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Zika virus (ZIKV) is a mosquito-borne flavivirus that has rapidly extended its geographic range around the world. Its association with abnormal fetal brain development, sexual transmission, and lack of a preventive vaccine have constituted a global health concern. Designing a safe and effective vaccine requires significant caution due to overlapping geographical distribution of ZIKV with dengue virus (DENV) and other flaviviruses, possibly resulting in more severe disease manifestations in flavivirus immune vaccinees such as Antibody-Dependent Enhancement (ADE, a phenomenon involved in pathogenesis of DENV, and a risk associated with ZIKV vaccines using the envelope proteins as immunogens). Here, we describe the development of an alternative vaccine strategy encompassing the expression of ZIKV non-structural-1 (NS1) protein from a clinically proven safe, Modified Vaccinia Ankara (MVA) vector, thus averting the potential risk of ADE associated with structural protein-based ZIKV vaccines. A single intramuscular immunization of immunocompetent mice with the MVA-ZIKV-NS1 vaccine candidate provided robust humoral and cellular responses, and afforded 100% protection against a lethal intracerebral dose of ZIKV (strain MR766). This is the first report of (i) a ZIKV vaccine based on the NS1 protein and (ii) single dose protection against ZIKV using an immunocompetent lethal mouse challenge model.

The immunologic consequences of using bactericidal versus bacteriostatic antibiotic treatments are unclear. We observed a bacteriostatic (growth halting) treatment was more protective than a bactericidal (bacteria killing) treatment in a murine peritonitis model. To understand this unexpected difference, we compared macrophage responses to bactericidal treated bacteria or bacteriostatic treated bacteria. We found that Gram-negative bacteria treated with bactericidal drugs induced more proinflammatory cytokines than those treated with bacteriostatic agents. Bacterial DNA – released only by bactericidal treatments – exacerbated inflammatory signaling through TLR9. Without TLR9 signaling, the in vivo efficacy of bactericidal drug treatment was rescued. This demonstrates that antibiotics can act in important ways distinct from bacterial inhibition: like causing treatment failure by releasing DNA that induces excessive inflammation. These data establish a novel link between how an antibiotic affects bacterial physiology and subsequent immune system engagement, which may be relevant for optimizing treatments to simultaneously clear bacteria and modulate inflammation. The immunologic differences induced by bactericidal versus bacteriostatic antibiotics remain unclear. Gross et al. show that, in contrast to static antibiotics, cidal antibiotics may drive harmful inflammation in acute infection via increased DNA release which stimulates TLR9 in mice.

Radio observations from normal pulsars indicate that the coherent radio emission is excited by curvature radiation from charge bunches. In this review, we provide a systematic description of the various observational constraints on the radio emission mechanism. We have discussed the presence of highly polarized time samples where the polarization position angle follow two orthogonal well-defined tracks across the profile that closely match the rotating vector model in an identical manner. The observations also show the presence of circular polarization, with both the right and left handed circular polarization seen across the profile. Other constraints on the emission mechanism are provided by the detailed measurements of the spectral index variation across the profile window, where the central part of the profile, corresponding to the core component, has a steeper spectrum than the surrounding cones. Finally, the detailed measurements of the subpulse drifting behaviour can be explained by considering the presence of non-dipolar field on the stellar surface and the formation of the partially screened gap (PSG) above the polar cap region. The PSG gives rise to a non-stationary plasma flow that has a multi-component nature, consisting of highly energetic primary particles, secondary pair plasma, and iron ions discharged from the surface, with large fragmentation resulting in dense plasma clouds and lower-density inter-cloud regions. The physical properties of the outflowing plasma and the observational constraints lead us to consider coherent curvature radiation as the most viable explanation for the emission mechanism in normal pulsars, where propagation effects due to adiabatic walking and refraction are largely inconsequential.

One of the key events in viral encephalitis is the ability of virus to enter the central nervous system (CNS). Several encephalitic viruses, including La Crosse Virus (LACV), primarily induce encephalitis in children, but not adults. This phenomenon is also observed in LACV mouse models, where the virus gains access to the CNS of weanling animals through vascular leakage of brain microvessels, likely through brain capillary endothelial cells (BCECs). To examine age and region-specific regulatory factors of vascular leakage, we used genome-wide transcriptomics and targeted siRNA screening to identify genes whose suppression affected viral pathogenesis in BCECs. Further analysis of two of these gene products, Connexin43 (Cx43/ Gja1 ) and EphrinA2 ( Efna2 ), showed a substantial effect on LACV pathogenesis. Induction of Cx43 by 4-phenylbutyric acid (4-PBA) inhibited neurological disease in weanling mice, while Efna2 deficiency increased disease in adult mice. Thus, we show that Efna2 and Cx43 expressed by BCECs are key mediators of LACV-induced neuroinvasion and neurological disease. La Crosse Virus predominantly causes encephalitis in children. Here, Basu et al. use transcriptomics and targeted siRNA screening to identify that age-dependent expression of EphrinA2 and Connexin43 by brain capillary endothelial cells is important for neuroinvasion.

The integration of supply chain theories and logistics is often given priority in agricultural studies, with a focus on retail firms. The study emphasizes how supply chain theories might be applied to agriculture to increase the productivity of food production. Takt time maintenance entails modifying production rates to satisfy customer requests, while cycle time and lead time increase productivity and shed light on inefficiencies. It also looks at how these techniques are used in Southeast Asian rice production, pointing out challenges like financial constraints and technological barriers to integrating technology into agricultural supply networks. Integrating production planning with lean principles in agriculture offers significant benefits, especially for developing countries facing climate, population, and food crises. Key strategies include optimizing resource use, reducing waste, standardizing processes, and improving supply chain coordination. These measures enhance agricultural efficiency, sustainability, and competitiveness, making them crucial for global and local supply chains. The research provides insights for policymakers, academics, and industry practitioners, addressing challenges like technological integration, financial constraints, and low automation in agricultural supply chains. It suggests remedies such as improved farmer training and financial support. The scope is limited by its reliance on Indian agri data, potentially limiting its broader applicability. Additionally, it does not compare lean principles with traditional agricultural methods, limiting insights into their relative effectiveness. The study emphasizes the need for better farmer training and financial subsidies.

Ebola virus (EBOV), isolate Makona, was the causative agent of the West African epidemic devastating predominantly Guinea, Liberia and Sierra Leone from 2013–2016. While several experimental vaccine and treatment approaches have been accelerated through human clinical trials, there is still no approved countermeasure available against this disease. Here, we report the construction and preclinical efficacy testing of a novel recombinant modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona glycoprotein GP and matrix protein VP40 (MVA-EBOV). GP and VP40 form EBOV-like particles and elicit protective immune responses. In this study, we report 100% protection against lethal EBOV infection in guinea pigs after prime/boost vaccination with MVA-EBOV. Furthermore, this MVA-EBOV protected macaques from lethal disease after a single dose or prime/boost vaccination. The vaccine elicited a variety of antibody responses to both antigens, including neutralizing antibodies and antibodies with antibody-dependent cellular cytotoxic activity specific for GP. This is the first report that a replication-deficient MVA vector can confer full protection against lethal EBOV challenge after a single dose vaccination in macaques.

Background A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. Methods To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. Results BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. Conclusions These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease.

The geographical regions contiguous to the Indian Ocean, Bay of Bengal and the Arabian Sea are prone to natural disasters and poor electric supply especially in rural and hard to reach coastal regions. Utilization of ocean resources for power generation such as tidal, thermal solar and wind for energy need to be incorporated in a broad framework for the region. Development of ocean-based energy systems can be integrated with early warning networks linked by satellite which can give a few hours to days warning to help mitigate the severity of natural disasters on human life. Ocean-based electricity extraction has; however, remained elusive for various reasons. Interest in these systems resumed after the oil crisis of the 1970's, but was uncoordinated. Extraction of ocean energy from the kinetic energy of waves and ocean currents depends on various mechanical devices with variable efficiencies. Apart from the efficiency, one must match the output phase of the feeder waveforms with that of the electrical grid. Also, the wavelengths of the typical wave are of the order of a few meters, the interception of which requires large devices. The mechanical efficiency of the turbine extraction system is further limited by the flow momentum considerations. Some applications and their implementation are looked at, specifically with reference to the difficulties of implementation in the region, and other factors like economic efficiency (rate of returns) in place of mechanical efficiency). Individual wave energy harvesters are thus bound to suffer from inefficiencies and it may be beneficial to use wave farm configurations from the point of view of the randomness of wave motion, the large wavelengths, and the added advantage of averaging fluctuations from large numbers of generators.

Here we report the construction, antigenicity and initial immunogenicity testing of DNA and modified vaccinia Ankara (MVA) vaccines expressing virus-like particles (VLPs) displaying sequential clade C Envelopes (Envs) that co-evolved with the elicitation of broadly neutralizing antibodies (bnAbs) to the CD4 binding site (CD4bs) in HIV-infected individual CH0505. The VLP-displayed Envs showed reactivity for conformational epitopes displayed on the receptor-binding form of Env. Two inoculations of the DNA-T/F vaccine, followed by 3 inoculations of the MVA-T/F vaccine and a final inoculation of the MVA-T/F plus a gp120-T/F protein vaccine elicited nAb to the T/F virus in 2 of 4 rhesus macaques (ID50 of ~175 and ~30). Neutralizing Ab plateaued at 100% neutralization and mapped to the CD4bs like the bnAbs elicited in CH0505. The nAb did not have breadth for other tier 2 viruses. Immunizations with T/F followed by directed-lineage vaccines, both with and without co-delivery of directed-lineage gp120 boosts, failed to elicit tier 2 neutralizing Ab for the CD4bs. Thus, pulsed exposures to DNA and MVA-expressed VLPs plus gp120 protein of a T/F Env can induce autologous tier 2 nAbs to the CD4bs.

GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine. clinicaltrials.gov NCT01378156.