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Salari R.,U.S. National Center for Biotechnology Information | Kimchi-Sarfaty C.,Center for Biologics Evaluation and Research | Gottesman M.M.,U.S. National Cancer Institute | Przytycka T.M.,U.S. National Center for Biotechnology Information
Nucleic Acids Research | Year: 2013

Single-nucleotide polymorphisms (SNPs) are often linked to critical phenotypes such as diseases or responses to vaccines, medications and environmental factors. However, the specific molecular mechanisms by which a causal SNP acts is usually not obvious. Changes in RNA secondary structure emerge as a possible explanation necessitating the development of methods to measure the impact of single-nucleotide variation on RNA structure. Despite the recognition of the importance of considering the changes in Boltzmann ensemble of RNA conformers in this context, a formal method to perform directly such comparison was lacking. Here, we solved this problem and designed an efficient method to compute the relative entropy between the Boltzmann ensembles of the native and a mutant structure. On the basis of this theoretical progress, we developed a software tool, remuRNA, and investigated examples of its application. Comparing the impact of common SNPs naturally occurring in populations with the impact of random point mutations, we found that structural changes introduced by common SNPs are smaller than those introduced by random point mutations. This suggests a natural selection against mutations that significantly change RNA structure and demonstrates, surprisingly, that randomly inserted point mutations provide inadequate estimation of random mutations effects. Subsequently, we applied remuRNA to determine which of the disease-associated non-coding SNPs are potentially related to RNA structural changes. © 2012 The Author(s). Published by Oxford University Press. Source


Cowley S.C.,Center for Biologics Evaluation and Research
Cellular and Molecular Life Sciences | Year: 2014

Mucosa-associated invariant T (MAIT) cells are a unique population of innate T cells that are abundant in humans. These cells possess an evolutionarily conserved invariant T cell receptor α chain restricted by the nonpolymorphic class Ib major histocompatibility (MHC) molecule, MHC class I-related protein (MR1). The recent discovery that MAIT cells are activated by MR1-bound riboflavin metabolite derivatives distinguishes MAIT cells from all other αβ T cells in the immune system. Since mammals lack the capacity to synthesize riboflavin, intermediates from the riboflavin biosynthetic pathway are distinct microbial molecular patterns that provide a unique signal to the immune system. Multiple lines of evidence suggest that MAIT cells, which produce important cytokines such as IFN-γ, TNF, and IL-17A, have the potential to influence immune responses to a broad range of pathogens. Here we will discuss our current understanding of MAIT cell biology and their role in pathogen defense. © 2014 Springer Basel (outside the USA). Source


Warfel J.M.,Center for Biologics Evaluation and Research | Edwards K.M.,Vanderbilt University
Current Opinion in Immunology | Year: 2015

Pertussis has re-emerged as an important public health concern. In the 1990s whole-cell pertussis vaccines were replaced with less reactogenic acellular vaccines consisting of purified pertussis components. However, recent data show that protection from acellular pertussis vaccines is not long-lasting. Antibody levels wane rapidly following vaccination, likely a result of the inability of acellular pertussis antigens to stimulate long-lasting B cell memory. In addition, T cell responses to acellular pertussis vaccines are mixed Th2/Th1, while whole-cell pertussis vaccination and infection stimulate Th17 responses, important for host defense against extracellular mucosal pathogens. Consistent with this T cell skewing, acellular vaccines did not prevent colonization or transmission following challenge in nonhuman primates while whole-cell vaccinated and previously infected animals cleared the infection more rapidly. © 2015 Elsevier Ltd. Source


Keller J.E.,Center for Biologics Evaluation and Research
Procedia in Vaccinology | Year: 2011

Vaccines are biological products made from living organisms. The natural complexity of biological molecules along with the inherent uncertainties of product manufacturing introduces the likelihood that random alterations can impact the quality of the vaccine each time it is made. The factors that can affect the final product are often unknown. Testing for potency of vaccine bulk or product dispensed into final containers was designed with the hope of ensuring that a vaccine is effective when used during its approved dating period and that its protective activity was not inadvertently altered during any phase of production. Ideally, potency testing measures a biological or biochemical property of the vaccine that is related to its ability to elicit protective immunity in the target population and provide some assurance that consistent clinical benefit is derived from each lot of product. Potency methods vary depending on the nature and composition of the vaccine. In vivo potency testing might entail immunizing groups of laboratory animals and then challenging them directly to measure survival, or involve serological potency assays in which sera from immunized laboratory animals are tested for the ability to neutralize pathogens or toxins. In the U.S., diphtheria toxoid and tetanus toxoid potency tests have customarily involved a serological method. This approach uses fewer animals than would have been required using a direct challenge method, while providing satisfactory evidence that each toxoid lot could induce protective immunity. This paper will discuss the details of the original U.S. test method for diphtheria and tetanus toxoid potency and present issues that must be considered when developing and validating non-animal-based approaches to refine or replace these tests. © 2011. Source


Banerjee R.,Center for Biologics Evaluation and Research | Khandelwal S.,Duke University | Kozakai Y.,Center for Biologics Evaluation and Research | Sahu B.,Center for Biologics Evaluation and Research | Kumar S.,Center for Biologics Evaluation and Research
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Several Plasmodium species exhibit a strong age-based preference for the red blood cells (RBC) they infect, which in turn is a major determinant of disease severity and pathogenesis. The molecular basis underlying this age constraint on the use of RBC and its influence on parasite burden is poorly understood. CD47 is a marker of self on most cells, including RBC, which, in conjunction with signal regulatory protein alpha (expressed on macrophages), prevents the clearance of cells by the immune system. In this report, we have investigated the role of CD47 on the growth and survival of nonlethal Plasmodium yoelii 17XNL (PyNL) malaria in C57BL/6 mice. By using a quantitative biotin-labeling procedure and a GFPexpressing parasite, we demonstrate that PyNL parasites preferentially infect high levels of CD47 (CD47hi)-expressing young RBC. Importantly, C57BL/6 CD47-/- mice were highly resistant to PyNL infection and developed a 9.3-fold lower peak parasitemia than their wild-type (WT) counterparts. The enhanced resistance to malaria observed in CD47-/- mice was associated with a higher percentage of splenic F4/80+ cells, and these cells had a higher percentage of phagocytized parasitized RBC than infected WT mice during the acute phase of infection, when parasitemia was rapidly rising. Furthermore, injection of CD47-neutralizing antibody caused a significant reduction in parasite burden in WT C57BL/6 mice. Together, these results strongly suggest that CD47hi young RBC may provide a shield to the malaria parasite from clearance by the phagocytic cells, which may be an immune escape mechanism used by Plasmodium parasites that preferentially infect young RBC. Source

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