Search Results (271)

We develop a collection of nontrivial examples that illustrate and test recent stability results for linear control systems ($LCS$) on Lie groups. We treat the main structural classes: Abelian (${\mathbb{R}}^n$), nilpotent (Heisenberg), solvable non-nilpotent (rigid motions of the plane $SE\left(2\right)$), compact semisimple ($SO\left(3\right)$), noncompact semisimple ($SL(2,\mathbb{R})$ via Iwasawa decomposition) and mixed/Levi-type groups. The examples are designed to (i) show the sharpness of geometric boundedness criteria, (ii) exhibit typical failure modes (exponential escape, polynomial central drift, noncompact neutrals), and (iii) demonstrate how the canonical quotient and suitable outputs recover $BIBO$ stability. The executive framework ($ICS$ existence/uniqueness, canonical quotient $G/\Gamma$, $BIBO$ characterization, robustness and ISS-type bounds) is briefly recalled; the main part of the paper consists of detailed worked examples implementing the practical checklist for applying these theorems. Full article

Background: Monoclonal antibodies (mAbs) initially played a major role in outpatient COVID-19 management by providing rapid passive immunity and reducing progression to severe disease. However, continuous SARS-CoV-2 evolution progressively compromised the effectiveness of several anti-spike products. This narrative review summarizes the trajectory of COVID-19 mAbs across three phases: early clinical efficacy, loss of efficacy due to immune escape, and future directions. Methods: We conducted a narrative review focusing on mechanisms of action, pivotal clinical trials, and real-world effectiveness of neutralizing anti-spike mAbs and host-directed immunomodulatory mAbs. Emphasis was placed on the impact of variants—especially Omicron—on susceptibility and clinical use, as well as on emerging next-generation platforms. Results: First-generation neutralizing mAbs substantially reduced the hospitalization rates during the Alpha and Delta waves, while immunomodulatory mAbs became standard options for the hyperinflammatory phase in hospitalized patients. With the emergence of Omicron and its sub-lineages, extensive immune escape led to marked reductions in neutralization for many earlier anti-spike agents and consequent restrictions in use. Later-generation approaches targeting more conserved epitopes provided temporary solutions but were also challenged by ongoing antigenic drift. Host-directed immunomodulators retained clinical relevance because their mechanism is independent of viral spike mutations. Conclusions: The clinical role of monoclonal antibodies in COVID-19 has been dynamic and increasingly constrained by viral evolution. Future strategies should prioritize broadly neutralizing antibodies targeting conserved epitopes, innovative delivery platforms, and integration with real-time surveillance to preserve clinical utility in the endemic phase and improve preparedness for future outbreaks. Full article

Background: Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen that has caused repeated epidemics across Africa and the Arabian Peninsula, posing a severe and growing threat to public health and livestock. Infection in ruminants causes high neonatal mortality and catastrophic abortion storms; human disease ranges from self-limiting febrile illness to hemorrhagic fever, encephalitis, and permanent blindness. No licensed human vaccines or specific antiviral therapeutics are available, creating an urgent unmet medical need. Methods: We systematically reviewed the peer-reviewed literature on RVFV neutralizing antibodies (NAbs), extracting and synthesizing data on antibody sources, epitope specificity, in vitro neutralizing potency, in vivo protective efficacy, and molecular mechanisms of action. Results: A growing body of work has identified potent NAbs from immunized rodents, rabbits, alpacas, non-human primates, and convalescent patients. These NAbs predominantly target the Gn and Gc envelope glycoproteins. Their mechanisms include blocking host receptor (LRP1) binding, preventing the pH-dependent conformational rearrangement of the Gn–Gc complex, and directly inhibiting viral membrane fusion. Lead candidates, such as RVFV-268 and RVFV-140, achieve sub-nanogram neutralization and confer robust protection in rodent models against lethal challenge, aerosol exposure, and vertical transmission. Bispecific antibodies and combination strategies further enhance potency and the genetic barrier to viral escape. Conclusions: Substantial progress has illuminated the epitope landscape and neutralization mechanisms of RVFV, yielding promising clinical candidates. Translational challenges remain, including viral immune escape, antibody thermostability, and the need for rigorous preclinical evaluation. Future efforts should prioritize structure-guided engineering, rational antibody combinations, and testing in clinically predictive animal models. Full article

The continued evolution of SARS-CoV-2 has enabled an escape from most monoclonal antibodies, yet a subset of broadly neutralizing antibodies targeting three newly identified super-conserved RBD epitopes—SCORE-A, SCORE-B, and SCORE-C—retains remarkable activity against even the most recent JN.1-derived sublineages. Here, we employed an integrated computational framework combining conformational dynamics, mutational scanning, MM-GBSA binding energetics, and frustration profiling to dissect the molecular mechanisms by which XGI antibodies achieve broad neutralization and resistance to immune escape. Structural analysis revealed that all three SCORE epitopes share a common architecture: a highly conserved, minimally frustrated core that provides stable anchoring, flanked by peripheral regions that accommodate antibody-specific variations. Conformational dynamics showed that SCORE-A antibodies (XGI-183) rigidify the lateral epitope while leaving the RBM partially mobile; SCORE-B antibodies (XGI-198, XGI-203) clamp the RBM apex, directly blocking ACE2; and SCORE-C antibodies (XGI-171) allosterically loosen the RBM loop, impairing receptor engagement indirectly. Mutational scanning identified a hierarchical hotspot organization where primary hotspots (e.g., K356, T500, Y380, T385) are evolutionarily constrained and minimally frustrated, while secondary hotspots (e.g., V503, Y508, S383) are neutrally frustrated and represent the principal sites of immune-driven mutations. MM-GBSA decomposition revealed that van der Waals-driven hydrophobic packing dominates binding, with electrostatic interactions providing auxiliary stabilization. Critically, frustration analysis demonstrated that immune escape hotspots reside precisely in zones of neutral frustration—“energetic playgrounds” that permit mutational exploration without destabilizing the RBD—while minimally frustrated cores are evolutionarily locked. The comparative analysis of conformational versus mutational frustration distributions revealed a unifying principle: aligned neutral frustration yields permissive, escape-prone interfaces; decoupling enables the targeting of constrained cores; and the convergence of minimal frustration in both distributions creates invulnerable interfaces. These findings establish that broad neutralization arises not from ultra-high-affinity anchors but from strategic energy distribution across rigid, evolutionarily informed interfaces, providing a roadmap for designing next-generation therapeutics that target the invulnerable cores of viral surface proteins. Full article

Despite prolonged viral inhibition with combination antiretroviral therapy (ART), HIV-1 survives as genetically intact, replication-capable proviruses within durable CD4+ T-cell fractions, involving central memory, transitional memory, and stem cell-like memory populations, as well as within tissue-resident compartments including lymphoid follicles and gut-associated lymphoid tissue. Reservoir stability is preserved via clonal growth of infected cells and epigenetic processes that impose proviral transcriptional silencing. As a result, current therapeutic approaches seek to either directly alter proviral survival or to improve immune-driven elimination of infected cells. At the molecular level, investigational strategies such as CRISPR–Cas9 and CRISPR–Cas12 gene-editing systems are intended to remove or induce inactivating mutations inside embedded proviral DNA, as well as alter host entrance co-receptors such as CCR5 to provide cellular resistance to infection. In addition, pharmacologic latency regulation is being studied via histone deacetylase inhibitors, protein kinase C agonists, and bromodomain inhibitors to reverse latency, along with Tat inhibitors and other transcriptional repressors aimed to persistently silence proviral expression. Moreover, immunological techniques aim to counteract inefficient endogenous antiviral defenses. Broadly neutralizing antibodies with tailored Fc-driven effector functions are under examination for both neutralization and antibody-dependent cellular cytotoxicity. Therapeutic vaccine approaches seek to elevate polyfunctional HIV-specific CD8+ T-cell responses, while adoptive cellular approaches, involving CAR-T cells aiming HIV envelope epitopes, remain in early clinical research. Immune checkpoint blockade is also being investigated to reverse T-cell depletion inside reservoir-rich tissues. Nevertheless, the key obstacles continue to be the diverse reservoir composition, restricted tissue penetration, viral escape, and safety limitations. The molecular and translational obstacles that characterize attempts toward an HIV cure must be addressed through ongoing multidisciplinary research. Full article

Background: People living with HIV (PLWH) constitute a vulnerable population during the COVID-19 pandemic; however, it remains uncertain whether long-term suppressive antiretroviral therapy (ART) restores sufficient immune competence to support robust hybrid immunity. While vaccination followed by breakthrough infection—termed hybrid immunity—typically elicits potent humoral responses in immunocompetent individuals, the functional quality and breadth of these responses against evolving Omicron subvariants remain poorly characterized in PLWH. This study aimed to assess functional antibody responses, including neutralizing activity and Fc effector functions, in vaccinated and unvaccinated PLWH who experienced breakthrough infection with Omicron subvariants BA.4/5 or BF.7. Methods: We enrolled three cohorts between December 5 and December 20, 2022: 25 HIV-negative individuals with breakthrough infection (BTI-HC), 20 ART-experienced PLWH with breakthrough infection following three-dose COVID-19 vaccination (BTI-HIV), and 10 ART-experienced PLWH with primary infection without prior vaccination (PI-HIV). All HIV-positive participants were receiving suppressive ART with regimens based on non-nucleoside reverse transcriptase inhibitors or integrase strand transfer inhibitors for a median of 3.4 years. We measured receptor-binding domain (RBD)-specific IgG, neutralizing antibody titers against ancestral D614G, Delta, BA.1, BA.4/5, BF.7, XDV, KP.2, and KP.3 variants, and antibody-dependent cellular cytotoxicity (ADCC) responses. Results: Despite lower absolute CD4⁺ T cell counts, BTI-HIV participants mounted RBD-binding IgG, neutralizing antibody, and ADCC responses that were comparable to BTI-HC and significantly exceeded PI-HIV across all tested variants. Both breakthrough infection cohorts exhibited immunological imprinting, with higher neutralizing titers against ancestral D614G than infecting BA.4/5 or BF.7 variants. Emerging variants XDV, KP.2, and KP.3 demonstrated substantial neutralization escape in all groups. PI-HIV showed markedly diminished neutralization breadth and failed to generate enough responses against all tested Omicron strains. Conclusions: Suppressive ART enables PLWH to mount hybrid immunity—conferred by vaccination followed by BF.7 or BA.4/5 breakthrough infection—with neutralizing and ADCC responses comparable to HIV-negative individuals, and significantly exceeding those of unvaccinated PLWH with primary infection. This underscores the critical role of vaccination in establishing effective hybrid immunity in this population. However, we observed immunological imprinting, with higher titers against ancestral strains than against infecting variants, and substantial escape by emerging sublineages XDV, KP.2, and KP.3 across all groups. These findings support prioritizing updated variant-containing vaccines for HIV-positive populations and reinforce the essential role of vaccination in this vulnerable group. Full article

Cosmological filaments, galaxy clusters, and galaxies are magnetized reservoirs of cosmic rays (CRs). The exchange of CRs across these structures is usually modeled assuming that they remain charged and magnetically confined. At high energies, hadronic interactions can convert CR protons to neutrons. This physics is routinely included in air-shower and ultra-high-energy (UHE) CR propagation Monte Carlo simulations used for composition studies but is rarely treated explicitly in propagation models of CR transport and exchange between magnetized reservoirs. CR neutrons are not affected by magnetic fields and can propagate ballistically over kpc-Mpc distances before decaying back into protons, with relativistic time dilation extending their effective decay length. We show how such charged–neutral switching modifies CR confinement and escape in four representative environments: a Milky Way-like galaxy, a starburst galaxy, a galaxy cluster, and a cosmological filament. By solving the transport of a confined CR proton population in each structure using a diffusion/streaming propagation approach with hadronic pp and p$\gamma$ interactions, and treating neutron production and decay as a stochastic Poisson “jump” process, we find that neutron-mediated steps can allow additional CR escape from large-scale cosmological structures at energies where charged-particle transport alone would predict strong CR confinement and attenuation in ambient radiation fields. These effects imply a qualitative shift in how ultra-high-energy CRs are transferred from embedded sources into filaments and voids once intermediate neutron propagation is considered, with consequences for the partitioning of CRs across the large-scale structure of the Universe. Full article

Background: The H1N1 influenza A virus evades host immunity through continuous antigenic drift, posing a significant challenge to broad-spectrum neutralizing antibody therapies. This study aims to systematically evaluate the neutralizing capacity of the broad-spectrum antibody C12H5 against H1N1 strains from different eras and identify key immune escape mutation sites. Methods: Three representative H1N1 virus strains from 2009, 2018, and 2023 were selected. An antigen–antibody binding prediction model based on the ESM-2 large language model was constructed by integrating 48,762 GISAID sequence data and deep mutation scanning data from the Bloom laboratory. Candidate escape sites were screened using SHAP (SHapley Additive exPlanations) value analysis. Mutant viruses were constructed via reverse genetics, and their neutralizing capacity and replication fitness were validated through hemagglutination inhibition assays, microneutralization assays, and viral growth kinetics analysis. Results: Machine learning scoring identified five potential escape sites, with K147 exhibiting the highest overall score (0.92). SHAP analysis revealed that the K147 site within the HA protein’s 130-loop region received the highest importance score (0.28), significantly surpassing other candidate sites. Experimental validation revealed that the K147N mutation reduced neutralizing potency against C12H5 by 8-fold (from 1:1024 to 1:128) and approximately 6-fold in microneutralization assays (from 8.3 log₂ to 5.7 log₂), while exhibiting a replication advantage in MDCK cells. Microneutralization assays further confirmed an approximately 6-fold reduction in neutralization sensitivity. Structural analysis indicated that K147 is located at the periphery of the HA receptor-binding domain, immediately adjacent to the receptor-binding site. Conclusions: K147N is identified as the critical mutation mediating C12H5 immune escape, and this mutation has emerged in 2023 circulating strains. This study provides important molecular targets and early warning mechanisms for broad-spectrum antibody optimization and influenza vaccine updates. Full article

SARS-CoV-2, which causes COVID-19, continues to circulate around the world, making it necessary to study the impact of rapidly emerging mutations on escape from neutralizing antibodies and pathogenesis. While RBD mutations are well characterized, mutations in the N-terminal domain (NTD) of the spike protein remain comparatively understudied despite their relevance to antibody recognition. This study investigates two phenotypically distinct SARS-CoV-2 mutants, which exhibited differences in plaque morphology on Vero cells. Whole-genome sequencing via Illumina identified a novel 12-nucleotide insertion in the spike NTD. This insertion induced a frameshift, introducing five new amino acids potentially altering viral behavior, receptor interactions, and antibody detection in ELISAs. The study further explores the pathogenicity of these variants in a hamster model. These findings underscore the importance of monitoring NTD mutations, which may contribute to immune evasion and influence therapeutic antibody efficacy, highlighting gaps in current research on SARS-CoV-2 evolution. Full article

Socialisation with humans and willingness to interact with them are essential traits for animals involved in animal-assisted services (AAS). This study examined whether goats without prior intensive socialisation with humans may show predispositions to AAS in terms of sociability towards people. Ten goats underwent four tests: (1) acceptance of human approach and touch, voluntary approach to (2) a passive and (3) an active human, and (4) a novel sound fear test. Tests 1–3 were conducted with the caretaker and a familiar neutral person, and 4 with the neutral person. The goats generally accepted being approached and touched but showed little interest in interacting voluntarily with humans. Goats’ responses did not differ between the caretaker and the neutral person (p > 0.05). In the fear test, goats escaped less often and returned more quickly after the sound playback when a human was present (p < 0.01). Female goats exhibited higher sociability towards humans. Overall, the goats demonstrated some predispositions to AAS, such as tolerance of human contact and a tendency to perceive humans as a source of support during stress. However, these traits alone are insufficient for participation in AAS. Additional training is needed to increase the goats’ willingness to initiate interactions with people. Full article

Background/Objective: Infectious bursal disease (IBD) is an acute and highly contagious immunosuppressive disease in chickens caused by infectious bursal disease virus (IBDV). In recent years, a novel variant IBDV (nVarIBDV) has emerged and spread widely, inducing severe immunosuppression and posing a substantial threat to the poultry industry. More importantly, owing to antigenic variations, nVarIBDV can escape the immune protection of the existing vaccines. Therefore, it is imperative to develop a new vaccine that is antigenically matched to nVarIBDV. Methods: The major protective antigen gene VP2 of the representative nVarIBDV strain SHG19 was inserted into the eukaryotic expression plasmid pCAGGS to construct the recombinant plasmid pCASHGVP2. Subsequently, pCASHGVP2 was encapsulated in lipid nanoparticles (LNPs) to form pCASHGVP2-LNP nanoparticles. Finally, using the SPF chicken model, the immune efficacy of pCASHGVP2-LNP was preliminarily assessed by administering two vaccine doses (10 and 20 μg) and two immunization regimens (single or double immunization). Results: Efficient VP2 protein expression from pCASHGVP2 was confirmed by in vitro transfection experiments. The prepared pCASHGVP2-LNP nanoparticles exhibited an optimal particle size distribution and acceptable polydispersity index, indicating a homogeneous formulation. Furthermore, animal experiments showed that the candidate DNA vaccine elicited specific neutralizing antibodies after double immunization and protected immunized chickens from disease induced by nVarIBDV challenge. Conclusions: This study reports the first development of an LNP-encapsulated VP2 DNA vaccine (pCASHGVP2-LNP) against nVarIBDV, highlighting its potential application for the prevention of nVarIBDV. Full article

The accelerated carbonation of fresh concrete and recycled aggregates is one of the safest methods of CO₂ sequestration as it mineralizes CO₂, preventing its escape into the atmosphere. CO₂ injection during batching of concrete improves its strength and may partially replace Portland cement, as with supplementary cementitious materials (SCMs). The curing of concrete by incorporation of CO₂ also accelerates early strength development, which may enable early stripping of formwork/moulds for precast and in situ construction. The carbonation process may also be used for the beneficiation of recycled aggregates sourced from demolition waste. The CO₂ mineralization technique may also be used for producing low-carbon, carbon-neutral, or carbon-negative concrete constituents via the carbonation of mineral feedstock, including industrial wastes like steel slag, mine tailings, or raw quarried minerals. This research paper analyses various available technologies for CO₂ storage in concrete, CO₂ curing and mixing of concrete, and CO₂ injection for improving the properties of recycled aggregates. Carbon dioxide can be incorporated into concrete both through reaction with hydrating cement and through incorporation in recycled aggregates, giving a product of similar properties to concrete made from virgin materials. In this contribution we explore the various methodologies available to incorporate CO₂ in both hydrating cement and recycled aggregates and develop a protocol for best practice. We find that the loss of concrete strength due to the incorporation of recycled aggregates can be mitigated by CO₂ curing of the aggregates and the hydrating concrete, giving no negative strength consequences and sequestering around 30 kg of CO₂ per cubic metre of concrete. Full article

Background/Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global COVID-19 pandemic, which led to hundreds of millions of human infections and more than seven million deaths worldwide. Major variants of concern, particularly the Omicron variant and its associated subvariants, can escape the vaccines developed so far to target previous strains/subvariants. Therefore, effective vaccines that broadly neutralize different Omicron subvariants and show good protective efficacy are needed to prevent further spread of Omicron. The spike (S) protein, including its receptor-binding domain (RBD), is a key vaccine target. Methods: Here, we designed a unique mRNA vaccine encoding Omicron-KP.3 RBD based on RBD-truncated S protein backbone of an earlier Omicron subvariant EG.5 (KP3 mRNA), and evaluated its stability, immunogenicity, neutralizing activity, and protective efficacy in a mouse model. Results: Our data showed that the nucleoside-modified, lipid nanoparticle-encapsulated mRNA vaccine was stable at various temperatures during the period of detection. In addition, the vaccine elicited potent antibody responses with broadly neutralizing activity against multiple Omicron subvariants, including KP.2, KP.3, XEC, and NB.1.8.1. This mRNA vaccine protected immunized transgenic mice from challenge with SARS-CoV-2 Omicron-KP.3. Immune serum also protected against subsequent virus challenge, with the level of protection associating positively with the serum neutralizing antibody titer. Conclusions: Taken together, the data presented herein suggest that this newly designed mRNA vaccine has potential against current and future Omicron subvariants. Full article

Because antigenic drift primarily generates amino-acid changes in the membrane-distal hemagglutinin (HA) head, broadly neutralizing antibodies (bNAbs) are being developed to target conserved epitopes in the membrane-proximal stem. Mutations to HA2 residue A44, a buried residue beneath the central stem epitope, in 2009 H1N1 viruses have been shown to cause resistance to stem-binding bNAbs. Here, we introduced A44V and A44T mutations into A/Tennessee/1-560/2009 (TN09) and A/Puerto Rico/15/2018 (PR18) and investigated their effects in cell culture, mice, and ferrets. In both virus strains, the mutations decreased HA and virus stability and decreased bNAb binding and neutralization in vitro. The mutations reduced pathogenicity and lung replication in DBA/2J mice. Ferrets were inoculated with PR18 wild-type (WT) or A44V virus, and the A44V mutation reduced day-1 and peak nasal virus titers. Airborne transmission in the A44V group occurred only after genotypic reversion (HA2-V44A) or acquisition of a distal re-stabilizing mutation (HA2-I77M). Compared to WT, an engineered PR18 virus containing both HA2 mutations (A44V and I77M) had similar growth and pathogenicity in mice in addition to decreased binding and neutralization by bNAbs. Overall, this work provides insight into the role of HA stability during HA stem-epitope remodeling that results in virus resistance to stem-binding bNAbs. Full article

Background/Objectives: The rise of immune escape variants of the SARS-CoV-2 virus has prompted the development of vaccines based on the variant’s spike antigen sequence. Since variant-specific SARS-CoV-2 vaccines are mostly administered as boosters to individuals previously vaccinated with reference (Ref.) strain-based vaccines, a better understanding of their immunogenicity in this context is essential. Protein subunit vaccines have a well-established track record of safety. Herein, we assessed the ability of variant-specific protein subunit vaccine formulations to boost pre-existing Ref. strain-specific immune responses compared to boosting with a Ref. strain-specific formulation in young and aged female Balb/c mice. Methods: Following a priming vaccination series with Ref. spike protein adjuvanted with sulfated lactosyl archaeol (SLA) archaeosomes on days 0 and 21, immune responses were evaluated in young and aged female Balb/c mice. On day 91, mice received a third immunization with Ref., Beta, or Delta spike protein formulations, with or without SLA archaeosomes. Antibody titers, neutralization activity, and cellular immune responses were measured to assess the impact of the booster formulation. Results: Aged mice exhibited lower antibody titers throughout the study and a decline over time compared to young mice. After a third immunization, responses were boosted by all vaccine formulations (Ref., Beta, or Delta), with or without adjuvant. However, variant-specific antigen formulations did not overcome immune imprinting from the priming series or increase neutralization activity against the corresponding SARS-CoV-2 variants in either age group. Conclusions: Variant-specific protein subunit vaccines enhanced immune responses but did not overcome immune imprinting induced by the Ref. strain’s priming. The inclusion of SLA archaeosomes improved cellular immunity, supporting their potential role in optimizing booster vaccine performance, particularly in aged populations. Full article