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Seattle, WA, United States

Seattle BioMed, known prior to 2010 as Seattle Biomedical Research Institute or SBRI, is the largest independent, non-profit organization in the United States focused solely on infectious disease discovery research. The mission of Seattle BioMed's 360+ employees is to eliminate the world's most devastating infectious diseases through leadership in scientific discovery. Seattle BioMed is headquartered and has research labs in the South Lake Union area of Seattle, WA. Seattle BioMed's research focuses on four areas of infectious disease: HIV/AIDS, malaria, tuberculosis , and Emerging & Neglected Diseases like African sleeping sickness, leishmaniasis, Chagas disease, and toxoplasmosis. Seattle BioMed is engaged in early stages of the scientific pipeline including bench science and malaria clinical trials and has expertise in immunology, vaccinology, and drug discovery. Wikipedia.

Sherman D.R.,Seattle Biomedical Research Institute | Gagneux S.,University of Basel
Nature Genetics | Year: 2011

Current models of Mycobacterium tuberculosis latency presume very low mycobacterial replication and mutation rates. In contrast to these models, a study reporting whole-genome sequencing of mycobacteria isolated from infected macaques shows that the mutational capacity of M. tuberculosis during latency is not reduced, a finding with important implications for tuberculosis research and control. © 2011 Nature America, Inc. All rights reserved. Source

Ptak C.,University of Alberta | Aitchison J.D.,Seattle Biomedical Research Institute | Wozniak R.W.,University of Alberta
Current Opinion in Cell Biology | Year: 2014

In addition to their established roles in nucleocytoplasmic transport, the intimate association of nuclear pore complexes (NPCs) with chromatin has long led to speculation that these structures influence peripheral chromatin structure and regulate gene expression. These ideas have their roots in morphological observations, however recent years have seen the identification of physical interactions between NPCs, chromatin, and the transcriptional machinery. Key insights into the molecular functions of specific NPC proteins have uncovered roles for these proteins in transcriptional activation and elongation, mRNA processing, as well as chromatin structure and localization. Here, we review recent studies that provide further molecular detail on the role of specific NPC components as distinct platforms for these chromatin dependent processes. © 2014 Elsevier Ltd. Source

Aitchison J.D.,Seattle Biomedical Research Institute | Rout M.P.,Rockefeller University
Genetics | Year: 2012

Exchange of macromolecules between the nucleus and cytoplasm is a key regulatory event in the expression of a cell's genome. This exchange requires a dedicated transport system: (1) nuclear pore complexes (NPCs), embedded in the nuclear envelope and composed of proteins termed nucleoporins (or "Nups"), and (2) nuclear transport factors that recognize the cargoes to be transported and ferry them across the NPCs. This transport is regulated at multiple levels, and the NPC itself also plays a key regulatory role in gene expression by influencing nuclear architecture and acting as a point of control for various nuclear processes. Here we summarize how the yeast Saccharomyces has been used extensively as a model system to understand the fundamental and highly conserved features of this transport system, revealing the structure and function of the NPC; the NPC's role in the regulation of gene expression; and the interactions of transport factors with their cargoes, regulatory factors, and specific nucleoporins. © 2012 by the Genetics Society of America. Source

Smith J.J.,Institute for Systems Biology | Aitchison J.D.,Seattle Biomedical Research Institute
Nature Reviews Molecular Cell Biology | Year: 2013

Peroxisomes carry out various oxidative reactions that are tightly regulated to adapt to the changing needs of the cell and varying external environments. Accordingly, they are remarkably fluid and can change dramatically in abundance, size, shape and content in response to numerous cues. These dynamics are controlled by multiple aspects of peroxisome biogenesis that are coordinately regulated with each other and with other cellular processes. Ongoing studies are deciphering the diverse molecular mechanisms that underlie biogenesis and how they cooperate to dynamically control peroxisome utility. These important challenges should lead to an understanding of peroxisome dynamics that can be capitalized upon for bioengineering and the development of therapies to improve human health. © 2013 Macmillan Publishers Limited. All rights reserved. Source

Mikolajczak S.A.,Seattle Biomedical Research Institute
Molecular Therapy | Year: 2014

Immunization with live-attenuated Plasmodium sporozoites completely protects against malaria infection. Genetic engineering offers a versatile platform to create live-attenuated sporozoite vaccine candidates. We previously generated a genetically attenuated parasite (GAP) by deleting the P52 and P36 genes in the NF54 wild-type (WT) strain of Plasmodium falciparum (Pf p52-/p36- GAP). Preclinical assessment of p52-/p36- GAP in a humanized mouse model indicated an early and severe liver stage growth defect. However, human exposure to >200 Pf p52-/p36- GAP-infected mosquito bites in a safety trial resulted in peripheral parasitemia in one of six volunteers, revealing that this GAP was incompletely attenuated. We have now created a triple gene deleted GAP by additionally removing the SAP1 gene (Pf p52-/p36-/sap1- GAP) and employed flippase (FLP)/flippase recognition target (FRT) recombination for drug selectable marker cassette removal. This next-generation GAP was indistinguishable from WT parasites in blood stage and mosquito stage development. Using an improved humanized mouse model transplanted with human hepatocytes and human red blood cells, we show that despite a high-dose sporozoite challenge, Pf p52-/p36-/sap1- GAP did not transition to blood stage infection and appeared to be completely attenuated. Thus, clinical testing of Pf p52-/p36-/sap1- GAP assessing safety, immunogenicity, and efficacy against sporozoite challenge is warranted.Molecular Therapy (2014); doi:10.1038/mt.2014.85. Source

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