Myb and NF-M: combinatorial activators of myeloid genes in heterologous cell types

The c-Myb transcription factor regulates the differentiation of immature erythroid, lymphoid, and myeloid cells, although only the latter cells become transformed by the v-myb oncogene. These are also the only cells that express the Myb-regulated gene mim-1, suggesting that Myb requires tissue-specific, cooperating factors to activate such genes. Here, we investigated the tissue-specific regulation of the mim-1 promoter and found that it not only contains binding sites for Myb but also for NF-M, a myeloid-specific transcription factor that probably corresponds to mammalian C/EBP beta. Both types of binding sites were found to be required for full activity of the promoter. Remarkably, ectopic coexpression of Myb and NF-M proteins in erythroid cells or fibroblasts was sufficient to induce endogenous markers of myeloid differentiation, like the mim-1 and lysozyme genes. Our results indicate that c-Myb and NF-M proteins act as a bipartite, combinatorial signal that regulates the expression of myeloid-specific genes, even in heterologous cell types

Novae Ejecta as Colliding Shells

Following on our initial absorption-line analysis of fifteen novae spectra we present additional evidence for the existence of two distinct components of novae ejecta having different origins. As argued in Paper I one component is the rapidly expanding gas ejected from the outer layers of the white dwarf by the outburst. The second component is pre-existing outer, more slowly expanding circumbinary gas that represents ejecta from the secondary star or accretion disk. We present measurements of the emission-line widths that show them to be significantly narrower than the broad P Cygni profiles that immediately precede them. The emission profiles of novae in the nebular phase are distinctly rectangular, i.e., strongly suggestive of emission from a relatively thin, roughly spherical shell. We thus interpret novae spectral evolution in terms of the collision between the two components of ejecta, which converts the early absorption spectrum to an emission-line spectrum within weeks of the outburst. The narrow emission widths require the outer circumbinary gas to be much more massive than the white dwarf ejecta, thereby slowing the latter's expansion upon collision. The presence of a large reservoir of circumbinary gas at the time of outburst is suggestive that novae outbursts may sometime be triggered by collapse of gas onto the white dwarf, as occurs for dwarf novae, rather than steady mass transfer through the inner Lagrangian point.Comment: 12 pages, 3 figures; Revised manuscript; Accepted for publication in Astrophysics & Space Scienc

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits

Two-electron elastic tunneling in low-dimensional conductors

This article was published in the journal, Physical Review B [© American Physical Society]. It is also available at: http://link.aps.org/abstract/PRB/v65/e155209.We solve the Lippmann-Schwinger equation describing one-dimensional elastic scattering of preformed pairs (e.g., bipolarons) off a short-range scattering center, and find the two-particle transmission through a thin potential barrier. While the pair transmission is smaller than the single-electron transmission in the strong-coupling limit, it is remarkably larger in the weak-coupling limit. We also calculate current-voltage characteristics of a molecule-barrier-molecule junction. They show unusual temperature and voltage behaviors which are experimentally verifiable at low temperatures in bulk and nanoscale molecular conductors

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk