BE Ursae Majoris: A detached binary with a unique reprocessing spectrum

New infrared photometry, optical and UV spectrophotometry, and a photographic ephemeris are presented for the detached binary BE UMa. Results show the primary to be a DO white dwarf with an effective temperature of 80,000 + or - 15,000 K and a mass of 0.6 + or - 0.1 solar masses. No evidence is found for variability of the primary. The main sequence secondary star is shown to be of early M spectral type, with a formal range of M1 to M5 being possible. A reflection effect in reprocessed line and continuum radiation is produced by EUV radiation from the primary incident on the secondary atmosphere. It is suggested that the temperature of the reprocessed component of the secondary's atmosphere is in the 5000 to 8500 K range, and that emission lines of decreasing ionization form deeper in the irradiated envelope. Relatively narrow He II and high excitation metal lines are formed from recombination and continuum fluorescence processes

Insulin Secretion: Movement at All Levels

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Impact of Treatment on Islet Function in Type 2 Diabetes

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Gene duplication and functional divergence of the zebrafish insulin‐like growth factor 1 receptors

Insulin‐like growth factor (IGF) 1 receptor (IGF1R)‐mediated signaling plays key roles in growth, development, and physiology. Recent studies have shown that there are two distinct igf1r genes in zebrafish, termed igf1ra and igf1rb. In this study, we tested the hypothesis that zebrafish igf1ra and igf1rb resulted from a gene duplication event at the igf1r locus and that this has led to their functional divergence. The genomic structures of zebrafish igf1ra and igf1rb were determined and their loci mapped. While zebrafish igf1ra has 21 exons and is located on linkage group (LG) 18, zebrafish igf1rb has 22 exons and mapped to LG 7. There is a strong syntenic relationship between the two zebrafish genes and the human IGF1R gene. Using a MO‐based loss‐of‐function approach, we show that both Igf1ra and Igf1rb are required for zebrafish embryo viability and proper growth and development. Although Igf1ra and Igf1rb demonstrated a large degree of functional overlap with regard to cell differentiation in the developing eye, inner ear, heart, and muscle, they also exhibited functional distinction involving a greater requirement for Igf1rb in spontaneous muscle contractility. These findings suggest that the duplicated zebrafish igf1r genes play largely overlapping but not identical functional roles in early development and provide novel insight into the functional evolution of the IGF1R/insulin receptor gene family.— Schlueter, P. J., Royer, T., Mohamed, H. F., Laser, B., Chan, S. J., Steiner, D. F., Duan, C. Gene duplication and functional divergence of the zebrafish insulin‐like growth factor 1 receptors. FASEB J. 20, E462–E471 (2006)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154460/1/fsb2fj053882fje.pd

Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene

Over the last decade our insight into the causes of neonatal diabetes has greatly expanded. Neonatal diabetes was once considered a variant of type 1 diabetes that presented early in life. Recent advances in our understanding of this disorder have established that neonatal diabetes is not an autoimmune disease, but rather is a monogenic form of diabetes resulting from mutations in a number of different genes encoding proteins that play a key role in the normal function of the pancreatic beta-cell. Moreover, a correct genetic diagnosis can affect treatment and clinical outcome. This is especially true for patients with mutations in the genes KCNJ11 or ABCC8 that encode the two protein subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive potassium channel. These patients can be treated with oral sulfonylurea drugs with better glycemic control and quality of life. Recently, mutations in the insulin gene (INS) itself have been identified as another cause of neonatal diabetes. In this article, we review the role of INS mutations in the pathophysiology of neonatal diabetes

Autoimmunity against INS-IGF2 expressed in human pancreatic islets.

Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine 1) expression of INS-IGF2 in human pancreatic islets and 2) autoantibodies in newly diagnosed type 1 diabetes children and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared to donors with either type 2 diabetes (p=0.006) or high HbA1c levels (p<0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed type 1 diabetes patients (n=304) compared to healthy controls (n=355; p<0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes

The proinsulin C-peptide—a multirole model

The C-peptide links the insulin A and B chains in proinsulin, providing thereby a means to promote their efficient folding and assembly in the endoplasmic reticulum during insulin biosynthesis. It then facilitates the intracellular transport, sorting, and proteolytic processing of proinsulin into biologically active insulin in the maturing secretory granules of the β cells. These manifold functions impose significant constraints on the C-peptide structure that are conserved in evolution. After cleavage of proinsulin, the intact C-peptide is stored with insulin in the soluble phase of the secretory granules and is subsequently released in equimolar amounts with insulin, providing a useful independent indicator of insulin secretion. This brief review highlights many aspects of its roles in biosynthesis, as a prelude to consideration of its possible additional role(s) as a physiologically active peptide after its release with insulin into the circulation in vivo

Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier–Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system’s components taken in isolation