The high resolution crystal structure of an N-terminal fragment of the IGF-I receptor, has been reported. While this fragment is itself devoid of ligand binding activity, mutational analysis has indicated that its N terminus (L1, amino acids 1-150) and the C terminus of its cysteine-rich domain (amino acids 190 -300) contain ligand binding determinants. Mutational analysis also suggests that amino acids 692-702 from the C terminus of the ␣ subunit are critical for ligand binding. A fusion protein, formed from these fragments, binds IGF-I with an affinity similar to that of the whole extracellular domain, suggesting that these are the minimal structural elements of the IGF-I binding site. To further characterize the binding site, we have performed structure directed and alanine-scanning mutagenesis of L1, the cysteinerich domain and amino acids 692-702. Alanine mutants of residues in these regions were transiently expressed as secreted recombinant receptors and their affinity was determined. In L1 alanine mutants of The insulin-like growth factors I and II are essential for normal fetal and post-natal growth (1). They were originally identified as circulating polypeptides with potent mitogenic activity, which mediated many of the actions of growth hormone, and were later shown to be structurally homologous to proinsulin. It is now apparent that these growth factors are produced by many cell types and have paracrine and autocrine as well as endocrine functions. Targeted disruption of the gene for IGF-I 1 in transgenic mice results in both embryonic and post-natal growth retardation (2). In contrast, the effects of disruption of the IGF-II gene are confined to growth retardation during the embryonic period (2). In addition to being mitogens, it is now evident that these peptides play a crucial role in cell survival (3) and contribute to transformation and the maintenance of the malignant phenotype in many tumor systems (4). However, despite extensive study, the signal transduction mechanisms underlying the biological effects of these peptides remain to be elucidated.The mitogenic effects of these growth factors appear to be mediated by receptors belonging to the insulin receptor subclass of receptor tyrosine kinases (for review see Ref. (5)). The type 1 IGF receptor binds both peptides with high affinity; the affinity for IGF-I being greater than that for IGF-II. Transgenic experiments indicate that the growth-promoting effects of both peptides can be mediated by this receptor (2, 6). Such studies also point to the role of a second receptor in mediating the mitogenic effects of IGF-II (2, 6), and recent in vitro studies indicate that this is the A isoform of the insulin receptor (7); this receptor binds IGF-II with high affinity and can mediate the growth-promoting effects of the peptide (8).The receptors in this family are dimeric protein-tyrosine kinases with significant homology (5). In higher vertebrates there are three known members, the insulin receptor (9, 10), the type 1 IGF receptor (11), and the orphan in...

We show that multivariate singular spectrum analysis (M-SSA) greatly helps study phase synchronization in a large system of coupled oscillators and in the presence of high observational noise levels. With no need for detailed knowledge of individual subsystems nor any a priori phase definition for each of them, we demonstrate that M-SSA can automatically identify multiple oscillatory modes and detect whether these modes are shared by clusters of phase- and frequency-locked oscillators. As an essential modification of M-SSA, here we introduce variance-maximization (varimax) rotation of the M-SSA eigenvectors to optimally identify synchronized-oscillator clustering.

Multichannel singular spectrum analysis (M-SSA) provides an efficient way to identify weak oscillatory behavior in high-dimensional data. To prevent the misinterpretation of stochastic fluctuations in short time series as oscillations, Monte Carlo (MC)-type hypothesis tests provide objective criteria for the statistical significance of the oscillatory behavior. Procrustes target rotation is introduced here as a key method for refining previously available MC tests. The proposed modification helps reduce the risk of type-I errors, and it is shown to improve the test's discriminating power. The reliability of the proposed methodology is examined in an idealized setting for a cluster of harmonic oscillators immersed in red noise. Furthermore, the common method of data compression into a few leading principal components, prior to M-SSA, is re-examined and its possibly negative effects are discussed. Finally, the generalized Procrustes test is applied to the analysis of interannual variability in the North Atlantic's sea surface temperature and sea level pressure fields. The results of this analysis provide further evidence for shared mechanisms of variability between the Gulf Stream and the North Atlantic Oscillation in the interannual frequency band.

We introduce a new method to visualize dependencies between two time series applying the concept of cross recurrence plots to the local ordinal structure. We derive a measure of the coupling strength which is robust against observational noise, nonlinear distortion of the amplitude and lowfrequency trends. Connections to the instantaneous phase and the determination of phase coupling of two coupled Rössler systems in standard and funnel regime are shown. An application to EEG data demonstrates that the method is robust with respect to artifacts.

To cite this article: Collins PW, Møss J, Knobe K, Groth A, Colberg T, Watson E. Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX. J Thromb Haemost 2012; 10: 2305-12.Summary. Background: nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half-life. Objectives: To provide information on potential dose regimens for N9-GP for phase 3 pivotal and surgery trials. Methods: A population pharmacokinetic model was developed from single-dose data derived from the first human-dose trial with N9-GP in hemophilia B patients, and was used to extrapolate to steady-state conditions for different N9-GP dose regimens for prophylaxis. The model was also used to compare prophylaxis using N9-GP with standard prophylactic regimens using rFIX or plasma-derived (pd) FIX (40 IU kg )1 every third day). Plasma activity following dosing with N9-GP, rFIX and pdFIX for surgery and on-demand treatment of bleeds was also simulated. Results: A linear twocompartmental model best described the pharmacokinetic profiles of N9-GP, rFIX and pdFIX. A prophylactic regimen of 10 U kg )1 N9-GP once weekly predicted mean peak and trough levels of 18 and 4.2 U dL , respectively. Standard prophylactic regimens with rFIX and pdFIX predicted mean peak and trough levels of 34 and 3.9 IU dL )1 for rFIX, and mean values of 43 and 2.1 IU dL )1 for pdFIX.Additional simulations predicted significantly reduced dosing frequency and factor concentrate consumption for N9-GP vs. rFIX and pdFIX for surgery and the treatment of bleeds.Conclusions: N9-GP may allow prophylaxis, surgical dosing regimens and on-demand treatment of bleeding episodes with less frequent injections and lower factor concentrate consumption; this possibility is being investigated in prospective clinical trials.