No abstract

The major histocompatibility complex (MHC) class I molecules present peptides on the cell surface by CD8 + T cells, which is critical for killing of virally infected or transformed cells. Precursors of MHC class I-presented peptides are trimmed to mature epitopes by endoplasmic reticulum aminopeptidase 1 (ERAP1). The US2-US11 genomic region of human cytomegalovirus (HCMV) is dispensable for viral replication and harbors 3 microRNAs (miRNAs). We show here the HCMV miR-US4-1 specifically down-regulates ERAP1 expression during viral infection. Accordingly, the trimming of HCMV-derived peptides is inhibited, leading to reduced susceptibility of infected cells to HCMV-specific cytotoxic T lymphocytes (CTLs). Our findings reveal a novel viral miRNA-based CTL evasion mechanism that targets a key step in the MHC class I antigen-processing pathway.MHC class I molecule binds peptides and presents them on the cell surface for recognition by CD8 + T cells. Cytosolic peptides generated by the proteasomes and prematurely translated peptides are transported to the endoplasmic reticulum (ER) through the transporter associated with antigen processing (TAP) complex 1, 2 . Some of these peptides are further processed by ER-resident aminopeptidases, such as ERAP1, and peptide trimming by ERAP1 (also known as A-LAP, ARTS-1, and PILS-AP) in the ER is a crucial step for determining the quality and quantity of optimal antigenic peptide production and the stability of the MHC class I-β 2 m-peptide heterotrimer [3][4][5][6] . ERAP1 trims relatively long * To whom correspondence should be addressed: Department of Biological Sciences, Seoul National University, Seoul 151-747, Korea, (Phone) +822-880-9233 (Fax) +822-872-1993 S.R.R cloned the HCMV-specific CTLs. S.K and K.A designed the overall study and wrote the paper. NIH Public AccessAuthor Manuscript Nat Immunol. Author manuscript; available in PMC 2012 December 20. peptides efficiently in a sequence-specific manner, resulting in the accumulation of 8-9 amino acid-long optimal peptides 5,7,8 . ERAP1 therefore acts as a 'molecular ruler' for antigenic peptide production 9 . In addition, genome-wide association studies have associated nonsynonymous single nucleotide polymorphisms in ERAP1 with ankylosing spondylitis 4 . Additionally, ERAP1 has non-peptide processing functions via its role in shedding of cytokine receptors 4 .MiRNAs are small RNAs 19 to 23 nucleotides long that regulate gene expression by complete or partial base-pairing with the 3′-untranslated region (UTR) of their target mRNA which leads to mRNA cleavage, destabilization, or translational repression 10 . Since the first report in 2004 that viruses express miRNAs 11 , numerous viral miRNAs have been discovered and are mainly related to viral proliferation and survival-related immune evasion, although this is based on a limited number of studies 12 . The β-herpesvirus HCMV expresses at least 14 miRNAs during productive infection 13,14 . One HCMV-encoded miRNA, miR-UL112-1 targets 3 HCMV genes involved in viral r...

MBCT may be effective at relieving anxiety and depressive symptoms in patients with panic disorder or generalized anxiety disorder. However, well-designed, randomized controlled trials are needed.

Plasmonic high-harmonic generation (HHG) drew attention as a means of producing coherent extreme ultraviolet (EUV) radiation by taking advantage of field enhancement occurring in metallic nanostructures. Here a metal-sapphire nanostructure is devised to provide a solid tip as the HHG emitter, replacing commonly used gaseous atoms. The fabricated solid tip is made of monocrystalline sapphire surrounded by a gold thin-film layer, and intended to produce EUV harmonics by the inter- and intra-band oscillations of electrons driven by the incident laser. The metal-sapphire nanostructure enhances the incident laser field by means of surface plasmon polaritons, triggering HHG directly from moderate femtosecond pulses of ∼0.1 TW cm−2 intensities. The measured EUV spectra exhibit odd-order harmonics up to ∼60 nm wavelengths without the plasma atomic lines typically seen when using gaseous atoms as the HHG emitter. This experimental outcome confirms that the plasmonic HHG approach is a promising way to realize coherent EUV sources for nano-scale near-field applications in spectroscopy, microscopy, lithography and atto-second physics.

IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6–stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6–dependent TF-1 cell proliferation. LMT-28 antagonized IL-6–induced TNF-α production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6Rα, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6Rα complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.