Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks.

Down syndrome (DS) is a genetic disorder caused by the presence of an extra partial or whole copy of chromosome 21. In addition to musculoskeletal and neurodevelopmental abnormalities, children with DS exhibit various hematologic disorders and have an increased risk of developing acute lymphoblastic leukemia and acute megakaryocytic leukemia. Using the Ts65Dn mouse model, we investigated bone marrow defects caused by trisomy for 132 orthologs of the genes on human chromosome 21.

An externalized polypeptide partitions between two distinct sites on genome-released poliovirus particles.

During cell entry, native poliovirus (160S) converts to a cell-entry intermediate (135S) particle, resulting in the externalization of capsid proteins VP4 and the amino terminus of VP1 (residues 1 to 53). Externalization of these entities is followed by release of the RNA genome (uncoating), leaving an empty (80S) particle. The antigen-binding fragment (Fab) of a monospecific peptide 1 (P1) antibody, which was raised against a peptide corresponding to amino-terminal residues 24 to 40 of VP1, was utilized to track the location of the amino terminus of VP1 in the 135S and 80S states of poliovirus particles via cryogenic electron microscopy (cryo-EM) and three-dimensional image reconstruction.

A community-based approach to translational research addressing breast cancer disparities.

Disparities in breast cancer survival rates suggest that biological processes contribute. Translational research addressing health disparities would benefit from using a community-based participatory approach (CBPR) to examine biological processes commonly seen as the proximal causes of illness as well as behavioral and social-ecological "causes of the causes" within an integrated conceptual framework. This paper describes a CBPR study that explored perceptions regarding breast cancer relevant behaviors, and the application of the study's results to develop translational research.

Six RNA viruses and forty-one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems.

We have used multiplexed high-throughput sequencing to characterize changes in small RNA populations that occur during viral infection in animal cells. Small RNA-based mechanisms such as RNA interference (RNAi) have been shown in plant and invertebrate systems to play a key role in host responses to viral infection. Although homologs of the key RNAi effector pathways are present in mammalian cells, and can launch an RNAi-mediated degradation of experimentally targeted mRNAs, any role for such responses in mammalian host-virus interactions remains to be characterized.

Immune surveillance as a rationale for immunotherapy?

The majority of pathogen vaccines are used within the prophylactic setting as opposed to the therapeutic setting proposed for cancer vaccines. Due to the intricate role of the immune system in tumorigenesis, tumor immunotherapy may have to borrow approaches from autoimmunity. The size of the malignant population that has to be eliminated, the associated immunosuppressive effects of the tumor, the diversion of inflammatory and immune processes by the organized stroma surrounding the tumor, the antigenic diversity of the tumor cell population leading to immune escape, all present barriers that predestine the failure of most attempts for active immunotherapy.

Defining carbohydrate antigens as HIV vaccine candidates.

The induction of high affinity antibodies capable of broad neutralization and protection against infection and/or disease is a major goal in the development of a vaccine for human immunodeficiency virus (HIV). Insights into the structure and function of the envelope (Env) protein of HIV-1 suggest that the virus is under strong selection pressure by the immune response leading to constant mutations in the Env protein including the N-glycosylation sites. Initially considered a shield against the immune system, the heavily glycosylated outer surface of the HIV Env protein has drawn attention lately as a legitimate target.

Carbohydrate mimotopes in the rational design of cancer vaccines.

The task of rationally designing vaccines that can effectively impact on the survival of cancer patients remains challenging. Monoclonal antibodies and T cell receptors have proven to be viable templates for the application of pharmacophore design principles to develop antigens and immunogens as these immune system molecules recognize a variety of sequentially and structurally unrelated ligands. This structural information combined with immunological assessment has contributed to the development of strategies to elicit effective humoral and cellular responses to cancer cells.

RNA interference is an antiviral defence mechanism in Caenorhabditis elegans.

RNA interference (RNAi) is an evolutionarily conserved sequence-specific post-transcriptional gene silencing mechanism that is well defined genetically in Caenorhabditis elegans. RNAi has been postulated to function as an adaptive antiviral immune mechanism in the worm, but there is no experimental evidence for this. Part of the limitation is that there are no known natural viral pathogens of C.

Virus-specific CD4+ and CD8+ cytotoxic T-cell responses and long-term T-cell memory in individuals vaccinated against polio.

The presence of poliovirus (PV)-specific CD4(+) T cells in individuals vaccinated against polio has been shown, but CD8(+) T-cell responses have not been described. Here, we functionally characterize the CD4(+) T-cell response and show for the first time that dendritic cells and macrophages can stimulate PV-specific CD8(+) T-cell responses in vitro from vaccinees. Both CD4(+) T and CD8(+) T cells secrete gamma interferon in response to PV antigens and are cytotoxic via the perforin/granzyme B-mediated pathway.

Dendritic cells and macrophages are productively infected by poliovirus.

Expression of the poliovirus receptor (PVR) on cells is a major host determinant of infection by poliovirus. Previously, the only immune cell type known to express PVR was the blood-derived monocyte, which is susceptible to infection at very low frequency. We demonstrate that professional antigen-presenting cells-macrophages and dendritic cells, generated upon differentiation of monocytes-retain expression of PVR and are highly susceptible to infection by type 1 Mahoney strain of poliovirus.

Poliovirus binding to its receptor in lipid bilayers results in particle-specific, temperature-sensitive channels.

Poliovirus (PV) infection starts with binding to its receptor (PVR), followed by a receptor-aided, temperature-sensitive conformational change of the infectious particle (sedimenting at 160S) to a particle which sediments at 135S. Reported in this communication is the successful incorporation into lipid bilayers of two forms of the receptor: the full-length human receptor and a modified clone in which the extracellular domains of the receptor were fused to a glycosylphosphatidylinositol tail. Addition of virus (160S) to receptor-containing bilayers leads to channel formation, whereas no channels were observed when the receptor-modified viral particle (135S) was added.

Cholesterol removal by methyl-beta-cyclodextrin inhibits poliovirus entry.

Upon binding to the poliovirus receptor (PVR), the poliovirus 160S particles undergo a conformational transition to generate 135S particles, which are believed to be intermediates in the virus entry process. The 135S particles interact with host cell membranes through exposure of the N termini of VP1 and the myristylated VP4 protein, and successful cytoplasmic delivery of the genomic RNA requires the interaction of these domains with cellular membranes whose identity is unknown. Because detergent-insoluble microdomains (DIMs) in the plasma membrane have been shown to be important in the entry of other picornaviruses, it was of interest to determine if poliovirus similarly required DIMs during virus entry.

c-Jun NH2-terminal kinase-mediated signaling is essential for Pseudomonas aeruginosa ExoS-induced apoptosis.

As an opportunistic bacterial pathogen, Pseudomonas aeruginosa mainly affects immunocompromised individuals as well as patients with cystic fibrosis. In a previous study, we showed that ExoS of P. aeruginosa, when injected into host cells through a type III secretion apparatus, functions as an effector molecule to trigger apoptosis in various tissue culture cells.

Genome delivery and ion channel properties are altered in VP4 mutants of poliovirus.

During entry into host cells, poliovirus undergoes a receptor-mediated conformational transition to form 135S particles with irreversible exposure of VP4 capsid sequences and VP1 N termini. To understand the role of VP4 during virus entry, the fate of VP4 during infection by site-specific mutants at threonine-28 of VP4 (4028T) was compared with that of the parental Mahoney type 1 virus. Three virus mutants were studied: the entry-defective, nonviable mutant 4028T.

Pseudomonas aeruginosa mediated apoptosis requires the ADP-ribosylating activity of exoS.

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that primarily infects immunocompromised individuals and patients with cystic fibrosis. Using a tissue culture system, invasive strains of P. aeruginosa were discovered to induce apoptosis at high frequency in HeLa and other epithelial and fibroblast cell lines.