Towards the synthesis of the ajudazols

The Ajudazols A and B are secondary metabolites, isolated in 2004 and exhibit anti-fungal and cytotoxic activity. The primary objective of the work presented in this thesis was to expand and develop our novel isobenzofuran oxidative rearrangement methodology for generation of isochromanones, and to apply this methodology towards the total synthesis of the ajudazols. An efficient, high yielding, regio- and diastereoselective oxidative rearrangement sequence has been developed, allowing for the generation of elaborately-functionalised isochromanone structures, from transient isobenzofuran intermediates. A flexible route to the synthesis of the ajudazol B eastern section was achieved, and this research culminated in the synthesis of ent-8-epi-ajudazol B

A massive cluster of Red Supergiants at the base of the Scutum-Crux arm

We report on the unprecedented Red Supergiant (RSG) population of a massive young cluster, located at the base of the Scutum-Crux Galactic arm. We identify candidate cluster RSGs based on {\it 2MASS} photometry and medium resolution spectroscopy. With follow-up high-resolution spectroscopy, we use CO-bandhead equivalent width and high-precision radial velocity measurements to identify a core grouping of 26 physically-associated RSGs -- the largest such cluster known to-date. Using the stars' velocity dispersion, and their inferred luminosities in conjuction with evolutionary models, we argue that the cluster has an initial mass of $\sim$40,000\msun, and is therefore among the most massive in the galaxy. Further, the cluster is only a few hundred parsecs away from the cluster of 14 RSGs recently reported by Figer et al (2006). These two RSG clusters represent 20% of all known RSGs in the Galaxy, and now offer the unique opportunity to study the pre-supernova evolution of massive stars, and the Blue- to Red-Supergiant ratio at uniform metallicity. We use GLIMPSE, MIPSGAL and MAGPIS survey data to identify several objects in the field of the larger cluster which seem to be indicative of recent region-wide starburst activity at the point where the Scutum-Crux arm intercepts the Galactic bulge. Future abundance studies of these clusters will therefore permit the study of the chemical evolution and metallicity gradient of the Galaxy in the region where the disk meets the bulge.Comment: 49 pages, 22 figures. Accepted for publication in ApJ. Version with hi-res figures can be found at http://www.cis.rit.edu/~bxdpci/RSGC2.pd

The cool supergiant population of the massive young star cluster RSGC1

We present new high-resolution near-IR spectroscopy and OH maser observations to investigate the population of cool luminous stars of the young massive Galactic cluster RSGC1. Using the 2.293\micron CO-bandhead feature, we make high-precision radial velocity measurements of 16 of the 17 candidate Red Supergiants (RSGs) identified by Figer et al. We show that F16 and F17 are foreground stars, while we confirm that the rest are indeed physically-associated RSGs. We determine that Star F15, also associated with the cluster, is a Yellow Hypergiant based on its luminosity and spectroscopic similarity to $\rho$ Cas. Using the cluster's radial velocity, we have derived the kinematic distance to the cluster and revisited the stars' temperatures and luminosities. We find a larger spread of luminosities than in the discovery paper, consistent with a cluster age 30% older than previously thought (12$\pm$2Myr), and a total initial mass of $(3\pm1) \times 10^{4}$\msun. The spatial coincidence of the OH maser with F13, combined with similar radial velocities, is compelling evidence that the two are related. Combining our results with recent SiO and H$_2$O maser observations, we find that those stars with maser emission are the most luminous in the cluster. From this we suggest that the maser-active phase is associated with the end of the RSG stage, when the luminosity-mass ratios are at their highest.Comment: 31 pages, 11 figures. Accepted for publication in Ap

Massive Stars In The W33 Giant Molecular Complex

Rich in H II regions, giant molecular clouds are natural laboratories to study massive stars and sequential star formation. The Galactic star-forming complex W33 is located at = ∼ ◦ l 12.8 and at a distance of 2.4 kpc and has a size of ≈10 pc and a total mass of ≈(0.8−8.0) × 105 M⊙. The integrated radio and IR luminosity of W33—when combined with the direct detection of methanol masers, the protostellar object W33A, and the protocluster embedded within the radio source W33 main—mark the region as a site of vigorous ongoing star formation. In order to assess the long-term star formation history, we performed an infrared spectroscopic search for massive stars, detecting for the first time 14 early-type stars, including one WN6 star and four O4–7 stars. The distribution of spectral types suggests that this population formed during the past ∼2–4 Myr, while the absence of red supergiants precludes extensive star formation at ages 6–30 Myr. This activity appears distributed throughout the region and does not appear to have yielded the dense stellar clusters that characterize other star-forming complexes such as Carina and G305. Instead, we anticipate that W33 will eventually evolve into a loose stellar aggregate, with Cyg OB2 serving as a useful, albeit richer and more massive, comparator. Given recent distance estimates, and despite a remarkably similar stellar population, the rich cluster Cl 1813–178 located on the northwest edge of W33 does not appear to be physically associated with W33

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Pictures, perspective and possibility

10.1007/s11098-009-9337-2Philosophical Studies1492135-15

Tyrosine kinase signalling in breast cancer: Tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer

The ability of growth factors and their cognate receptors to induce mammary epithelial proliferation and differentiation is dependent on their ability to activate a number of specific signal transduction pathways. Aberrant expression of specific receptor tyrosine kinases (RTKs) has been implicated in the genesis of a significant proportion of sporadic human breast cancers. Indeed, mammary epithelial expression of activated RTKs such as ErbB2/neu in transgenic mice has resulted in the efficient induction of metastatic mammary tumours. Although it is clear from these studies that activation these growth factor receptor signalling cascades are directly involved in mammary tumour progression, the precise interaction of each of these signalling pathways in mammary tumourigenesis and metastasis remains to be elucidated. The present review focuses on the role of several specific signalling pathways that have been implicated as important components in RTK-mediated signal transduction. In particular, it focuses on two well characterized transgenic breast cancer models that carry the polyomavirus middle T(PyV mT) and neu oncogenes

Consensus-based guidance for conducting and reporting multi-analyst studies

International audienceAny large dataset can be analyzed in a number of ways, and it is possible that the use of different analysis strategies will lead to different results and conclusions. One way to assess whether the results obtained depend on the analysis strategy chosen is to employ multiple analysts and leave each of them free to follow their own approach. Here, we present consensus-based guidance for conducting and reporting such multi-analyst studies, and we discuss how broader adoption of the multi-analyst approach has the potential to strengthen the robustness of results and conclusions obtained from analyses of datasets in basic and applied research

Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients