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[Display omitted] • LTD occurs reliably at cortical inputs into the amygdala. • The plasticity of synaptic connections is an evolving and dynamic process. • Pyramidal neurons exhibit similar LTD despite different spiking patterns. • The LTD in the amygdala is progressively stronger upon recurrent stimuli. • Gradually stronger LTD exhibits similitude to that of LTP. The convergence of conditioned and unconditioned stimuli (CS and US) into the lateral amygdala (LA) serves as a substrate for an adequate fear response in vivo. This well-known Pavlovian paradigm modulates the synaptic plasticity of neurons, as can be proved by the long-term potentiation (LTP) phenomenon in vitro. Although there is an increasing body of evidence for the existence of LTP in the amygdala, only a few studies were able to show a reliable long-term depression (LTD) of excitation in this structure. We have used coronal brain slices and conducted patch-clamp recordings in pyramidal neurons of the lateral amygdala (LA). After obtaining a stable baseline excitatory postsynaptic current (EPSC) response at a holding potential of −70 mV, we employed a paired-pulse paradigm at 1 Hz at the same membrane potential and could observe a reliable LTD. The different durations of stimulation (ranging between 1.5–24 min) were tested first in the same neuron, but the intensity was kept constant. The latter paradigm resulted in a step-wise LTD with a gradually increasing magnitude under these conditions. [ABSTRACT FROM AUTHOR]

In wheat, the transition of the inflorescence meristem to a terminal spikelet (IM→TS) determines the spikelet number per spike (SNS), an important yield component. In this study, we demonstrate that the plant-specific transcription factor LEAFY (LFY) physically and genetically interacts with WHEAT ORTHOLOG OF APO1 (WAPO1) to regulate SNS and floret development. Loss-of-function mutations in either or both genes result in significant and similar reductions in SNS, as a result of a reduction in the rate of spikelet meristem formation per day. SNS is also modulated by significant genetic interactions between LFY and the SQUAMOSA MADS-box genes VRN1 and FUL2, which promote the IM→TS transition. Singlemolecule fluorescence in situ hybridization revealed a downregulation of LFY and upregulation of the SQUAMOSA MADS-box genes in the distal part of the developing spike during the IM→TS transition, supporting their opposite roles in the regulation of SNS in wheat. Concurrently, the overlap of LFY and WAPO1 transcription domains in the developing spikelets contributes to normal floret development. Understanding the genetic network regulating SNS is a necessary first step to engineer this important agronomic trait. [ABSTRACT FROM AUTHOR]

Since Coronavirus disease 2019 (COVID-19) still presents a considerable threat, it is beneficial to provide therapeutic supplements against it. In this respect, glycoprotein lactoferrin (LF) and lactoferricin (LFC), a natural bioactive peptide yielded upon digestion from the N-terminus of LF, are of utmost interest, since both have been shown to reduce infections of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, in particular via blockade of the virus priming and binding. Here, we, by means of biochemical and biophysical methods, reveal that LF directly binds to the S-protein of SARS-CoV-2. We determined thermodynamic and kinetic characteristics of the complex formation and mapped the mutual binding sites involved in this interaction, namely the N-terminal region of LF and the receptor-binding domain of the S-protein (RBD). These results may not only explain many of the observed protective effects of LF and LFC in SARS-CoV-2 infection but may also be instrumental in proposing potent and cost-effective supplemental tools in the management of COVID-19. [ABSTRACT FROM AUTHOR]

Anti-spike monoclonal antibodies represent one of the most tolerable prophylaxis and therapies for COVID-19 in frail and immunocompromised patients. Unfortunately, viral evolution in Omicron has led all of them to failure. We review here the current pipeline of anti-spike mAb's, discussing in detail the most promising candidates. We scanned PubMed, ClinicalTrials.gov and manufacturers' press releases for clinical studies on anti-spike monoclonal antibodies. We present state-of-art data clinical progress for AstraZeneca's AZD3152, Invivyd's VYD222, Regeneron's REGN-17092 and Aerium Therapeutics' AER-800. The anti-spike monoclonal antibody clinical pipeline is currently limited to few agents (most being single antibodies) with unknown efficacy against the dominant JN.1 sublineage. The field of antibody-based therapies requires boosting by both manufacturers and institutions. [ABSTRACT FROM AUTHOR]

Beginning in 2022, following widespread infection and vaccination among the global population, the SARS-CoV-2 virus mainly evolved to evade immunity derived from vaccines and past infections. This review covers the convergent evolution of structural, nonstructural, and accessory proteins in SARS-CoV-2, with a specific look at common mutations found in long-lasting infections that hint at the virus potentially reverting to an enteric sarbecovirus type. [ABSTRACT FROM AUTHOR]

Introduction: Complex neuronal interactions underlie cortical information processing that can be compromised in altered states of consciousness. Here intracortical microstimulation was applied to investigate anesthetic statedependent effective connectivity of neurons in rat visual cortex in vivo. Methods: Extracellular activity was recorded at 32 sites in layers 5/6 while stimulating with charge-balanced discrete pulses at each electrode in random order. The same stimulation pattern was applied at three levels of anesthesia with desflurane and in wakefulness. Spikes were sorted and classified by their waveform features as putative excitatory and inhibitory neurons. Network motifs were identified in graphs of effective connectivity constructed from monosynaptic cross-correlograms. Results: Microstimulation caused early (<10 ms) increase followed by prolonged (11-100 ms) decrease in spiking of all neurons throughout the electrode array. The early response of excitatory but not inhibitory neurons decayed rapidly with distance from the stimulation site over 1 mm. Effective connectivity of neurons with significant stimulus response was dense in wakefulness and sparse under anesthesia. The number of network motifs, especially those of higher order, increased rapidly as the anesthesia was withdrawn indicating a substantial increase in network connectivity as the animals woke up. Conclusion: The results illuminate the impact of anesthesia on functional integrity of local cortical circuits affecting the state of consciousness. [ABSTRACT FROM AUTHOR]

One of the entry mechanisms of the SARS-CoV-2 coronavirus into host cells involves endosomal acidification. It has been proposed that under acidic conditions, the fusion peptide proximal region (FPPR) of the SARS-CoV-2 spike glycoprotein acts as a pH-dependent switch, modulating immune response accessibility by influencing the positioning of the receptor binding domain (RBD). This would provide indirect coupling of RBD opening to the environmental pH. Here, we explored this possible pH-dependent conformational equilibrium of the FPPR within the SARS-CoV-2 spike glycoprotein. We analyzed hundreds of experimentally determined spike structures from the Protein Data Bank and carried out pH-replica exchange molecular dynamics to explore the extent to which the FPPR conformation depends on pH and the positioning of the RBD. A meta-analysis of experimental structures identified alternate conformations of the FPPR among structures in which this flexible regions was resolved. However, the results did not support a correlation between the FPPR conformation and either RBD position or the reported pH of the cryo-EM experiment. We calculated pKa values for titratable side chains in the FPPR region using PDB structures, but these pKa values showed large differences between alternate PDB structures that otherwise adopt the same FPPR conformation type. This hampers the comparison of pKa values in different FPPR conformations to rationalize a pH-dependent conformational change. We supplemented these PDB-based analyses with all-atom simulations and used constant-pH replica exchange molecular dynamics to estimate pKa values in the context of flexibility and explicit water. The resulting titration curves show good reproducibility between simulations, but they also suggest that the titration curves of the different FPPR conformations are the same within the error bars. In summary, we were unable to find evidence supporting the previously published hypothesis of an FPPR pH-dependent equilibrium: neither from existing experimental data nor from constant-pH MD simulations. The study underscores the complexity of the spike system and opens avenues for further exploration into the interplay between pH and SARS-CoV-2 viral entry mechanisms. [ABSTRACT FROM AUTHOR]

Background: The manufacturing processes of plasma products include steps that can remove prions. The efficacy of these steps is measured in validation studies using animal brain‐derived prion materials called spikes. Because the nature of the prion agent in blood is not known, the relevance of these spikes, particularly with steps that are based on retention mechanisms such as nanofiltration, is important to investigate. Study Design and Methods: The aggregation and sizes of PrPres assemblies of microsomal fractions (MFs) extracted from 263K‐infected hamster brains were analyzed using velocity gradients. The separated gradient fractions were either inoculated to Tg7 mice expressing hamster‐PrPc to measure infectivity or used in Protein Misfolding Cyclic Amplification for measuring seeding activity. The collected data allowed for reanalyzing results from previous nanofiltration validation studies. Results: A significant portion of MFs was found to be composed of small PrPres assemblies, estimated to have a size ≤24 mers (~22–528 kDa), and to contain a minimum of 20% of total prion infectivity. With this data we could calculate reductions of 4.10 log (15 N), 2.53 log (35 N), and 1.77 log (35 N) from validation studies specifically for these small PrPres objects. Conclusion: Our gradient data provided evidence that nanofilters can remove the majority of the smallest PrPres entities within microsomes spikes, estimated to be in a size below 24 mers, giving insight about the fact that, in our conditions, size exclusion may not be the only mechanism for retention nanofiltration. [ABSTRACT FROM AUTHOR]

Background: Porcine epidemic diarrhea virus (PEDV) mainly causes acute and severe porcine epidemic diarrhea (PED), and is highly fatal in neonatal piglets. No reliable therapeutics against the infection exist, which poses a major global health issue for piglets. Luteolin is a flavonoid with anti-viral activity toward several viruses. Results: We evaluated anti-viral effects of luteolin in PEDV-infected Vero and IPEC-J2 cells, and identified IC50 values of 23.87 µM and 68.5 µM, respectively. And found PEDV internalization, replication and release were significantly reduced upon luteolin treatment. As luteolin could bind to human ACE2 and SARS-CoV-2 main protease (Mpro) to contribute viral entry, we first identified that luteolin shares the same core binding site on pACE2 with PEDV-S by molecular docking and exhibited positive pACE2 binding with an affinity constant of 71.6 µM at dose-dependent increases by surface plasmon resonance (SPR) assay. However, pACE2 was incapable of binding to PEDV-S1. Therefore, luteolin inhibited PEDV internalization independent of PEDV-S binding to pACE2. Moreover, luteolin was firmly embedded in the groove of active pocket of Mpro in a three-dimensional docking model, and fluorescence resonance energy transfer (FRET) assays confirmed that luteolin inhibited PEDV Mpro activity. In addition, we also observed PEDV-induced pro-inflammatory cytokine inhibition and Nrf2-induced HO-1 expression. Finally, a drug resistant mutant was isolated after 10 cell culture passages concomitant with increasing luteolin concentrations, with reduced PEDV susceptibility to luteolin identified at passage 10. Conclusions: Our results push forward that anti-PEDV mechanisms and resistant-PEDV properties for luteolin, which may be used to combat PED. [ABSTRACT FROM AUTHOR]

Copyright of FME Transactions is the property of University of Belgrade, Faculty of Mechanical Engineering and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The class spike is an important class of 3-connected matroids. For an integer [Formula: see text], each matroid that is obtained by relaxing one of the circuit-hyperplanes of an r-spike (spike with rank r) is isomorphic to another r-spike and repeating this procedure will produce other r-spikes. So it will be useful to characterize the collection of circuit-hyperplanes of a spike. In this paper, we first introduce a technique to characterize the only two ternary r-spikes in terms of their matrix representations, circuit-hyperplanes, and [Formula: see text]-circuits and then we generalize this technique to characterize the class of r-spikes that is representable over the field GF(p), for all primes p. Moreover, we pose a conjecture which would characterize the class of all r-spikes by using all GF(p)-representable r-spikes.

Abstract Background Porcine epidemic diarrhea virus (PEDV) mainly causes acute and severe porcine epidemic diarrhea (PED), and is highly fatal in neonatal piglets. No reliable therapeutics against the infection exist, which poses a major global health issue for piglets. Luteolin is a flavonoid with anti-viral activity toward several viruses. Results We evaluated anti-viral effects of luteolin in PEDV-infected Vero and IPEC-J2 cells, and identified IC50 values of 23.87 µM and 68.5 µM, respectively. And found PEDV internalization, replication and release were significantly reduced upon luteolin treatment. As luteolin could bind to human ACE2 and SARS-CoV-2 main protease (Mpro) to contribute viral entry, we first identified that luteolin shares the same core binding site on pACE2 with PEDV-S by molecular docking and exhibited positive pACE2 binding with an affinity constant of 71.6 µM at dose-dependent increases by surface plasmon resonance (SPR) assay. However, pACE2 was incapable of binding to PEDV-S1. Therefore, luteolin inhibited PEDV internalization independent of PEDV-S binding to pACE2. Moreover, luteolin was firmly embedded in the groove of active pocket of Mpro in a three-dimensional docking model, and fluorescence resonance energy transfer (FRET) assays confirmed that luteolin inhibited PEDV Mpro activity. In addition, we also observed PEDV-induced pro-inflammatory cytokine inhibition and Nrf2-induced HO-1 expression. Finally, a drug resistant mutant was isolated after 10 cell culture passages concomitant with increasing luteolin concentrations, with reduced PEDV susceptibility to luteolin identified at passage 10. Conclusions Our results push forward that anti-PEDV mechanisms and resistant-PEDV properties for luteolin, which may be used to combat PED.

The recent emergence of the omicron variant of the SARS-CoV-2 virus with large numbers of mutations has raised concern about a potential new surge in infections. Here we use molecular dynamics to study the biophysics of the interface of the BA1 and BA2 omicron spike protein binding to (i) the ACE2 receptor protein, (ii) antibodies from all known binding regions, and (iii) the furin binding domain. Our simulations suggest that while there is a significant reduction of antibody (Ab) binding strength corresponding to escape, the omicron spikes pay a cost in terms of weaker receptor binding as measured by interfacial hydrogen bonds (H-bond). The furin cleavage domain (FCD) is the same or weaker binding than the delta variant, suggesting lower fusogenicity resulting in less viral load and disease intensity than the delta variant. IMPORTANCE The BA1 and BA2 and closely related BA2.12.2 and BA.5 omicron variants of SARS-CoV-2 dominate the current global infection landscape. Given the high number of mutations, particularly those which will lead to antibody escape, it is important to establish accurate methods that can guide developing health policy responses that identify at a fundamental level whether omicron and its variants are more threatening than its predecessors, especially delta. The importance of our work is to demonstrate that simple in silico simulations can predict biochemical binding details of the omicron spike protein that have epidemiological consequences, especially for binding to the cells and for fusing the viral membrane with the cells. In each case, we predicted weaker binding of the omicron spike, which agreed with subsequent experimental results. Future virology experiments will be needed to test these predictions further.

This paper is concerned with the dynamical stability of spiky steady states to a chemotaxis-consumption model with signal-dependent motilities on the half space, where no-flux boundary condition for the bacteria and inhomogeneous Dirichlet boundary condition for the nutrient are prescribed. The motilities of bacteria depend on the concentration of nutrient in the form of power law, which means that they are degenerate if the power-law exponent is positive and are singular if the exponent is negative at the zero state of nutrient. We show that in both cases the spiky patterns admitted by the model are nonlinearly stable under appropriate perturbations. We introduce a unified approach to dealing with both degeneracy and singularity in the diffusivity for this model. The approach is based on a combination of weighted energy estimates and weighted elliptic estimates, where various weights are artfully constructed to capture the complex behaviors of solutions near the zero state. Numerical simulations are also carried out to confirm our theoretical results. [ABSTRACT FROM AUTHOR]

Copyright of Retos: Nuevas Perspectivas de Educación Física, Deporte y Recreación is the property of Federacion Espanola de Asociaciones de Docentes de Educacion Fisica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Natural infection and vaccination against SARS-CoV-2 is associated with the development of immunity against the structural proteins of the virus. Specifically, the two most immunogenic are the S (spike) and N (nucleocapsid) proteins. Seroprevalence studies performed in university students provide information to estimate the number of infected patients (symptomatic or asymptomatic) and generate knowledge about the viral spread, vaccine efficacy, and epidemiological control. Which, the aim of this study was to evaluate IgG antibodies against the S and N proteins of SARS-CoV-2 at university students from Southern Mexico. Methods A total of 1418 serum samples were collected from eighteen work centers of the Autonomous University of Guerrero. Antibodies were detected by Indirect ELISA using as antigen peptides derived from the S and N proteins. Results We reported a total seroprevalence of 39.9% anti-S/N (positive to both antigens), 14.1% anti-S and 0.5% anti-N. The highest seroprevalence was reported in the work centers from Costa Grande, Acapulco and Centro. Seroprevalence was associated with age, COVID-19, contact with infected patients, and vaccination. Conclusion University students could play an essential role in disseminating SARS-CoV-2. We reported a seroprevalence of 54.5% against the S and N proteins, which could be due to the high population rate and cultural resistance to safety measures against COVID-19 in the different regions of the state.

Objective This study examines the impact of fatigue on kinetic variables during landing after performing a spike in professional volleyball players. Fatigue can significantly affect athletic performance and increase the risk of lower limb injuries, particularly in movements that require precise landings. Methods In this study, 28 professional volleyball players performed a spike over the net and landed on a force plate before and after inducing fatigue. Kinetic variables, including ground reaction forces and loading rates, were evaluated at both stages. A paired t-test was used to examine the effect of fatigue on these variables during the landing task after the spike. All statistical analyses were conducted using SPSS software with a significance level set at P

Abstract Purpose The performance of swing movement during spikes and serves plays a crucial role in determining the outcomes of volleyball matches. This study aims to explore the effects of the participation of the trunk and lower limbs’ involvement on the velocity and power of the swing movement of adolescent male volleyball players, as well as the differences in power and velocity performance of the swing movement among different ages and specific positions. Methods The study involved 22 adolescent male volleyball players, with 11 high school students and 11 middle school students. The Kineo Globus equipment was used to assess the swing movement performance involving different segments, including arm swing movement only involving arm limb participation; upper swing movement involving trunk and arm limb participation; and whole body swing movement involving lower limb, trunk, and arm limb participation. The measured parameters included power and velocity performance levels. Before the test, each subject practiced three movement patterns twice. Results The study found that swing movement involving both the trunk and arm limbs had significantly higher average (F = 17.70, p

Introduction: Infection with SARS-CoV-2 begins in the upper respiratory tract and can trigger the production of mucosal spike-specific secretory IgA (sIgA), which provides protection against reinfection. It has been recognized that individuals with high level of nasal spike-specific IgA have a lower risk of reinfection. However, mucosal spike-specific sIgA wanes over time, and different individuals may have various level of spike-specific sIgA and descending kinetics, leading to individual differences in susceptibility to reinfection. A method for detecting spike-specific sIgA in the nasal passage would be valuable for predicting the risk of reinfection so that people at risk can have better preparedness. Methods: In this study, we describe the development of a colloidal gold-based immunochromatographic (ICT) strip for detecting SARS-CoV-2 Omicron spikespecific sIgA in nasal mucosal lining fluids (NMLFs). Results: The ICT strip was designed to detect 0.125 µg or more spike-specific sIgA in 80 µL of NMLFs collected using a nasal swab. Purified nasal sIgA samples from individuals who recently recovered from an Omicron BA.5 infection were used to demonstrate that this ICT strip can specifically detect spike-specific sIgA. The signal levels positively correlated with neutralizing activities against XBB. Subsequent analysis revealed that people with low or undetectable levels of spike-specific sIgA in the nasal passage were more susceptible to SARSCoV-2 reinfection. Conclusions: This nasal spike-specific sIgA ICT strip provides a non-invasive, rapid, and convenient method to assess the risk of reinfection for achieving precision preparedness. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 vaccines have contributed to attenuating the burden of the COVID-19 pandemic by promoting the development of effective immune responses, thus reducing the spread and severity of the pandemic. A clinical trial with the Sputnik-V vaccine was conducted in Venezuela from December 2020 to July 2021. The aim of this study was to explore the antibody reactivity of vaccinated individuals towards different regions of the spike protein (S). Neutralizing antibody (NAb) activity was assessed using a commercial surrogate assay, detecting NAbs against the receptor-binding domain (RBD), and a plaque reduction neutralization test. NAb levels were correlated with the reactivity of the antibodies to the spike regions over time. The presence of Abs against nucleoprotein was also determined to rule out the effect of exposure to the virus during the clinical trial in the serological response. A high serological reactivity was observed to S and specifically to S1 and the RBD. S2, although recognized with lower intensity by vaccinated individuals, was the subunit exhibiting the highest cross-reactivity in prepandemic sera. This study is in agreement with the high efficacy reported for the Sputnik V vaccine and shows that this vaccine is able to induce an immunity lasting for at least 180 days. The dissection of the Ab reactivity to different regions of S allowed us to identify the relevance of epitopes outside the RBD that are able to induce NAbs. This research may contribute to the understanding of vaccine immunity against SARS-CoV-2, which could contribute to the design of future vaccine strategies. [ABSTRACT FROM AUTHOR]

Swine acute diarrhea syndrome coronavirus (SADS‐CoV) has caused severe intestinal diseases in pigs. It originates from bat coronaviruses HKU2 and has a potential risk of cross‐species transmission, raising concerns about its zoonotic potential. Viral entry‐related host factors are critical determinants of susceptibility to cells, tissues, or species, and remain to be elucidated for SADS‐CoV. Type II transmembrane serine proteases (TTSPs) family is involved in many coronavirus infections and has trypsin‐like catalytic activity. Here we examine all 18 members of the TTSPs family through CRISPR‐based activation of endogenous protein expression in cells, and find that, in addition to TMPRSS2 and TMPRSS4, TMPRSS13 significantly facilitates SADS‐CoV infection. This is confirmed by ectopic expression of TMPRSS13, and specific to trypsin‐dependent SADS‐CoV. Infection with pseudovirus bearing SADS‐CoV spike protein indicates that TMPRSS13 acts at the entry step and is sensitive to serine protease inhibitor Camostat. Moreover, both human and pig TMPRSS13 are able to enhance the cell‐cell membrane fusion and cleavage of spike protein. Overall, we demonstrate that TMPRSS13 is another host serine protease promoting the membrane‐fusion entry of SADS‐CoV, which may expand its host tropism by using diverse TTSPs. [ABSTRACT FROM AUTHOR]

Two pairs of disjoint bases P 1 = (R 1 , B 1) and P 2 = (R 2 , B 2) of a matroid M are called equivalent if P 1 can be transformed into P 2 by a series of symmetric exchanges. In 1980, White conjectured that such a sequence always exists whenever R 1 ∪ B 1 = R 2 ∪ B 2 . A strengthening of the conjecture was proposed by Hamidoune, stating that the minimum length of an exchange is at most the rank of the matroid. We propose a weighted variant of Hamidoune's conjecture, where the weight of an exchange depends on the weights of the exchanged elements. We prove the conjecture for several matroid classes: strongly base orderable matroids, split matroids, graphic matroids of wheels, and spikes. [ABSTRACT FROM AUTHOR]

Purpose: The performance of swing movement during spikes and serves plays a crucial role in determining the outcomes of volleyball matches. This study aims to explore the effects of the participation of the trunk and lower limbs’ involvement on the velocity and power of the swing movement of adolescent male volleyball players, as well as the differences in power and velocity performance of the swing movement among different ages and specific positions. Methods: The study involved 22 adolescent male volleyball players, with 11 high school students and 11 middle school students. The Kineo Globus equipment was used to assess the swing movement performance involving different segments, including arm swing movement only involving arm limb participation; upper swing movement involving trunk and arm limb participation; and whole body swing movement involving lower limb, trunk, and arm limb participation. The measured parameters included power and velocity performance levels. Before the test, each subject practiced three movement patterns twice. Results: The study found that swing movement involving both the trunk and arm limbs had significantly higher average (F = 17.70, p < 0.001) and peak power performance (F = 31.47, p < 0.001), as well as in average (F = 9.14, p = 0.03) and peak velocity performance (F = 23.17, p < 0.001). There were no significant differences in average (F = 17.70; p = 0.46) and peak power (F = 31.47, p = 0.94), as well as in average (F = 9.14, p = 0.99) and peak velocity performance (F = 23.17, p = 0.90) between movements involving the whole body and those involving the trunk and upper limbs. Among different age groups, the swing movement performance of middle school athletes showed significant enhancements in both average (F = 9.20, p < 0.001) and peak power (F = 19.93, p < 0.001), as well as in average (F = 10.75, p < 0.001) and peak velocity (F = 34.35, p < 0.001) when arm swing with trunk involvement was compared to arm swing movement. High school athletes also showed significant improvements in peak velocity (F = 34.35, p < 0.001), peak power (F = 17.31, p < 0.001), and average power (F = 9.41, p < 0.001) during upper swing movements, except for average velocity performance (F = 1.56, p = 0.21), when compared to arm swing movement. The increase rate in average velocity performance of swing movements involving trunk participation was significantly higher in middle school athletes than in high school athletes (p < 0.001). Among athletes in specific positions, Middle Blocker (MB) players exhibited significantly better average power performance in swing movements involving trunk and arm limb participation compared to Outside Hitter (OH) players (p = 0.04). Furthermore, the rate of average (p = 0.01) and peak (p = 0.03) power change during upper swing movements involving lower limb participation was significantly higher among OH players than MB players. Conclusions: The involvement of the trunk segment has been observed to significantly improve power and velocity in swing movements during spike and serves among adolescent male volleyball players. This underscores the importance of coordination between the trunk and arm in influencing swing movement performance during spikes and serves. High school athletes demonstrate superior power and velocity in arm swing movements compared to middle school athletes. MB exhibits greater power in upper limb swing movements than OH, although OH players show better coordination between the arm, trunk, and lower limb segments in the swing movement. To enhance swing movement performance in adolescent male volleyball players, particularly focusing on the trunk segment was crucial. Specialized physical training programs should target improving both arm strength and rotational power of the trunk simultaneously. This approach would help in consistently enhancing coordination between the trunk and arms, ultimately leading to optimized force generation during swing movements such as spikes and serves. [ABSTRACT FROM AUTHOR]

Current measurement systems based on the IEEE-1159 standard have some limitations and robustness problems under noisy and fast-changing conditions. Besides, applying different methods for each Power Quality Disturbance (PQD) to every window is required but time-consuming and not feasible. Therefore, different kinds of two-stage methods, Detection and Classification (D&C), have been improved in many studies. Then, the required measurement can be performed to define disturbance. For this purpose, a new approach based on features of subcomponents with Machine Learning Algorithms (MLAs) to detect and classify PQDs is proposed. 21-class dataset including single and multiple PQDs under different noisy conditions was prepared randomly. Of this dataset, determined features were extracted and some of these were selected. Then, selected features were trained and tested with some MLAs in a workstation. Results obtained from comparative MLAs and the other classification methods show that the best MLA with related features is Random Forest with 96.97% while LightGBM, k-Nearest Neighbors, and XGBoost 96.85%, 96.73%, and 92.82% accuracy, respectively. Because the selected features, optimized parameters, and the related MLA were obtained by investigating for features provided from the PQDs in the whole parameter space, this approach brings the advantages of high accuracy, low D&C complexity, and computing load. [ABSTRACT FROM AUTHOR]

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast-spreading viral pathogen and poses a serious threat to human health. New SARS-CoV-2 variants have been arising worldwide; therefore, is necessary to explore more therapeutic options. The interaction of the viral spike (S) protein with the angiotensin-converting enzyme 2 (ACE2) host receptor is an attractive drug target to prevent the infection via the inhibition of virus cell entry. In this study, Ligand- and Structure-Based Virtual Screening (LBVS and SBVS) was performed to propose potential inhibitors capable of blocking the S receptor-binding domain (RBD) and ACE2 interaction. The best five lead compounds were confirmed as inhibitors through ELISA-based enzyme assays. The docking studies and molecular dynamic (MD) simulations of the selected compounds maintained the molecular interaction and stability (RMSD fluctuations less than 5 Å) with key residues of the S protein. The compounds DRI-1, DRI-2, DRI-3, DRI-4, and DRI-5 efficiently block the interaction between the SARS-CoV-2 spike protein and receptor ACE2 (from 69.90 to 99.65% of inhibition) at 50 µM. The most potent inhibitors were DRI-2 (IC50 = 8.8 µM) and DRI-3 (IC50 = 2.1 µM) and have an acceptable profile of cytotoxicity (CC50 > 90 µM). Therefore, these compounds could be good candidates for further SARS-CoV-2 preclinical experiments. [ABSTRACT FROM AUTHOR]

An intensive care unit (ICU) is a special ward in the hospital for patients who require intensive care. It is equipped with many instruments monitoring patients' vital signs and supported by the medical staff. However, continuous monitoring demands a massive workload of medical care. To ease the burden, we aim to develop an automatic detection model to monitor when brain anomalies occur. In this study, we focus on electroencephalography (EEG), which monitors the brain electroactivity of patients continuously. It is mainly for the diagnosis of brain malfunction. We propose the gated-recurrent-unit-based (GRU-based) model for detecting brain anomalies; it predicts whether the spike or sharp wave happens within a short time window. Based on the banana montage setting, the proposed model exploits characteristics of multiple channels simultaneously to detect anomalies. It is trained, validated, and tested on separated EEG data and achieves more than 90% testing performance on sensitivity, specificity, and balanced accuracy. The proposed anomaly detection model detects the existence of a spike or sharp wave precisely; it will notify the ICU medical staff, who can provide immediate follow-up treatment. Consequently, it can reduce the medical workload in the ICU significantly. [ABSTRACT FROM AUTHOR]

Globally, over 772 million cases of COVID-19 have been reported. New variants of interest with corresponding spikes in case numbers continue to be identified. Vulnerable patients, including older adults or patients with severe comorbidities, continue to be at risk. A large body of evidence has been accumulated regarding anti-SARS-CoV-2-antibodies and COVID-19 but the usefulness of antibody measurements remains unclear. This systematic review aims to assess the prognostic value of anti-SARS-CoV-2-antibodies and their usefulness for guiding booster vaccinations. Studies in English and published between January 2020 and October 2023 were included. Studies that relied on multiparameter-models or comprised fewer than 100 participants were excluded. PubMed and via the WHO COVID-19 research database, Embase and Medline databases were searched. Study selection and quality assessment was conducted independently by two researchers. After screening 1,160 studies, 33 studies comprising >30 million individuals were included. Anti-SARS-CoV-2-antibodies were strongly associated with reduced risk of SARS-CoV-2-infection and better outcomes, including mortality. Risk of infection and COVID-19 severity decreased with increasing antibody levels. Anti-SARS-CoV-2-antibodies are useful for early identification of high-risk patients and timely adjustment of therapy. Protective thresholds may be applied to advise booster vaccinations but verification in separate cohorts is required. [ABSTRACT FROM AUTHOR]

The evolution of severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has continued, enabling the virus to escape from host immunity by changing its spike antigen, while biased toward the receptor-binding domain and N-terminal domain. Here, we isolated a novel pan-SARS-CoV-2 neutralizing antibody (which we named MO11) for even the recent dominators XBB.1.16 and EG.5.1, from a convalescent patient who had received three doses of an original mRNA COVID-19 vaccination. A cryo-electron microscopy analysis of the spike-MO11 complex at 2.3 Å atomic resolution revealed that it recognizes a conserved epitope hidden behind a glycan shield at N331 on subdomain 1 (SD1), holding both the N- and C-terminal segments comprising SD1. Our identification of MO11 unveiled the functional importance of SD1 for the spike's function, and we discuss the potential availability of a novel common epitope among the SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

The aim of the study was to highlight morpho-physiological changes like plant height, spike characteristics and stomata features in wheat induced by salt stress. Seeds of wheat var. Alex were sown, in mezo-phyto-cosmos, in five repetitions, under six saline doses, 0, 15, 30, 45, 60, and 75 mM NaCl. The experiment was conducted under field conditions. The assessments including plant height, arista, and spike length were taken and evaluated at the end of the experiment. Adaxial stomatal imprints have been sampled and the stomata density (number of stomata/mm2) and their size were assessed under the microscope. Wheat morphological parameters were affected by the highest salinity dose. Plant height was significantly reduced in the 60 and 75 mM NaCl doses by 16% and 20%. The spike length showed a significant reduction only in the highest saline dose treatment. Arista length registered the highest value in the 15 mM NaCl treatment with 23% more compared to the control. Stomata density reported the highest value in the 15 mM NaCl treatment, significantly higher compared to the 0 mM NaCl dose. The highest salinity doses significantly reduced plant height and spike length. Arista length and stomata density showed similar patterns. [ABSTRACT FROM AUTHOR]

Salinity stress has effects on plants as harmful as those caused by drought. This research aim was to evaluate the changes in wheat total chlorophyll content estimation under salinity stress. The experiment was set up on October 15, 2022, by sowing wheat seeds var. Alex in field conditions, in mezo-phyto-cosmos, under six treatments, 0, 15, 30, 45, 60, and 75 mM NaCl. The total chlorophyll content estimation of leaves, flag leaves, and spikes was measured with a chlorophyll meter. The assessments were taken periodically for leaf greenness during in (Biologische Bundesanstalt, Bundessortenamt und CHemische Industrie) BBCH 11, 14, 51 and at the end of the experiment for flag leaves and spikes greenness. The highest values for leaves total chlorophyll were registered at all treatments except 75 mM NaCl at the fourth evaluation. For flag leaves chlorophyll content, measured at the end of the experiment, the highest value was registered in the control treatment, significantly higher compared to the 15, 45, 60, and 75 mM NaCl by 38%, 86%, 88%, and 91%. The spike chlorophyll content showed no significant differences between all the treatments. Higher doses of saline treatment significantly affect the leaves chlorophyll content, decrease the flag leaf, and spike greenness. [ABSTRACT FROM AUTHOR]

Ad26.COV2.S vaccination can lead to vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare but severe adverse effect, characterized by thrombocytopenia and thrombosis. The mechanism of VITT induction is unclear and likely multifactorial, potentially including the activation of platelets and endothelial cells mediated by the vaccine-encoded spike protein (S protein). Here, we investigated the biodistribution of the S protein after Ad26.COV2.S dosing in three animal models and in human serum samples. The S protein was transiently present in draining lymph nodes of rabbits after Ad26.COV2.S dosing. The S protein was detected in the serum in all species from 1 day to 21 days after vaccination with Ad26.COV2.S, but it was not detected in platelets, the endothelium lining the blood vessels, or other organs. The S protein S1 and S2 subunits were detected at different ratios and magnitudes after Ad26.COV2.S or COVID-19 mRNA vaccine immunization. However, the S1/S2 ratio did not depend on the Ad26 platform, but on mutation of the furin cleavage site, suggesting that the S1/S2 ratio is not VITT related. Overall, our data suggest that the S-protein biodistribution and kinetics after Ad26.COV2.S dosing are likely not main contributors to the development of VITT, but other S-protein-specific parameters require further investigation. [ABSTRACT FROM AUTHOR]

Spike protein sequences in SARS-CoV-2 have been employed for vaccine epitopes, but many short constituent sequences (SCSs) in the spike protein are present in the human proteome, suggesting that some anti-spike antibodies induced by infection or vaccination may be autoantibodies against human proteins. To evaluate this possibility of "molecular mimicry" in silico and in vitro, we exhaustively identified common SCSs (cSCSs) found both in spike and human proteins bioinformatically. The commonality of SCSs between the two systems seemed to be coincidental, and only some cSCSs were likely to be relevant to potential self-epitopes based on three-dimensional information. Among three antibodies raised against cSCS-containing spike peptides, only the antibody against EPLDVL showed high affinity for the spike protein and reacted with an EPLDVL-containing peptide from the human unc-80 homolog protein. Western blot analysis revealed that this antibody also reacted with several human proteins expressed mainly in the small intestine, ovary, and stomach. Taken together, these results showed that most cSCSs are likely incapable of inducing autoantibodies but that at least EPLDVL functions as a self-epitope, suggesting a serious possibility of infection-induced or vaccine-induced autoantibodies in humans. High-risk cSCSs, including EPLDVL, should be excluded from vaccine epitopes to prevent potential autoimmune disorders. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 virus variants of concern (VOCs) have rapidly changed their transmissibility and pathogenicity primarily through mutations in the structural proteins. Herein, we present molecular details with dynamics of the ferritin nanocages stitched with synthetic chimeras displaying the Spike receptor binding domains (RBDs). Our findings demonstrated the potential usage of ferritin-based vaccines that may effectively inhibit viral entry by blocking the Spike–ACE2 network and may induce cross-protective antibody responses. Taking the nanocage constructs into consideration, we evaluated the effects of variants on the docked interface of the SARS-CoV-2 Spike RBD with the ACE2 (angiotensin-converting enzyme 2) host cell receptor and neutralizing antibodies (Abs). Investigating the VOCs revealed that most of the mutations reported a possibly reduced structural stability within the Spike RBD domain. Point mutations have moderate or no effect for VVH-72, CR3022, and S309 Abs when bound with the Spike RBD, whereas a significant effect was observed for B38, CB6, and m396 over the surface of the H-ferritin nanocage. In addition to providing useful therapeutic approaches against COVID-19 (coronavirus disease 2019), these structural details can also be used to fight future coronavirus outbreaks. [ABSTRACT FROM AUTHOR]

Antigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding domain of spike protein. In contrast, whether antigenic drift occurs in the S2 domain remains largely elusive. Here, we perform a deep mutational scanning experiment to identify S2 mutations that affect binding of SARS-CoV-2 spike to three S2 apex public antibodies. Our results indicate that spatially diverse mutations, including D950N and Q954H, which are observed in Delta and Omicron variants, respectively, weaken the binding of spike to these antibodies. Although S2 apex antibodies are known to be nonneutralizing, we show that they confer protection in vivo through Fc-mediated effector functions. Overall, this study indicates that the S2 domain of SARS-CoV-2 spike can undergo antigenic drift, which represents a potential challenge for the development of more universal coronavirus vaccines. [ABSTRACT FROM AUTHOR]

Booster doses of the SARS-CoV-2 vaccine have been recommended to improve and prolong immunity, address waning immunity over time, and contribute to the control of the COVID-19 pandemic. A heterologous booster vaccine strategy may offer advantages over a homologous approach. To compare the immunogenicity of two doses of BNT162b2 mRNA COVID-19 vaccine with a ChAdOx1-S booster dose, immunoglobulin G (IgG) anti-spike (anti-S) and anti-nucleocapsid (anti-N) antibody titers (Ab) were compared over 1 year and post-booster vaccination. Results showed that, at 3- to 9-month assessments in vaccinated subjects, an-ti-N Ab were undetectable in participants with no history of COVID-19. In contrast, anti-S Ab measurements were lower than those with COVID-19, and a decrease was observed during the 9 months of observation. After booster vaccination, no differences were found in anti-S between participants who reported a history of COVID-19 and those who did not. Anti-S levels were higher after booster vaccination measurement vs. at 9 months in participants with COVID-19 and without COVID-19, i.e., independent of an infection history. Vaccine administration elicited a response of higher anti-S IgG levels in those infected before vaccination, although levels decreased during the first nine months. IgG anti-N titers were higher in participants with a history of declared infection and who were asymptomatic. The ChAdOx1-S booster increased anti-S Ab levels in participants regardless of whether they had been infected or not to a significantly higher value than with the first two vaccines. These findings underscore the importance of booster vaccination in eliciting a robust and sustained immune response against COVID-19, regardless of the prior infection status. [ABSTRACT FROM AUTHOR]

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel porcine enteric coronavirus, and the broad interspecies infection of SADS-CoV poses a potential threat to human health. This study provides experimental evidence to dissect the roles of distinct domains within the SADS-CoV spike S1 subunit in cellular entry. Specifically, we expressed the S1 and its subdomains, S1A and S1B. Cell binding and invasion inhibition assays revealed a preference for the S1B subdomain in binding to the receptors on the cell surface, and this unknown receptor is not utilized by the porcine epidemic diarrhea virus. Nanoparticle display demonstrated hemagglutination of erythrocytes from pigs, humans, and mice, linking the S1A subdomain to the binding of sialic acid (Sia) involved in virus attachment. We successfully rescued GFP-labeled SADS-CoV (rSADS-GFP) from a recombinant cDNA clone to track viral infection. Antisera raised against S1, S1A, or S1B contained highly potent neutralizing antibodies, with anti-S1B showing better efficiency in neutralizing rSADS-GFP infection compared to anti-S1A. Furthermore, depletion of heparan sulfate (HS) by heparinase treatment or pre-incubation of rSADS-GFP with HS or constituent monosaccharides could inhibit SADS-CoV entry. Finally, we demonstrated that active furin cleavage of S glycoprotein and the presence of type II transmembrane serine protease (TMPRSS2) are essential for SADS-CoV infection. These combined observations suggest that the wide cell tropism of SADS-CoV may be related to the distribution of Sia or HS on the cell surface, whereas the S1B contains the main protein receptor binding site. Specific host proteases also play important roles in facilitating SADS-CoV entry. IMPORTANCE Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel pathogen infecting piglet, and its unique genetic evolution characteristics and broad species tropism suggest the potential for cross-species transmission. The virus enters cells through its spike (S) glycoprotein. In this study, we identify the receptor binding domain on the C-terminal part of the S1 subunit (S1B) of SADS-CoV, whereas the sugar-binding domain located at the S1 N-terminal part of S1 (S1A). Sialic acid, heparan sulfate, and specific host proteases play essential roles in viral attachment and entry. The dissection of SADS-CoV S1 subunit's functional domains and ident ification of cellular entry cofactors will help to explore the receptors used by SADS-CoV, which may contribute to exploring the mechanisms behind cross-species transmission and host tropism. [ABSTRACT FROM AUTHOR]

During the Covid-19 pandemic, the resurgence of SARS-CoV-2 was due to the development of novel variants of concern (VOC). Thus, genomic surveillance is essential to monitor continuing evolution of SARS-CoV-2 and to track the emergence of novel variants. In this study, we performed phylogenetic, mutation, and selection pressure analyses of the Spike, nsp12, nsp3, and nsp5 genes of SARS-CoV-2 isolates circulating in Yogyakarta and Central Java provinces, Indonesia from May 2021 to February 2022. Various bioinformatics tools were employed to investigate the evolutionary dynamics of distinct SARS-CoV-2 isolates. During the study period, 213 and 139 isolates of Omicron and Delta variants were identified, respectively. Particularly in the Spike gene, mutations were significantly more abundant in Omicron than in Delta variants. Consistently, in all of four genes studied, the substitution rates of Omicron were higher than that of Delta variants, especially in the Spike and nsp12 genes. In addition, selective pressure analysis revealed several sites that were positively selected in particular genes, implying that these sites were functionally essential for virus evolution. In conclusion, our study demonstrated a distinct evolutionary pattern of SARS-CoV-2 variants circulating in Yogyakarta and Central Java provinces, Indonesia. [ABSTRACT FROM AUTHOR]

The emergence of new SARS-CoV-2 variants continues to cause challenging problems for the effective control of COVID-19. In this study, we tested the hypothesis of whether a strategy of multivalent and sequential heterologous spike protein vaccinations would induce a broader range and higher levels of neutralizing antibodies against SARS-CoV-2 variants and more effective protection than homologous spike protein vaccination in a mouse model. We determined spike-specific IgG, receptor-binding inhibition titers, and protective efficacy in the groups of mice that were vaccinated with multivalent recombinant spike proteins (Wuhan, Delta, Omicron), sequentially with heterologous spike protein variants, or with homologous spike proteins. Trivalent (Wuhan + Delta + Omicron) and sequential heterologous spike protein vaccinations were more effective in inducing serum inhibition activities of receptor binding to spike variants and virus neutralizing antibody titers than homologous spike protein vaccination. The higher efficacy of protection was observed in mice with trivalent and sequential heterologous spike protein vaccination after a challenge with a mouse-adapted SARS-CoV-2 MA10 strain compared to homologous spike protein vaccination. This study provides evidence that a strategy of multivalent and sequential heterologous variant spike vaccination might provide more effective protection against emerging SARS-CoV-2 variants than homologous spike vaccination and significantly alleviate severe inflammation due to COVID-19. [ABSTRACT FROM AUTHOR]

In this study, the penetration process of three kinds of spikes with different geometries has been investigated while penetrating in rib-knitted fabrics with different proportions of elastic yarn existence. Besides, the tensile behaviour of the fabrics including the breaking force, breaking elongation, work of rupture and tensile modulus of the samples have been measured and their relation to the resistance of the samples against the penetration performance of spikes were analysed. In this regard, the force, depth, and energy required for penetration have been estimated. In addition, the images of the damages caused by the penetration of spikes were compared, immediately and, after the passage of 24 h and 48 h. The obtained results indicate that the elasticity of the fabric as well as the geometry and point angle of the spike are effective on the penetration resistance. According to the outcomes, 55% increase in the presence of elastic yarn in the fabric structure has led to a growth in fabric's strength (approximately 21%) and a decrease in tensile modulus (about 15%). In addition, a sample with a higher tensile modulus had a higher penetration force and a lower penetration depth and energy. In addition, the geometry of the utilised spikes is an influential factor in the penetration performance and fabric resistance, including penetration force, penetration depth, and penetration energy. In case of about 38% diminish in the spike point angle, the resistance to penetration decreases around 40%. [ABSTRACT FROM AUTHOR]

Viral variants of concern continue to arise for SARS-CoV-2, potentially impacting both methods for detection and mechanisms of action. Here, we investigate the effect of an evolving spike positive charge in SARS-CoV-2 variants and subsequent interactions with heparan sulfate and the angiotensin converting enzyme 2 (ACE2) in the glycocalyx. We show that the positively charged Omicron variant evolved enhanced binding rates to the negatively charged glycocalyx. Moreover, we discover that while the Omicron spike-ACE2 affinity is comparable to that of the Delta variant, the Omicron spike interactions with heparan sulfate are significantly enhanced, giving rise to a ternary complex of spike-heparan sulfate-ACE2 with a large proportion of double-bound and triple-bound ACE2. Our findings suggest that SARS-CoV-2 variants evolve to be more dependent on heparan sulfate in viral attachment and infection. This discovery enables us to engineer a second-generation lateral-flow test strip that harnesses both heparin and ACE2 to reliably detect all variants of concern, including Omicron.

ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic caused the biggest public health crises in recent history. Many expect future coronavirus introductions into the human population. Hence, it is essential to understand the basic biology of these viruses. In natural infection, the SARS-CoV-2 Spike (S) glycoprotein is co-expressed with all other viral proteins, which modify cellular compartments to maximize virion assembly. By comparison, most of S is degraded when the protein is expressed in isolation, as in current molecular vaccines. To probe the maturation pathway of S, we redirected its maturation by fusing S to the tetraspanin protein CD81. CD81 is a defining constituent of extracellular vesicles (EVs) or exosomes. EVs are generated in large numbers by all cells, extruded into blood and lymph, and transfer cargo between cells and systemically (estimated 1012 EVs per mL plasma). EVs, like platelets, can be transfused between unrelated donors. When fusing the proline-stabilized form of strain Delta S into the flexible, large extracellular loop of CD81 rather than being degraded in the lysosome, S was extruded into EVs. CD81-S fusion containing EVs were produced in large numbers and could be isolated to high purity. Purified CD81::S EVs bound ACE2, and S displayed on individual EV was observed by cryogenic electron microscopy (EM). The CD81::S-fusion EVs were non-toxic and elicited an anti-S trimer and anti-RBD antibody response in mice. This report shows a design path to maximize viral glycoprotein assembly and release without relying on the co-expression of potentially pathogenic nonstructural viral proteins.IMPORTANCEThe severe acute respiratory syndrome coronavirus 2 pandemic caused the biggest public health crises in recent history. To understand the maturation pathway of S, we fused S to the tetraspanin protein CD81. The resulting molecule is secreted in extracellular vesicles and induces antibodies in mice. This may be a general design path for viral glycoprotein vaccines.

ABSTRACT Numerous host factors, in addition to human angiotensin-converting enzyme 2 (hACE2), have been identified as coreceptors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and diversified druggable potential. We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor. Multiple inhibition assays revealed that antihistamine drugs broadly inhibited the infection of various SARS-CoV-2 mutants with an average IC50 of 2.4 µM. The prophylactic function of these drugs was further confirmed by authentic SARS-CoV-2 infection assays and humanized mouse challenge experiments, demonstrating the therapeutic potential of antihistamine drugs for combating coronavirus disease 19.IMPORTANCEIn addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.

SARS-CoV-2 viral-derived particles have been proposed to have a causal role in tissue inflammation. Macrophage is the culprit cell in the pathogenesis of destructive inflammatory response to the SARS-CoV-2 virus. We investigated whether the spike protein might play a role in perturbing the physiological process of resolution of inflammation. Using an in vitro model of M2 polarized macrophages, we found that recombinant spike protein produced typical M1 morphological features in these alternative differentiated cells. In the presence of spike, M2-macrophages lose their elongated morphology, become rounded and acquire a strong capability to stimulate lymphocyte activation and proliferation. Moreover, in M2 macrophages, spike activated the signal transducer and activator-1 (STAT1) the pivotal mediator of pro-inflammatory macrophages. We observed STAT1 activation also in endothelial cells cultured with recombinant spike, accompanied by Bax upregulation and cell death. Blockade of beta3 integrin with the RGD mimetic tirofiban reverted the spike-induced costimulatory effects on M2 macrophages. Also, tirofiban counteracted STAT1 and Bax activation in endothelial cells cultured with spike and reduced endothelial cell death. In conclusion, we found that some proinflammatory effects of the spike protein can involve the integrin pathway and provide elements supporting use of RGD mimetics against SARS-Cov-2.

IntroductionComplex neuronal interactions underlie cortical information processing that can be compromised in altered states of consciousness. Here intracortical microstimulation was applied to investigate anesthetic state-dependent effective connectivity of neurons in rat visual cortex in vivo.MethodsExtracellular activity was recorded at 32 sites in layers 5/6 while stimulating with charge-balanced discrete pulses at each electrode in random order. The same stimulation pattern was applied at three levels of anesthesia with desflurane and in wakefulness. Spikes were sorted and classified by their waveform features as putative excitatory and inhibitory neurons. Network motifs were identified in graphs of effective connectivity constructed from monosynaptic cross-correlograms.ResultsMicrostimulation caused early (

The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with stabilized Spike ectodomain. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high-affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high-affinity (0.53-4.2 nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron and Delta pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

Effective deduction of air heating load and drag is a critical issue in hypersonic vehicle engineering applications. In this research, seven various geometrical models have been proposed to study and compare the effect of each configuration on the flow field, drag, and aerodynamic heating deduction under the same flow conditions. The presented configurations in this study: (a) blunt-body geometry as a reference of comparison, (b) blunt-body geometry with a spike, (c) blunt-body geometry with an counter flow jet, (d) blunt-body geometry with a spike and counter flow jet, (e) blunt-body geometry with a spike and aerodisk, (f) blunt-body geometry with a spike, aerodisk, and root counter flow jet, (g) blunt-body geometry with a spike, four aerodisks and root counter flow jet. The Reynolds-Averaged equations have been solved using the Finite Volume Method (FVM) along with the shear stress turbulence model (k-ω SST). The flow is assumed compressible, steady-state, and axisymmetric with a free stream Mach number of 6. According to the study of each configuration’s performance related to the parameters of drag, maximum pressure, and maximum heat flux factors on the blunt-body walls, (g) configuration with a drag factor of 0.2699, maximum pressure factor of 209.8, and maximum heat flux factor of 25.1, has the most deduction on the blunt-body walls among the seven configurations. The deduction percentage of drag, maximum pressure, and maximum heat flux factors of (g) configuration to (a) configuration are %72.1, %94.5, and %79.9, respectively, which significantly diminished drag and heat flux. Also, the best configuration scenarios for drag and aerodynamic heating deduction are geometrical models of g, f, d, e, c, b, and a, respectively.