Adenoviral-Vectored Centralized Consensus Hemagglutinin Vaccine Provides Broad Protection against H2 Influenza a Virus

Several influenza pandemics have occurred in the past century, one of which emerged in 1957 from a zoonotic transmission of H2N2 from an avian reservoir into humans. This pandemic caused 2–4 million deaths and circulated until 1968. Since the disappearance of H2N2 from human populations, there has been waning immunity against H2, and this subtype is not currently incorporated into seasonal vaccines. However, H2 influenza remains a pandemic threat due to consistent circulation in avian reservoirs. Here, we describe a method of pandemic preparedness by creating an adenoviral-vectored centralized consensus vaccine design against human H2 influenza. We also assessed the utility of serotype-switching to enhance the protective immune responses seen with homologous prime-boosting strategies. Immunization with an H2 centralized consensus showed a wide breadth of antibody responses after vaccination, protection against challenge with a divergent human H2 strain, and significantly reduced viral load in the lungs after challenge. Further, serotype switching between two species C adenoviruses enhanced protective antibody titers after heterologous boosting. These data support the notion that an adenoviral-vectored H2 centralized consensus vaccine has the ability to provide broadly cross-reactive immune responses to protect against divergent strains of H2 influenza and prepare for a possible pandemic

Expanding Mouse-Adapted Yamagata-like Influenza B Viruses in Eggs Enhances In Vivo Lethality in BALB/c Mice

Despite the yearly global impact of influenza B viruses (IBVs), limited host range has been a hurdle to developing a readily accessible small animal disease model for vaccine studies. Mouseadapting IBV can produce highly pathogenic viruses through serial lung passaging in mice. Previous studies have highlighted amino acid changes throughout the viral genome correlating with increased pathogenicity, but no consensus mutations have been determined. We aimed to show that growth system can play a role in mouse-adapted IBV lethality. Two Yamagata-lineage IBVs were serially passaged 10 times in mouse lungs before expansion in embryonated eggs or Madin–Darby canine kidney cells (London line) for use in challenge studies. We observed that virus grown in embryonated eggs was significantly more lethal in mice than the same virus grown in cell culture. Ten additional serial lung passages of one strain again showed virus grown in eggs was more lethal than virus grown in cells. Additionally, no mutations in the surface glycoprotein amino acid sequences correlated to differences in lethality. Our results suggest growth system can influence lethality of mouse-adapted IBVs after serial lung passaging. Further research can highlight improved mechanisms for developing animal disease models for IBV vaccine research

Production planning tools and techniques for agile manufacturing

Effective use of resources shared among multiple products or processes is critical for agile manufacturing. This paper describes development and implementation of a computerized model to support production planning in a complex manufacturing system at Pantex Plant. The model integrates two different production processes (nuclear weapon dismantlement and stockpile evaluation) which use common facilities and personnel, and reflects the interactions of scheduling constraints, material flow constraints, and resource availability. These two processes reflect characteristics of flow-shop and job-shop operations in a single facility. Operational results from using the model are also discussed

Planning tools and techniques for production evaluation and disassembly

This paper describes the development and implementation of a computerized model to support production planning in a specialized type of remanufacturing facility, the Pantex Plant operated for the US Department of Energy. The model integrates two different production processes (nuclear weapon dismantlement and stockpile evaluation) which use common facilities and personnel, and reflects the interactions of scheduling constraints, material flow constraints and resource availability. These two processes reflect characteristics of flow-shop and job-shop operations in a single facility. Operational results from using the model are also discussed

Adenoviral-vectored epigraph vaccine elicits robust, durable, and protective immunity against H3 influenza A virus in swine

Current methods of vaccination against swine Influenza A Virus (IAV-S) in pigs are infrequently updated, induce strain-specific responses, and have a limited duration of protection. Here, we characterize the onset and duration of adaptive immune responses after vaccination with an adenoviral-vectored Epigraph vaccine. In this longitudinal study we observed robust and durable antibody responses that remained above protective titers six months after vaccination. We further identified stable levels of antigen-specific T cell responses that remained detectable in the absence of antigen stimulation. Antibody isotyping revealed robust class switching from IgM to IgG induced by Epigraph vaccination, while the commercial comparator vaccine failed to induce strong antibody class switching. Swine were challenged six months after initial vaccination, and Epigraph-vaccinated animals demonstrated significant protection from microscopic lesion development in the trachea and lungs, reduced duration of viral shedding, lower presence of infectious virus and viral antigens in the lungs, and significant recall of antigen-specific T cell responses following challenge. The results obtained from this study are useful in determining the kinetics of adaptive immune responses after vaccination with adjuvanted whole inactivated virus vaccines compared to adenoviral vectored vaccines and contribute to the continued efforts of creating a universal IAVS vaccine

Single-machine scheduling with stepwise tardiness costs and release times

We study a scheduling problem that belongs to the yard operations component of the railroad planning problems, namely the hump sequencing problem. The scheduling problem is characterized as a single-machine problem with stepwise tardiness cost objectives. This is a new scheduling criterion which is also relevant in the context of traditional machine scheduling problems. We produce complexity results that characterize some cases of the problem as pseudo-polynomially solvable. For the difficult-to-solve cases of the problem, we develop mathematical programming formulations, and propose heuristic algorithms. We test the formulations and heuristic algorithms on randomly generated single-machine scheduling problems and real-life datasets for the hump sequencing problem. Our experiments show promising results for both sets of problems

Living in Living Cities

This paper presents an overview of current and potential applications of living technology to some urban problems. Living technology can be described as technology that exhibits the core features of living systems. These features can be useful to solve dynamic problems. In particular, urban problems concerning mobility, logistics, telecommunications, governance, safety, sustainability, and society and culture are presented, while solutions involving living technology are reviewed. A methodology for developing living technology is mentioned, while supraoptimal public transportation systems are used as a case study to illustrate the benefits of urban living technology. Finally, the usefulness of describing cities as living systems is discussed.Comment: 40 pages, 4 figures, overview pape

IL-33-mediated protection against experimental cerebral malaria is linked to induction of Type 2 innate lymphoid cells, M2 macrophages and regulatory T cells

Author Summary Cerebral malaria (CM) caused by the parasite Plasmodium sp . is a fatal disease, especially in children. Currently there is no effective treatment. We report here our investigation on the role of a recently discovered cytokine IL-33, in treating experimental cerebral malaria (ECM) in the susceptible C57BL/6 mice. IL-33 protects the mice against ECM. The protection is accompanied by a reduction of Th1 response and the enhancement of type 2 cytokine response. We also found that IL-33 mediates its protective effect by inducing a population of type 2 innate lymphoid cells (ILC2), which then polarize macrophages to alternatively-activated phenotypes (M2). M2 in turn expand regulatory T cells (Tregs) which suppress the deleterious Th1 response. Our report therefore reveals hitherto unrecognised mechanisms of the regulation of ECM and provide a novel function of IL-33