is presented. The developed dual‐side fabrication allows the placement of a larger number of microelectrodes and multimodal sensors without increasing the probe dimension by utilizing both sides of the shank. Using the dual‐side fabrication, a dual‐sided SU‐8 neural probe array is fabricated which consists of an array of gold and platinum microelectrodes and a micron‐scale three‐electrode system. Moreover, the design space of the micron‐scale three‐electrode systems on the dual‐side neural probe is explored. Through successful in vivo neural spike recording and dopamine (DA) measurements in a brain phantom using the fabricated dual‐side neural probe, it is confirmed that the dual‐sided microfabrication is a reliable and viable solution.

Naturally occurring spike mutations influence the infectivity and immunogenicity of SARS-CoV-2.

Mutations in SARS-CoV-2 variants of concern (VOCs) have enhanced transmissibility and immune evasion with respect to current vaccines and neutralizing antibodies (NAbs). How naturally occurring spike mutations affect the infectivity and antigenicity of VOCs remains to be investigated. The entry efficiency of individual spike mutations was determined in vitro using pseudotyped viruses. BALB/c mice were immunized with 2-dose DNA vaccines encoding B.1.1.7, B.1.351, B.1.1.529 and their single mutations. Cellular and humoral immune responses were then compared to determine the impact of individual mutations on immunogenicity. In the B.1.1.7 lineage, Del69–70 and Del 144 in NTD, A570D and P681H in SD1 and S982A and D1118H in S2 significantly increased viral entry, whereas T716I resulted in a decrease. In the B.1.351 lineage, L18F and Del 242–244 in the NTD, K417N in the RBD and A701V in S2 also increased viral entry. S982A weakened the generation of binding antibodies. All sera showed reduced cross-neutralization activity against B.1.351, B.1.617.2 (Delta) and B.1.1.529 (Omicron BA.1). S982A, L18F, and Del 242–244 hindered the induction of cross-NAbs, whereas Del 69–70, Del144, R246I, and K417N showed the opposite effects. B.1.351 elicited adequate broad cross-NAbs against both B.1.351 and B.1.617.2. All immunogens tested, however, showed low neutralization against circulating B.1.1.529. In addition, T-cell responses were unlikely affected by mutations tested in the spike. We conclude that individual spike mutations influence viral infectivity and vaccine immunogenicity. Designing VOC-targeted vaccines is likely necessary to overcome immune evasion from current vaccines and neutralizing antibodies.

Temporal Coding in Spiking Neural Networks With Alpha Synaptic Function: Learning With Backpropagation.

The timing of individual neuronal spikes is essential for biological brains to make fast responses to sensory stimuli. However, conventional artificial neural networks lack the intrinsic temporal coding ability present in biological networks. We propose a spiking neural network model that encodes information in the relative timing of individual spikes. In classification tasks, the output of the network is indicated by the first neuron to spike in the output layer. This temporal coding scheme allows the supervised training of the network with backpropagation, using locally exact derivatives of the postsynaptic spike times with respect to presynaptic spike times. The network operates using a biologically plausible synaptic transfer function. In addition, we use trainable pulses that provide bias, add flexibility during training, and exploit the decayed part of the synaptic function. We show that such networks can be successfully trained on multiple data sets encoded in time, including MNIST. Our model outperforms comparable spiking models on MNIST and achieves similar quality to fully connected conventional networks with the same architecture. The spiking network spontaneously discovers two operating modes, mirroring the accuracy-speed tradeoff observed in human decision-making: a highly accurate but slow regime, and a fast but slightly lower accuracy regime. These results demonstrate the computational power of spiking networks with biological characteristics that encode information in the timing of individual neurons. By studying temporal coding in spiking networks, we aim to create building blocks toward energy-efficient, state-based biologically inspired neural architectures. We provide open-source code for the model.

Latency correction in sparse neuronal spike trains

Background:In neurophysiological data, latency refers to a global shift of spikes from one spike train to the next, either caused by response onset fluctuations or by finite propagation speed. Such systematic shifts in spike timing lead to a spurious decrease in synchrony which needs to be corrected. New Method:We propose a new algorithm of multivariate latency correction suitable for sparse data for which the relevant information is not primarily in the rate but in the timing of each individual spike. The algorithm is designed to correct systematic delays while maintaining all other kinds of noisy disturbances. It consists of two steps, spike matching and distance minimization between the matched spikes using simulated annealing. Results:We show its effectiveness on simulated and real data: cortical propagation patterns recorded via calcium imaging from mice before and after stroke. Using simulations of these data we also establish criteria that can be evaluated beforehand in order to anticipate whether our algorithm is likely to yield a considerable improvement for a given dataset. Comparison with Existing Method(s):Existing methods of latency correction rely on adjusting peaks in rate profiles, an approach that is not feasible for spike trains with low firing in which the timing of individual spikes contains essential information. Conclusions:For any given dataset the criterion for applicability of the algorithm can be evaluated quickly and in case of a positive outcome the latency correction can be applied easily since the source codes of the algorithm are publicly available.

Evaluation of humoral immune responses induced by different SARS-CoV-2 spike trimers from wild-type and emerging variants with individual, sequential, and combinational delivered strategies.

The spike trimer of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is an effective target for inducing neutralizing antibodies by coronavirus disease 2019 (COVID‐19) vaccines. However, the diversity of spike protein from emerging SASR‐CoV‐2 variants has become the major challenge for development of a universal vaccine. To investigate the immunogenicity of spike proteins from various circulating strains including wild type, Delta, and Omicron variants, we produced various natural spike trimers and designed three vaccination strategies, that is, individual, sequential, and bivalent regimens to assess autologous and heterogenous antibody responses in a mouse model. The results indicated that monovalent vaccine strategy with individual spike trimer could only induce binding and neutralizing antibodies against homologous viruses. However, sequential and bivalent immunization with Delta and Omicron spike trimers could induce significantly broader neutralizing antibody responses against heterogenous SARS‐CoV‐2. Interestingly, the spike trimer from Omicron variant showed superior immunogenicity in inducing antibody response against recently emerging XE variant. Taken together, our data supported the development of novel vaccination strategies or multivalent vaccine against emerging variants.

A Non-Invasive Sound Technology to Monitor Rumen Contractions.

Simple SummaryThe recording of rumen sounds can be an important tool to assess the health status of a herd, as the frequency and amplitude of rumen contractions are associated with the flow and fermentation patterns of feed particles in the ruminoreticulum compartment. In this technical report, using a wireless device (CURO MkII), we recorded high-quality rumen sound waves that differentiate rumen contractions between cows of different production statuses (dry cow vs. lactating cow) and physiological stages (pregnant vs. non-pregnant). We envision that the rumen sound recordings will be a new form of technology to detect the onset of metabolic diseases, such as acidosis and hypocalcemia, which usually cause changes in the physicochemical properties of the rumen environment and reduce the frequency of rumen contractions. However, this technology still needs further improvement and validation through recordings of rumen movements in animals experiencing metabolic diseases, which will enable early detection of the problem and reduce treatment costs and production losses.This technical report used a wireless device (CURO MkII) that recorded high-quality rumen sound waves from cows of different production statuses (dry cow vs. lactating cow) and physiological stages (pregnant vs. non-pregnant). Recordings from a dry Jersey heifer fed a diet based on haylage and straw showed a few high-amplitude spikes (3 at 6 dB) but mostly infrequent signals (9 at 12 dB and 22 at 18 dB), with pauses of approx. 2 min with no rumen sounds in between. Analysis of a few individual spikes in the 12 dB range showed that wave frequencies ranged from 230 to 250 Hz and lasted 4 s. Recordings of the high-yielding Red Danish cow fed a total mixed ration (TMR) showed an almost constant frequency of the rumen sounds with considerable amplitude of the waves. Rumen sounds from the Red Danish dry and pregnant cow fed on TMR were less frequent, with a lower amplitude than those from the high-yielding cow. These preliminary results demonstrate that wireless sound recording units are capable of measuring rumen sounds in a production setting and can discern between animals of different production and physiological stages, but more studies are needed to confirm our findings.