Measuring β-cell function in vivo to understand the pathophysiology of type 2 diabetes

Diabetes arises when insulin secretion is inadequate for the prevailing metabolic conditions. As such appropriate measurement of β-cell function is necessary for a better understanding of the pathophysiology of prediabetes and diabetes. Unfortunately this is not a straightforward process and requires utilization of mathematical modelling to best appreciate its complexities. This is because insulin concentrations in the plasma represent a balance between the processes of secretion, hepatic extraction and clearance. In isolation such simple measures reveal very little about β-cell function. Moreover, since insulin lowers glucose accounting for the effect of the former on the latter it is a key part of understanding insulin action. The development of the minimal model has allowed simultaneous measurement of the dynamic relationship between insulin secretion and insulin action and produces a quantitative number – the Disposition Index – which quantifies β-cell function. At present this remains the best functional measure of islet health, however, it may not capture other phenotypes such as β-cell senescence or the effect of incretin hormones on β-cell function. Future ongoing development and interaction with other technologies, such as functional imaging, should enhance the contribution of this functional testing to the prevention, treatment and understanding of type 2 diabetes.peer-reviewe

Rethinking the Effective Sample Size

The effective sample size (ESS) is widely used in sample-based simulation methods for assessing the quality of a Monte Carlo approximation of a given distribution and of related integrals. In this paper, we revisit and complete the approximation of the ESS in the specific context of importance sampling (IS). The derivation of this approximation, that we will denote as $\widehat{\text{ESS}}$, is only partially available in Kong [1992]. This approximation has been widely used in the last 25 years due to its simplicity as a practical rule of thumb in a wide variety of importance sampling methods. However, we show that the multiple assumptions and approximations in the derivation of $\widehat{\text{ESS}}$, makes it difficult to be considered even as a reasonable approximation of the ESS. We extend the discussion of the ESS in the multiple importance sampling (MIS) setting, and we display numerical examples. This paper does not cover the use of ESS for MCMC algorithms

Reasoning From Fossils: Learning From the Local Black Hole Population About the Evolution of Quasars

We discuss a simple model for the growth of supermassive black holes (BHs) at the center of spheroidal stellar systems. In particular, we assess the hypotheses that (1) star formation in spheroids and BH fueling are proportional to one another, and (2) the BH accretion luminosity stays near the Eddington limit during luminous quasar phases. With the aid of this simple model, we are able to interpret many properties of the QSO luminosity function, including the puzzling steep decline of the characteristic luminosity from redshift z=2 to to z=0: indeed the residual star formation in spheroidal systems is today limited to a small number of bulges, characterized by stellar velocity dispersions a factor of 2-3 smaller those of the elliptical galaxies hosting QSOs at z > 2. A simple consequence of our hypotheses is that the redshift evolution of the QSO emissivity and of the star formation history in spheroids should be roughly parallel. We find this result to be broadly consistent with our knowledge of the evolution of both the global star formation rate, and of the evolution of the QSO emissivity, but we identify interesting discrepancies at both low and high redshifts, to which we offer tentative solutions. Finally, our hypotheses allow us to present a robust method to derive the duty cycle of QSO activity, based on the observed QSO luminosity function, and on the present-day relation between the masses of supermassive BHs and those of their spheroidal host stellar systems. The duty cycle is found to be substantially less than unity, with characteristic values in the range (3-6)x10^(-3), and we compute that the average bolometric radiative efficiency is epsilon=0.07. Finally, we find that the growth in mass of individual black holes at high redshift (z>2) can be dominated by mergers, and is therefore not necessarily limited by accretion.Comment: Submitted to ApJ, 26 preprint pages with 3 figure

What does the local black hole mass distribution tell us about the evolution of the quasar luminosity function?

We present a robust method to derive the duty cycle of QSO activity based on the empirical QSO luminosity function and on the present-day linear relation between the masses of supermassive black holes and those of their spheroidal host stellar systems. It is found that the duty cycle is substantially less than unity, with characteristic values in the range $3-6\times 10^{-3}$. Finally, we tested the expectation that the QSO luminosity evolution and the star formation history should be roughly parallel, as a consequence of the above--mentioned relation between BH and galaxy masses.Comment: 2 pages, to appear on ESO Astrophysics Symposia "The Mass of Galaxies at Low and High Redshift", R. Bender and A. Renzini, ed

The contrasting activity of iodido versus chlorido ruthenium and osmium arene azo- and imino-pyridine anticancer complexes : control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway

Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X]+ where M = RuII or OsII and X ═ Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells. Not only are the iodido complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin. They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes. They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. The iodido complexes retain potency in p53 mutant colon cells. All complexes activate caspase 3. In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor l-buthionine sulfoxime. The work illustrates how subtle changes to the design of low-spin d6 metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity