Nuclear factor -B (NF-B)-regulated inflammatory genes, such as TNF-␣ (tumor necrosis factor-␣), play key roles in the pathogenesis of inflammatory diseases, including diabetes and the metabolic syndrome. However, the nuclear chromatin mechanisms are unclear. We report here that the chromatin histone H3-lysine 4 methyltransferase, SET7/9, is a novel coactivator of NF-B. Gene silencing of SET7/9 with small interfering RNAs in monocytes significantly inhibited TNF-␣-induced inflammatory genes and histone H3-lysine 4 methylation on these promoters, as well as monocyte adhesion to endothelial or smooth muscle cells. Chromatin immunoprecipitation revealed that SET7/9 small interfering RNA could reduce TNF-␣-induced recruitment of NF-B p65 to inflammatory gene promoters. Inflammatory gene induction by ligands of the receptor for advanced glycation end products was also attenuated in SET7/9 knockdown monocytes. In addition, we also observed increased inflammatory gene expression and SET7/9 recruitment in macrophages from diabetic mice. Microarray profiling revealed that, in TNF-␣-stimulated monocytes, the induction of 25% NF-B downstream genes, including the histone H3-lysine 27 demethylase JMJD3, was attenuated by SET7/9 depletion. These results demonstrate a novel role for SET7/9 in inflammation and diabetes.NF-B is a pleiotropic transcription factor that plays a pivotal role in regulating multiple biological functions, such as inflammation, immunity, cell proliferation, and apoptosis (1, 2). NF-B plays an important role in the regulation of proinflammatory genes, such as TNF-␣ (tumor necrosis factor ␣) and MCP-1 (monocyte-chemoattractant protein-1), that are associated with several inflammatory diseases, including atherosclerosis, insulin resistance, metabolic syndrome, and diabetes and its complications (3-7). These genes also lead to monocyte activation associated with these inflammatory diseases.NF-B consists of homo-or heterodimers of different subunits, such as p50, p52, p65/RelA, RelB, and c-Rel, with p65/ RelA and p50 being the most common and well studied (1,8). In most unstimulated cells, NF-B resides in the cytoplasm in an inactive latent form complexed with its inhibitor subunit, IB␣. Multiple extracellular stimuli, including inflammatory cytokines, such as TNF-␣, and ligands of the receptor for advanced glycation end products (RAGE), 2 can induce NF-B activation by promoting IB␣ phosphorylation and its proteasomal degradation (6, 9). The released p65-p50 dimer then translocates to the nucleus, where it binds to the promoters of NF-B-dependent inflammatory genes, such as TNF-␣, MCP-1, and IL-6 (interleukin-6), to induce their expression (2). p65 protein is a key transcriptionally active component of NF-B whose transactivation potential is enhanced by several coactivators, including CREB-binding protein/p300, p/CAF, and SRC1 (10), which have histone acetyltransferase activity, and CARM1, which has arginine methyltransferase activity (11,12). Recently, we showed that histone H3 lysine acetylation is enriched...

Massive star formation occurs in Giant Molecular Clouds (GMCs); an understanding of the evolution of GMCs is a prerequisite to develop theories of star formation and galaxy evolution. We report the highest-fidelity observations of the grand-design spiral galaxy M51 in carbon monoxide (CO) emission, revealing the evolution of GMCs vis-a-vis the large-scale galactic structure and dynamics. The most massive GMCs (Giant Molecular Associations -GMAs) are first assembled and then broken up as the gas flow through the spiral arms. The GMAs and their H 2 molecules are not fully dissociated into atomic gas as predicted in stellar feedback scenarios, but are fragmented into smaller GMCs upon leaving the spiral arms. The remnants of GMAs are detected as the chains of GMCs that emerge from the spiral arms into interarm regions. The kinematic shear within the spiral arms is sufficient to unbind the GMAs against self-gravity. We conclude that the evolution of GMCs is driven by largescale galactic dynamics -their coagulation into GMAs is due to spiral arm streaming motions upon entering the arms, followed by fragmentation due to shear as they leave the arms on the downstream side. In M51, the majority of the gas remains molecular from arm entry through the inter-arm region and into the next spiral arm passage.

We present the first weak-lensing-based scaling relation between galaxy cluster mass, M WL , and integrated Compton parameter Y sph . Observations of 18 galaxy clusters at z 0.2 were obtained with the Subaru 8.2-m telescope and the Sunyaev-Zel'dovich Array. The M WL −Y sph scaling relations, measured at ∆ = 500, 1000, and 2500 ρ c , are consistent in slope and normalization with previous results derived under the assumption of hydrostatic equilibrium (HSE). We find an intrinsic scatter in M WL at fixed Y sph of 20%, larger than both previous measurements of M HSE − Y sph scatter as well as the scatter in true mass at fixed Y sph found in simulations. Moreover, the scatter in our lensing-based scaling relations is morphology dependent, with 30 -40% larger M WL for undisturbed compared to disturbed clusters at the same Y sph at r 500 . Further examination suggests that the segregation may be explained by the inability of our spherical lens models to faithfully describe the three-dimensional structure of the clusters, in particular, the structure along the line-of-sight. We find that the ellipticity of the brightest cluster galaxy, a proxy for halo orientation, correlates well with the offset in mass from the mean scaling relation, which supports this picture. This provides empirical evidence that line-of-sight projection effects are an important systematic uncertainty in lensing-based scaling relations.

We investigate the utility of a new, self-similar pressure profile for fitting Sunyaev-Zel'dovich (SZ) effect observations of galaxy clusters. Current SZ imaging instruments-such as the Sunyaev-Zel'dovich Array (SZA)-are capable of probing clusters over a large range in a physical scale. A model is therefore required that can accurately describe a cluster's pressure profile over a broad range of radii from the core of the cluster out to a significant fraction of the virial radius. In the analysis presented here, we fit a radial pressure profile derived from simulations and detailed X-ray analysis of relaxed clusters to SZA observations of three clusters with exceptionally high-quality X-ray data: A1835, A1914, and CL J1226.9+3332. From the joint analysis of the SZ and X-ray data, we derive physical properties such as gas mass, total mass, gas fraction and the intrinsic, integrated Compton y-parameter. We find that parameters derived from the joint fit to the SZ and X-ray data agree well with a detailed, independent X-ray-only analysis of the same clusters. In particular, we find that, when combined with X-ray imaging data, this new pressure profile yields an independent electron radial temperature profile that is in good agreement with spectroscopic X-ray measurements.