374 research outputs found
Chemokines and their receptors: Drug targets in immunity and inflammation
No full textThe chemokine system coordinates leukocyte migration in immunity and inflammation and is implicated in the pathogenesis of many human diseases. Although several successful strategies have been identified to develop drugs targeting chemokines and their receptors, this has not yet resulted in many new therapeutics. This is likely due to a complexity of the chemokine system, which was not initially appreciated, that is characterized by redundancy, pleiotropy, and differences among species. Nevertheless, our understanding of chemokine biology is continuing to grow and several promising drugs are currently being tested in late-stage clinical trials. In this review, we examine the role of chemokines in health and diseases and discuss strategies to target the chemokine system
Color and Golden Shine of Silver Islamic Luster
No full textGolden-like luster decorations on glazed ceramics from early
Islamic times (9–12th centuries AD) consist of a nanocomposite
submicrometric layer made of silver metal nanoparticles. The
color and golden-like reflectivity of these decorations are dominated
by the nonlinear optical response and Mie scattering of
the silver nanoparticles. We demonstrate that the enhanced
golden-like reflectivity occurs only for dense nanoparticulated
layers and that they were obtained by adding PbO to the alkaline
glaze. This resulted in reduced diffusivity of silver in the
glaze leading to more concentrated and thinner luster layers that
formed closer to the glaze surface. The result obtained adds new
insights into the high technological level attained during Islamic
times and also has important historical implications, giving both
new clues concerning the lead enrichment of the glazes during
this period, and some basis for the medieval Alchemy search for
the production of ‘‘gold’’ from other metals
Structure revision of meroterpenoid natural products enabled by biomimetic total synthesis
No full textMeroterpenoids constitute a vast and structurally diverse family of natural products with mixed biosynthetic origins, found across nearly all forms of life on Earth. Despite their often intricate architectures, meroterpenoid biosynthesis follows a remarkably consistent and predictable chemical logic, driven largely by interactions between electron-rich aromatic rings and terpene-derived building blocks. However, the structural elucidation of these stereochemically complex molecules remains challenging, and misassignments are common. This review highlights the pivotal role of biomimetic total synthesis in enabling the structural reassignment of meroterpenoids, whilst also rationalising their biosynthetic origin, inspiring the design of novel cascade reactions, and even guiding the prediction and discovery of previously unknown natural products
Do organizations that have reached the excellence level in the Wisconsin Forward Award process benefit from an increase in bottom line results?
No full textPlan BWhether it be large corporations or small companies, all organizations have and always are looking for ways to improve. In the past, improvement meant simply concentrating on production and finding ways to make it faster, more efficient, cheaper and better. Since that time, there have been many changes in the way people think about what improvement really means to an organization. The present and future of continuous improvement for companies is for them to constantly concentrate on the quality of their many operating systems to maximize the efficiency of all the criteria that makes their organization successful. Today’s quality professionals from a wide range of organizations and industries use quality programs such as; Total Quality Management (TQM), the Malcom Baldrige National Quality Award program (MBNQA), the Wisconsin Forward Award program (WFA), and other state programs. All improvement programs have in common that if they are not proven to provide bottom line results, organizations will not use them. Many researchers over the past ten years have worked to show the relationship between quality programs and bottom line results. The quality programs that have most commonly been studied are Total Quality Management (TQM) and the Malcolm Baldrige National Quality Award program. This study is designed to show the relationship between Wisconsin’s version of the Baldrige Award, the Wisconsin Forward Award program, and bottom line results. In this research paper, the researcher will study the performance of organizations who have reached the highest level of performance in the Wisconsin Forward Award program. The results will be used to conclude whether or not their bottom line results have improved since implementing the WFA process
Role for Chemokine-Mediated Immune Cell Trafficking in Cervicovaginal HIV Dissemination
No full textMentor: Andrew D. Luster, Harvard University
From the Washington University Undergraduate Research Digest: WUURD, Volume 8, Issue 2, Spring 2013. Published by the Office of Undergraduate Research, Joy Zalis Kiefer Director of Undergraduate Research and Assistant Dean in the College of Arts & Sciences; Kristin Sobotka, Editor
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Rational Design of CD8+ T Cell Vaccines for SARS-CoV-2
No full textSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2, of the sarbecovirus subgenus), the etiologic agent for CoronaVirus Disease 2019 (COVID-19) disease, has infected over 700 million people and caused over seven million deaths in the last four years. Soon after the pandemic’s onset, the urgent need for effective vaccines was clear, with multiple primarily antibody-inducing vaccines available within a year. However, waning antibody titers and variant escape from convalescent and vaccine-induced antibody neutralization underscored the importance of engagement of the cellular arm of the adaptive immune response to mitigate against severe COVID-19 and provide durable cross-protection of emerging variants. To design immune-focusing CD8+ T cell vaccines for SARS-CoV-2, we applied structure-based network analysis and assessments of human leukocyte antigen (HLA) class I-peptide stability to identify highly networked, mutation-constrained epitopes across the viral proteome. These epitopes impair pseudotyped lentivirus infectivity when mutated, elicit CD8+ T cell reactivity in convalescent individuals, and have resisted ongoing viral evolution over the course of the pandemic, highlighting their potential utility in second-generation vaccines.
Upon emergence of the highly infectious Omicron variant, numerous studies demonstrated escape from naturally occurring and vaccine-induced neutralizing antibodies and preservation of T cell reactivity in convalescent and vaccinated individuals. However, we observed that a subset of individuals had >50% reduction in effector and memory CD8+ T cell responses to the Omicron spike protein. The ability of SARS-CoV-2 variants to escape T cell responses emphasized the need for a mutation-constrained T cell epitope vaccine that includes epitopes from proteins beyond the highly mutable spike protein. We therefore designed an immunogen comprised of highly networked, HLA-stabilizing epitopes from SARS-CoV-2 structural, accessory, and RNA-dependent RNA polymerase proteins as well as immunogenic epitopes across the viral proteome that enhance HLA coverage of the vaccine cassette. Prime-boost intramuscular vaccinations of our immunogen delivered via lipid nanoparticle-encapsulated mRNA to K18-hACE2 and B cell-deficient mice were immunogenic, with induction of robust proliferative and reactive CD8+ T cell responses. Co-immunization of our T cell cassette with a covalently linked spike N-terminal domain (NTD) and receptor binding domain (RBD) immunogen revealed augmentation of CD8+ and CD4+ T cell responses to non-spike epitopes within the T cell cassette and NTD-RBD epitopes within the domain-based NTD-RBD immunogen. This demonstrates the potential synergism between the T cell- and antibody-inducing mRNA vaccines, providing a novel basis for generating enhanced vaccine-induced immunity against SARS-CoV-2.
Our experience with SARS-CoV-2 revealed the difficulty of rapidly identifying putative T cell epitopes and the potential for computational tools to accelerate T cell vaccine design. This led us to leverage deep learning approaches to develop MUNIS, a novel HLA class I epitope prediction tool. We show that MUNIS outperforms current state-of-the-art prediction algorithms in identifying peptides presented by HLA class I alleles and predicting immunodominance hierarchies for viral pathogens. In addition, application of MUNIS to protein sequences from the Epstein-Barr virus and subsequent experimental validation led to the identification of new CD8+ T cell epitopes, illustrating the capacity for deep learning models to rapidly identify immunogenic CD8+ T cell epitopes in never-before-seen viral proteomes.
In summary, this thesis demonstrates the rational design of a CD8+ T cell vaccine for SARS-CoV-2 to mitigate against the emergence of T cell escape in more recent SARS-CoV-2 variants, the potential synergy afforded by dual immunization with T cell- and antibody-inducing vaccines to provide broad protection against SARS-CoV-2 variants, and the potential for deep learning approaches to rapidly accelerate the design of T cell vaccines for future pandemic preparedness.Medical SciencesMedical Science
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