Breaking T cell tolerance to beta cell antigens by merocytic dendritic cells

In type 1 diabetes (T1D), a break in central and peripheral tolerance results in antigen-specific T cells destroying insulin-producing, pancreatic beta cells. Herein, we discuss the critical sub-population of dendritic cells responsible for mediating both the cross-presentation of islet antigen to CD8⁺ T cells and the direct presentation of beta cell antigen to CD4⁺ T cells. These cells, termed merocytic dendritic cells (mcDC), are more numerous in non-obese diabetic (NOD), and antigen-loaded mcDC rescue CD8⁺ T cells from peripheral anergy and deletion, and stimulate islet-reactive CD4⁺ T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDC can break peripheral T cell tolerance to beta cell antigens in vivo and induce rapid onset T cell-mediated T1D in young NOD mouse. Thus, the mcDC subset appears to represent the long-sought critical antigen-presenting cell responsible for breaking peripheral tolerance to beta cell antigen in vivo.     

Regulation of the type III InsP3 receptor and its role in beta cell function

The type III inositol 1,4,5-trisphosphate receptor (InsP3R) is an important intracellular calcium (Ca2+) release channel in the pancreatic beta cell. Pancreatic beta cells secrete insulin following a characteristic change in membrane potential that leads to an increase in cytoplasmic Ca2+. Both extracellular Ca2+ and Ca2+ mobilized from InsP3-sensitive stores contribute to this increase. RIN-m5F cells, an insulin-secreting beta cell line, preferentially express the type III InsP3R. These cells have been useful in determining the regulatory properties of the type III InsP3R and the role of this isoform in an intact cell. The type III InsP3R is ideal for signal initiation because high cytoplasmic Ca2+ does not inhibit its activity. Altered insulin secretion, the result of changes in Ca2+ handling by the beta cell, has significant clinical consequences.     

Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

Pancreatic beta cell damage caused by pro-inflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNγ-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1β, IFNγ, TNFα. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFNγ in beta cells. In summary, we show that interference with IFNγ signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death.     

The incomplete beta function — a historical profile

Summary A history of the development of the incomplete beta function is outlined as well as of some of the analytical and approximation techniques used for its numerical evaluation. Dedicated to W. Edwards Deming, my teacher and my friend     

Evaluations of the beta probability integral by bayes and price

Summary The contribution of Bayes to statistical inference has been much discussed, whereas his evaluations of the beta probability integral have received little attention, and Price's improvements of these results have never been analysed in detail. It is the purpose of the present paper to redress this state of affairs and to show that the Bayes-Price approximation to the two-sided beta probability integral is considerably better than the normal approximation, which became popular under the influence of Laplace, although it had been stated by Price.The Bayes-Price results are obtained by approximating the skew beta density by a symmetric beta density times a factor tending to unity for n , the two functions having the same maximum and the same points of inflection. Since the symmetric beta density converges to the normal density, all the results of Laplace based on the normal distribution can be obtained as simple limits of the results of Bayes and Price. This fact was not observed either by Laplace or by Todhunter.     

Multiplicity of beta lactamases: a problem of isoenzymes]

Analytical isoelectric focusing of beta lactamases is a very sensitive and powerful technique which generally shows a number of satellites near the main enzymatic spike. By this technique we studied two bacterial groups known to produce different beta lactamases, but only one by germ. Analytical isoelectric focusing showed that all bacteria from the same group produce the same satellite system which differs only in relative activity.     

An analysis on the predictability of CAPM beta for momentum returns

This paper demonstrates that the forecasted capital asset pricing model (CAPM) beta of momentum portfolios explains a large portion of the return, ranging from 40% to 60% for stock‐level momentum, and from 30% to 50% for industry‐level momentum. Beta forecasts are from a realized beta estimator using daily returns over the prior year. Periods such as 1969–1989 have been found in earlier studies to contain abnormal profits from momentum trading; however, we show that these were spuriously generated by measurement error in systematic risk. These results cast further doubt on the ability of standard momentum trading strategies to generate abnormal profits.     

Euler’s beta integral in Pietro Mengoli’s works

Beta integrals for several non-integer values of the exponents were calculated by Leonhard Euler in 1730, when he was trying to find the general term for the factorial function by means of an algebraic expression. Nevertheless, 70 years before, Pietro Mengoli (1626–1686) had computed such integrals for natural and half-integer exponents in his Geometriae Speciosae Elementa (1659) and Circolo(1672) and displayed the results in triangular tables. In particular, his new arithmetic–algebraic method allowed him to compute the quadrature of the circle. The aim of this article is to show how Mengoli calculated the values of these integrals as well as how he analysed the relation between these values and the exponents inside the integrals. This analysis provides new insights into Mengoli’s view of his algorithmic computation of quadratures.     

Risk factor beta conditional value‐at‐risk

We propose a new approach to the estimation of the portfolio Value‐at‐Risk. Based on the assumption that the same macroeconomic factors affect returns of all assets in a portfolio, this methodology allows the generation of the sequence of hypothetical future equilibrium portfolio returns given the historical values of the underlying macroeconomic factors and the asset betas with respect to these factors. Value‐at‐Risk is then found as an appropriate percentile of the corresponding hypothetical distribution of the portfolio profits and losses. The backtesting results for the six Fama–French benchmark portfolios and the S&P500 index show that this approach yields reasonably accurate estimates of the portfolio Value‐at‐Risk. Copyright © 2008 John Wiley & Sons, Ltd.     

Vinculin in cell–cell and cell–matrix adhesions

Vinculin was identified as a component of focal adhesions and adherens junctions nearly 40 years ago. Since that time, remarkable progress has been made in understanding its activation, regulation and function. Here we discuss the current understanding of the roles of vinculin in cell–cell and cell–matrix adhesions. Emphasis is placed on the how vinculin is recruited, activated and regulated. We also highlight the recent understanding of how vinculin responds to and transmits force at integrin- and cadherin-containing adhesion complexes to the cytoskeleton. Furthermore, we discuss roles of vinculin in binding to and rearranging the actin cytoskeleton.     

Problems in the determination of isoelectric points of beta lactamases]

Analytical isoelectric focusing in polyacrylamide gels and preparative electrofocusing in density gradients may give very different pI determination for the same beta lactamase. This difference seems due to a lack of enzyme migration in some parts of the cross-linked polyacrylamide gel. This migration appears easier in density gradient isoelectricfocusing, and thus this technique yields more significant absolute pI values. Analytical isoelectric focusing should only be used for comparison studies.     

An experimental method of tissue surface measurements of beta activityin vivo

Riassunto Gli autori descrivono una tecnica che consente di attuare determinazioni esterne di radioattività β su tessuti superficiali nel topo, mantenendo costante il rendimento di misura per una durata di alcune ore. Vengono presentati e brevemente commentati alcuni esempi di curve ottenute con questa tecnica in seguito ad iniezioni di P³² per via endovenosa, endoperitoneale e sottocutanea.      

Interleukin-17 stimulates inducible nitric oxide synthase-dependent toxicity in mouse beta cells

The influence of the proinflammatory cytokine interleukin (IL)-17 on inducible nitric oxide (NO) synthase (iNOS)-mediated NO release was investigated in the mouse insulinoma cell line MIN6 and mouse pancreatic islets. IL-17 markedly augmented iNOS mRNA/protein expression and subsequent NO production induced in MIN6 cells or pancreatic islets by different combinations of interferon-γ, tumor necrosis factor-α, and IL-1β. The induction of iNOS by IL-17 was preceded by phosphorylation of p38 mitogen-activated protein kinase (MAPK), and inhibition of p38 MAPK activation completely abolished IL-17-stimulated NO release. IL-17 enhanced the NO-dependent toxicity of proinflammatory cytokines toward MIN6 cells, while IL-17-specific neutralizing antibody partially reduced the NO production and rescued insulinoma cells and pancreatic islets from NO-dependent damage induced by activated T cells. Finally, a significant increase in blood IL-17 levels was observed in a multiple low-dose streptozotocin model of diabetes, suggesting that T cell-derived IL-17 might be involved in NO-dependent damage of beta cells in this disease. Received 14 June 2005; received after revision 17 September 2005; accepted 21 September 2005     

Regulation of estrogen receptor beta activity and implications in health and disease

Together with the estrogen receptor (ER) alpha, estrogen receptor beta (ERβ) mediates many of the physiological effects of estrogens. As ERβ is crucially involved in a variety of important physiological processes, its activity should be tightly regulated. ERβ regulation is achieved by hormone binding as well as by posttranslational modifications of the receptor. Furthermore, ERβ expression levels are under circadian control and can be regulated by DNA methylation of the ERβ promoter region. There are also a number of factors that can interfere with ERβ activity, such as phytoestrogens, endocrine disruptive chemicals, and growth factors. In this article, we outline different mechanisms of ERβ regulation and how they are implicated in various diseases. We also discuss how these insights might help to specifically target ERβ in drug design.