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Bharat Narasimhan,1 Arundhati Calambur,2 Errol Moras,3 Lingling Wu,4 Wilbert Aronow5 1Department of Cardiology, Debakey Cardiovascular Institute, Houston Methodist, Houston, TX, USA; 2University of California San Diego, La Jolla, CA, USA; 3Department of Medicine, Icahn School of Medicine; Mount Sinai, New York, NY, USA; 4Department of Medicine, East Carolina University, Greenvile, NC, USA; 5Department of Cardiology, Westchester Medical Center, Valhalla, NY, USACorrespondence: Wilbert Aronow, Department of Cardiology, Westchester Medical Center, New York Medical College, 100 Woods Road, Macy Pavilion, Room 141, Valhalla, NY, 10595, USA, Email wsaronow@aol.comAbstract: The long-term implications of COVID-19 have garnered increasing interest in recent months, with Long-COVID impacting over 65 million individuals worldwide. Postural orthostatic tachycardia syndrome (POTS) has emerged as an important component of the Long-COVID umbrella, estimated to affect between 2 and 14% of survivors. POTS remains very challenging to diagnose and manage – this review aims to provide a brief overview of POTS as a whole and goes on to summarize the available literature pertaining to POTS in the setting of COVID-19. We provide a review of available clinical reports, outline proposed pathophysiological mechanisms and end with a brief note on management considerations.Keywords: POTS, COVID-19, long COVID, review

Ross Darling,1 Sujata Senapati,2 John Christiansen,1 Luman Liu,2 Amanda E Ramer-Tait,3 Balaji Narasimhan,2,4 Michael Wannemuehler1,4 1Department of Veterinary Microbiology and Preventative Medicine, Iowa State University, Ames, IA, USA; 2Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA; 3Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE, USA; 4Nanovaccine Institute, Iowa State University, Ames, IA, USACorrespondence: Michael Wannemuehler; Balaji Narasimhan Email mjwannem@iastate.edu; nbalaji@iastate.eduIntroduction: Adjuvants and immunotherapies designed to activate adaptive immunity to eliminate infectious disease and tumors have become an area of interest aimed at providing a safe and effective strategy to prevent or eliminate disease. Existing approaches would benefit from the development of immunization regimens capable of inducing efficacious cell-mediated immunity directed toward CD8+ T cell-specific antigens. This goal is critically dependent upon appropriate activation of antigen-presenting cells (APCs) most notably dendritic cells (DCs). In this regard, polyanhydride particles have been shown to be effectively internalized by APCs and induce activation.Methods: Here, a prophylactic vaccine regimen designed as a single-dose polyanhydride nanovaccine encapsulating antigen is evaluated for the induction of CD8+ T cell memory in a model system where antigen-specific protection is restricted to CD8+ T cells. Bone marrow-derived dendritic cells (BMDCs) are used as an in vitro model system to evaluate the magnitude and phenotype of APC activation. Primary DCs, particularly those with described ability to activate CD8+ T cells, are also evaluated for their in vitro responses to polyanhydride nanoparticles.Results: Herein, polyanhydride nanoparticles are shown to induce potent in vitro upregulation of costimulatory molecules on the cell surface of BMDCs. In contrast to the classically used TLR agonists, nanoparticles did not induce large amounts of pro-inflammatory cytokines, did not induce characteristic metabolic response of DCs, nor produce innate antimicrobial effector molecules, such as nitric oxide (NO). The polyanhydride nanovaccine results in protective CD8+ T cell responses as measured by inhibition of tumor progression and survival.Discussion: Together, these results suggest that the use of a polyanhydride-based nanovaccine can be an effective approach to inducing antigen-specific CD8+ T cell memory by providing antigen delivery and DC activation while avoiding overt inflammatory responses typically associated with traditional adjuvants.Keywords: nanovaccine, metabolism, nitric oxide, T cell memory, inflammation

Sankar Renu,1,2,* Ashley D Markazi,3,* Santosh Dhakal,1,2 Yashavanth S Lakshmanappa,1,2 Suren R Gourapura,1,2 Revathi Shanmugasundaram,3 Sujata Senapati,4 Balaji Narasimhan,4 Ramesh K Selvaraj,5 Gourapura J Renukaradhya1,2 1Food Animal Health Research Program, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA; 2Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA; 3Department of Animal Sciences, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA; 4Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA; 5Department of Poultry Science, University of Georgia, Athens, GA 30602, USA *These authors contributed equally to this work Purpose: Salmonellosis is a severe economic threat in poultry and a public health concern. Currently available vaccines are ineffective, and thus, developing effective oral Salmonella vaccine is warranted. Especially, a potent oral vaccine such as the mucoadhesive polyanhydride nanoparticle (PNP) protects the vaccine cargo and delivers to intestinal immune sites to elicit robust mucosal immunity and mitigate Salmonella colonization and shedding.Materials and methods: We designed a Salmonella subunit vaccine using PNP containing immunogenic Salmonella outer membrane proteins (OMPs) and flagellar (F) protein-entrapped and surface F-protein-coated PNPs (OMPs-F-PNPs) using a solvent displacement method. Using high-throughput techniques, we characterized the OMPs-F-PNPs physicochemical properties and analyzed its efficacy in layer birds vaccinated orally.Results: The candidate vaccine was resistant in acidic microenvironment and had ideal physicochemical properties for oral delivery in terms of particle size, charge, morphology, biocompatibility, and pH stability. In vitro, in vivo, and ex vivo studies showed that F-protein surface-anchored nanoparticles were better targeted to chicken immune cells in peripheral blood and splenocytes and intestinal Peyer’s patch sites. In layer chickens inoculated orally with OMPs-F-PNPs, substantially higher OMPs-specific IgG response and secretion of Th1 cytokine IFN-γ in the serum, enhanced CD8+/CD4+ cell ratio in spleen, and increased OMPs-specific lymphocyte proliferation were observed. OMPs-F-PNPs vaccination also upregulated the expression of toll-like receptor (TLR)-2 and -4, TGF-β, and IL-4 cytokines’ genes in chicken cecal tonsils (lymphoid tissues). Importantly, OMPs-F-PNPs vaccine cleared Salmonella cecal colonization in 33% of vaccinated birds.Conclusion: This pilot in vivo study demonstrated the targeted delivery of OMPs-F-PNPs to ileum mucosal immune sites of chickens and induced specific immune response to mitigate Salmonella colonization in intestines. Keywords: Salmonella antigens, polyanhydride nanoparticles, oral delivery, ileum, chickens

Kathleen A Ross,1 Hyelee Loyd,2 Wuwei Wu,2 Lucas Huntimer,3 Shaheen Ahmed,4 Anthony Sambol,5 Scott Broderick,6 Zachary Flickinger,2 Krishna Rajan,6 Tatiana Bronich,4 Surya Mallapragada,1 Michael J Wannemuehler,3 Susan Carpenter,2 Balaji Narasimhan1 1Chemical and Biological Engineering, Iowa State University, Ames, IA, USA; 2Animal Science, Iowa State University, Ames, IA, USA; 3Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, USA; 4Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA; 5Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; 6Materials Science and Engineering, Iowa State University, Ames, IA, USA Abstract: H5N1 avian influenza is a significant global concern with the potential to become the next pandemic threat. Recombinant subunit vaccines are an attractive alternative for pandemic vaccines compared to traditional vaccine technologies. In particular, polyanhydride nanoparticles encapsulating subunit proteins have been shown to enhance humoral and cell-mediated immunity and provide protection upon lethal challenge. In this work, a recombinant H5 hemagglutinin trimer (H53) was produced and encapsulated into polyanhydride nanoparticles. The studies performed indicated that the recombinant H53 antigen was a robust immunogen. Immunizing mice with H53 encapsulated into polyanhydride nanoparticles induced high neutralizing antibody titers and enhanced CD4+ T cell recall responses in mice. Finally, the H53-based polyanhydride nanovaccine induced protective immunity against a low-pathogenic H5N1 viral challenge. Informatics analyses indicated that mice receiving the nanovaccine formulations and subsequently challenged with virus were similar to naïve mice that were not challenged. The current studies provide a basis to further exploit the advantages of polyanhydride nanovaccines in pandemic scenarios. Keywords: polymer, nanoparticle, vaccine, subunit, neutralizing antibody

Latrisha K Petersen,1 Lucas Huntimer,2 Katharine Walz,1 Amanda Ramer-Tait,2 Michael J Wannemuehler,2 Balaji Narasimhan11Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA; 2Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, USAAbstract: Several challenges are associated with current vaccine strategies, including repeated immunizations, poor patient compliance, and limited approved routes for delivery, which may hinder induction of protective immunity. Thus, there is a need for new vaccine adjuvants capable of multi-route administration and prolonged antigen release at the site of administration by providing a depot within tissue. In this work, we designed a combinatorial platform to investigate the in vivo distribution, depot effect, and localized persistence of polyanhydride nanoparticles as a function of nanoparticle chemistry and administration route. Our observations indicated that the route of administration differentially affected tissue residence times. All nanoparticles rapidly dispersed when delivered intranasally but provided a depot when administered parenterally. When amphiphilic and hydrophobic nanoparticles were administered intranasally, they persisted within lung tissue. These results provide insights into the chemistry- and route-dependent distribution and tissue-specific association of polyanhydride nanoparticle-based vaccine adjuvants.Keywords: combinatorial, polyanhydride, nanoparticle, live animal imaging, distribution

Quantification of minimal residual disease (MRD) following allogeneic hematopoietic cell transplantation (allo-HCT) predicts post-transplant relapse in patients with chronic lymphocytic leukemia (CLL). We utilized an MRD-quantification method that amplifie

PSO-GPSR (Particle Swarm Optimization-based Load Balancing with Geographic Routing using Greedy Perimeter Stateless Routing), a unique strategy designed specifically for WSNs, is presented in this work. Using Particle Swarm Optimization (PSO) to provide load balancing across sensor nodes, the proposed PSO-GPSR technique reduces energy disparities and increases the operational lifetime of the network. Additionally, it interfaces with the geographic routing protocol Greedy Perimeter Stateless Routing (GPSR) to enable effective data forwarding based on geographic locations, minimizing communication overhead and improving scalability. PSO-GPSR's efficacy is shown against traditional load balancing and routing methods via comprehensive simulations and performance assessments. The network lifetime, energy efficiency, throughput, packet delivery ratio, and delay have all significantly showed better performance, according to the results. Additionally, the PSO-GPSR algorithm demonstrates robustness against node failures and issues related to scalability, indicating a significant potential for real-world implementation in various WSN scenarios. [ABSTRACT FROM AUTHOR]