Enhancing Health Care in the Veteran Community Through Synergistic Research Funding.

The veteran population faces myriad health burdens, particularly regarding mental health. As veterans age, combined genetic, environmental, and biochemical factors with natural biological processes may increase their susceptibility to mental health disorders as well as neuropsychiatric and dementia-related disorders that present as persistent cognitive impairment. Multi-organizational, multidisciplinary research partnerships help explore relevant evidence-based methodologies and create a two-way continuum between basic science and clinical application to address veterans', often complex, health care needs. The Congressionally Directed Medical Research Programs (CDMRP), a global funding organization located within the U.S. Army Medical Research and Development Command (USAMRDC), fosters novel approaches to biomedical research in response to the expressed needs of stakeholders and, as directed by Congress, many CDMRP programs focus on topics that are relevant to the health care of veterans. The CDMRP's foundation as a research management organization includes a two-tier review process and fully integrates consumer advocates. The CDMRP complements the U.S. Department of Veterans Affairs (VA) research through collaborative partnerships and synergistic award mechanisms tailored to areas of greatest need. Continued partnerships between the VA and CDMRP can facilitate translation of basic research to clinical application and enhance health care in the veteran community. This perspective highlights the need for research to address mental health issues affecting the veteran community, describes how the CDMRP integrates veterans into its processes, and discusses how the CDMRP's processes and collaborations with the VA have the capacity to improve mental health care for veterans.

Making an Impact: Congressionally Directed Medical Research Programs Complement Other Sources of Biomedical Funding.

Research programs fill important research gaps through evaluation of the funding landscape, identification of the research gaps, and the development of novel award mechanisms.

IL-27 inhibits HIV-1 infection in human macrophages by down-regulating host factor SPTBN1 during monocyte to macrophage differentiation.

The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down-regulating spectrin ß nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27-treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir.

Cutting edge: Ku70 is a novel cytosolic DNA sensor that induces type III rather than type I IFN.

Cytosolic foreign DNA is detected by pattern recognition receptors and mainly induces type I IFN production. We found that transfection of different types of DNA into various untreated cells induces type III IFN (IFN-λ1) rather than type I IFN, indicating the presence of uncharacterized DNA sensor(s). A pull-down assay using cytosolic proteins identified that Ku70 and Ku80 are the DNA-binding proteins. The knockdown studies and the reporter assay revealed that Ku70 is a novel DNA sensor inducing the IFN-lambda1 activation. The functional analysis of IFNL1 promoter revealed that positive-regulatory domain I and IFN-stimulated response element sites are predominantly involved in the DNA-mediated IFNL1 activation. A pull-down assay using nuclear proteins demonstrated that the IFN-λ1 induction is associated with the activation of IFN regulatory factor-1 and -7. Thus, to our knowledge, we show for the first time that Ku70 mediates type III IFN induction by DNA.

Spliced leader RNA-mediated trans-splicing in a dinoflagellate, Karenia brevis.

Spliced leader (SL) trans-splicing is a form of mRNA processing originally described in parasitic kinetoplastids. During this reaction, a short RNA sequence is transferred from the 5'-end of an SL transcript to a splice acceptor site on pre-mRNA molecules. Here we report numerous mRNAs from a dinoflagellate, Karenia brevis, which contain an identical leader sequence at their 5'-terminal end. Furthermore, we have isolated a gene from K. brevis encoding a putative SL RNA containing the conserved splice donor site immediately following the leader sequence. A 1,742-bp DNA fragment encoding a K. brevis 5S gene repeat was found to encode the SL RNA gene, as well as a U6 small nuclear RNA (snRNA) gene, and binding sites for the core components of the splicesome (Sm proteins) involved in RNA splicing. Therefore the K. brevis SL RNA appears to be in a genomic arrangement typical of SL genes in a number of species known to mature their mRNAs by trans-splicing. Additionally, we show that the SL gene exists as a stable snRNA and has a predicted secondary structure typical of SL RNAs. The data presented here support the hypothesis that an SL RNA is present in K. brevis and that maturation of a percentage of mRNAs in K. brevis occurs via a trans-splicing process in which a common SL sequence is added to the 5'-end of mature mRNAs. The occurrence of SL trans-splicing in a dinoflagellate extends the known phylogenetic range of this process.

Gene expression in Florida red tide dinoflagellate Karenia brevis: analysis of an expressed sequence tag library and development of DNA microarray.

Karenia brevis (Davis) is the dinoflagellate responsible for nearly annual red tides in the Gulf of Mexico. Although the mechanisms regulating the growth and toxicity of this problematic organism are of considerable interest, little information is available on its molecular biology. We therefore constructed a complementary DNA library from which to gain insight into its expressed genome and to develop tools for studying its gene expression. Large-scale sequencing yielded 7001 high-quality expressed sequence tags (ESTs), which clustered into 5280 unique gene groups. The vast majority of genes expressed fell into a low-abundance class, with the highest expressed gene accounting for only 1% of the total ESTs. Approximately 29% of genes were found to have similarity to known sequences in other organisms after BLAST similarity comparisons to the GenBank public protein database using a cutoff of P < 10e(-4). We identified for the first time in a dinoflagellate a suite of conserved eukaryotic genes involved in cell cycle control, intracellular signaling, and the transcription and translation machinery. At least 40% of gene clusters displayed single nucleotide polymorphisms, suggesting the presence of multiple gene copies. The average GC content of ESTs was 51%, with a slight preference for G or C in the third codon position (53.5%). The ESTs were used to develop an oligonucleotide microarray containing 4629 unique features and 3462 replicate probes. Microarray labeling has been optimized, and the microarray has been validated for probe specificity and reproducibility. This is the first information to be developed on the expressed genome of K. brevis and provides the basis from which to begin functional genomic studies on this harmful algal bloom species.