Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain

The SH2-B protein is an SH2-domain-containing molecule that interacts with a number of phosphorylated kinase and receptor molecules including the insulin receptor. Two isoforms of the SH2-B have been identified and have been proposed to arise through alternate splicing. Here we have identified a third isoform of the SH2-B protein, SH2-Bγ, that interacts specifically with the insulin receptor. This interaction required phosphorylation of residue Y1146 in the triple tyrosine motif within the activation loop of the IR kinase and is one of only two signaling molecules shown to interact directly with this residue of the insulin receptor kinase domain. The intron/exon structure of the SH2-B gene was determined. Alternate splice sites utilized to generate the different isoforms of the SH2-B protein were identified in the 3′ end of the SH2-B gene immediately downstream of the exon encoding the core of the SH2 domain. Additionally, the chromosomal location of the SH2-B gene was determined to be the distal arm of mouse Chromosome (Chr) 7 in a region linked to obesity in mice. Received: 13 May 1999 / Accepted: 13 August 1999     

The real-life value of ST2 monitoring during heart failure decompensation: impact on long-term readmission and mortality

Context: Prognostic value of ST2 levels and dynamics has not been investigated in acute heart failure (AHF) using prospective real-life measurements.

Objective: The objective of this study is to investigate the prognostic value of ST2 in AHF.

Methods: ST2 levels were determined at admission (n?=?182) and discharge (n?=?85). Primary endpoint was the composite of all-cause death and HF rehospitalisation at one year.

Results: Discharge ST2 (HR 2.42 [95% CI 1.46–4], p?=?0.001) and ΔST2 (HR 2.32 [95% CI 1.21–4.57], p?=?0.01) but not admission ST2, remained independently prognostic for the primary endpoint after comprehensive multivariable adjustment. ST2 significantly improved prognosis stratification on top of clinical variables and NTproBNP.

Conclusions: Routine clinical use of discharge ST2 and ST2 dynamics provide independent prognostic information.     

COMPARATIVE STUDIES ON RESPIRATION : IX. THE EFFECTS OF ANTAGONISTIC SALTS ON THE RESPIRATION OF ASPERGILLUS NIGER.

1. In the presence of 0.05 per cent dextrose the respiration of Aspergillus niger is increased by NaCl in concentrations of 0.25 to 0.5M, and by 0.5M CaCl₂. 2. Stronger concentrations, as 2M NaCl and 1.25M CaCl₂, decrease the respiration. The decrease in the higher concentrations is probably an osmotic effect of these salts. 3. A mixture of 19 cc. of NaCl and 1 cc. of CaCl₂ (both 0.5M) showed antagonism, in that the respiration was normal, although each salt alone caused an increase. 4. Spores of Aspergillus niger did not germinate on 0.5M NaCl (plus 0.05 per cent dextrose) while they did on 0.5M CaCl₂ (plus 0.05 per cent dextrose) and on various mixtures of the two. This shows that a substance may have different effects on respiration from those which it has upon growth.     

Studies on enzymes in the developing sea urchin egg

The relative activity of a number of different enzymes has been determined in different developmental stages of normal and Li treated sea urchin eggs.Some enzymes show a constant activity throughout development, whereas the activity of other enzymes is constant up to mesenchymeblastula stage and then increases. A short review of enzymatic changes in other embryonic material is presented. This demonstrated a striking agreement with the sea urchin egg in essential points.It has been suggested that the enzymes which rise in activity at mesenchymeblastula stage are localized in mitochondria, whereas enzymes with constant activity are non-mitochondrial.Li treatment during cleavage stages, which causes vegetalization, inhibits the rise in activity of apyrase, cathepsin II, glutaminase, and according to preliminary experiments also of succinodehydrogenase.The authors conclude that Li treatment during cleavage stages interferes with the later development of mitochondria, possibly by inhibiting the development of their precursors.According to these results, the ectodermal development is characterized by a more important mitochondrial activity, i.e. a more elaborate mechanism of synthesis, than the mesentodermal development. This is at least the case during earlier stages of development.     

Comparative study of the interactions of cisplatin and carboplatin with nucleotides using UV resonance raman spectroscopy

We have obtained the UV excited resonance Raman spectra of five mononucleotides bound to cisplatin and to carboplatin using excitation in resonance with the first electronic absorption bands of the nucleotide bases. Substantial changes in the spectra are observed following interaction with both platinum drugs, indicating modifications to nucleotide structure. Pt (II) binds to base portions of the nucleotide molecules, altering their normal modes of vibration significantly. We present comparative data of cisplatin and carboplatin, and discuss the implications of these results. The kinetics of the drug/nucleotide reactions differ, but final products are found to be similar. © 1993 John Wiley & Sons, Inc.     

Simplified Bayesian Sensitivity Analysis for Mismeasured and Unobserved Confounders

Summary We examine situations where interest lies in the conditional association between outcome and exposure variables, given potential confounding variables. Concern arises that some potential confounders may not be measured accurately, whereas others may not be measured at all. Some form of sensitivity analysis might be employed, to assess how this limitation in available data impacts inference. A Bayesian approach to sensitivity analysis is straightforward in concept: a prior distribution is formed to encapsulate plausible relationships between unobserved and observed variables, and posterior inference about the conditional exposure–disease relationship then follows. In practice, though, it can be challenging to form such a prior distribution in both a realistic and simple manner. Moreover, it can be difficult to develop an attendant Markov chain Monte Carlo (MCMC) algorithm that will work effectively on a posterior distribution arising from a highly nonidentified model. In this article, a simple prior distribution for acknowledging both poorly measured and unmeasured confounding variables is developed. It requires that only a small number of hyperparameters be set by the user. Moreover, a particular computational approach for posterior inference is developed, because application of MCMC in a standard manner is seen to be ineffective in this problem.     

Alterations in P-glycoprotein expression in mouse tissues by doxorubicin: implications for pharmacokinetics in multiple dosing regimens.

The purpose of the studies presented here is to determine if alterations in doxorubicin (DOX) pharmacokinetics that seem to occur following multiple-dosing are due to changes in DOX elimination via P-glycoprotein (PGP) mediated transport in the liver, kidney and gut. A pharmacokinetic study in female Balb/c mice was carried out with blood and tissue DOX levels measured in animals following a single DOX treatment (6 mg/kg), and in animals following a second DOX treatment after receiving a DOX treatment a week earlier. The pharmacokinetics of DOX in blood and tissues was altered by earlier exposure to DOX, as the animals that were treated once a week for 2 weeks showed an increased rate of DOX elimination from blood and tissues following the second treatment. Immunoblot analysis of PGP expression in liver and kidney from na?ve and DOX-treated mice showed an approximately 1.2-fold elevation of PGP protein in these tissues in response to DOX exposure. Immunohistochemical staining of liver and small intestine sections for PGP showed 1.6-fold and 1.9-fold increases, respectively, in the DOX-treated tissues. These results have implications both in multiple-dosing regimens, as well as multiple-drug regimens, where DOX is used in combination with other drugs that are substrates for PGP-mediated efflux. Increases in PGP expression in both hepatic and extrahepatic tissues can lead to changes in the pharmacokinetics of DOX, as well as other drugs that are transported by PGP.