The Insulin-Like Growth Factor System and Neurological Complications in Diabetes

The IGF system plays vital roles in neuronal development, metabolism, regeneration and survival. It consists of IGF-I, IGF-II, insulin, IGF-I-receptor, and those of IGF-II and insulin as well as IGF-binding proteins. In the last decades it has become clear that perturbations of the IGF system play important roles in the pathogenesis of diabetic neurological complications. In the peripheral nervous system IGF-I, insulin, and C-peptide particularly in type 1 diabetes participate in the development of axonal degenerative changes and contributes to impaired regenerative capacities. These abnormalities of the IGF system appear to be less pronounced in type 2 diabetes, which may in part account for the relatively milder neurological complications in this type of diabetes. The members of the IGF system also provide anti-apoptotic effects on both peripheral and central nervous system neurons. Furthermore, both insulin and C-peptide and probably IGF-I possess gene regulatory capacities on myelin constituents and axonal cytoskeletal proteins. Therefore, replenishment of various members of the IGF system provides a reasonable rational for prevention and treatment of diabetic neurological complications

C-Peptide Prevents Hippocampal Apoptosis in Type 1 Diabetes

To explore mechanisms underlying central nervous system (CNS) complications in diabetes, we examined hippocampal neuronal apoptosis and loss, and the effect of C-peptide replacement in type 1 diabetic BB/W rats. Apoptosis was demonstrated after 8 months of diabetes, by DNA fragmentation, increased number of apoptotic cells, and an elevated ratio of Bax/Bcl-xL, accompanied by reduced neuronal density in the hippocampus. No apoptotic activity was detected and neuronal density was unchanged in 2-month diabetic hippocampus, whereas insulin-like growth factor (IGF) activities were impaired. In type 1 diabetic BB/W rats replaced with C-peptide, no TdT-mediated dUTP nick-end labeling (TUNEL)- positive cells were shown and DNA laddering was not evident in hippocampus at either 2 or 8 months. C-peptide administration prevented the preceding perturbation of IGF expression and reduced the elevated ratio of Bax/Bcl-xL. Our data suggest that type 1 diabetes causes a duration-dependent programmed cell death of the hippocampus, which is partially prevented by C-peptide

Crystal structure of the DNA-binding domain of Myelin-gene Regulatory Factor

Myelin-gene Regulatory Factor (MyRF) is one of the master transcription factors controlling myelin formation and development in oligodendrocytes which is crucial for the powerful brain functions. The N-terminal of MyRF, which contains a proline-rich region and a DNA binding domain (DBD), is auto-cleaved from the ER membrane, and then enters the nucleus to participate in transcription regulation of the myelin genes. Here we report the crystal structure of MyRF DBD. It shows an Ig-fold like architecture which consists of two antiparallel β-sheets with 7 main strands, packing against each other, forming a β-sandwich. Compared to its homolog, Ndt80, MyRF has a smaller and less complex DBD lacking the helices and the big loops outside the core. Structural alignment reveals that MyRF DBD possess less interaction sites with DNA than Ndt80 and may bind only at the major groove of DNA. Moreover, the structure reveals a trimeric assembly, agreeing with the previous report that MyRF DBD functions as a trimer. The mutant that we designed based on the structure disturbed trimer formation, but didn't affect the auto-cleavage reaction. It demonstrates that the activation of self-cleavage reaction of MyRF is independent of the presence of its N-terminal DBD homotrimer. The structure reported here will help to understand the molecular mechanism underlying the important roles of MyRF in myelin formation and development

The Effects of C-peptide on Type 1 Diabetic Polyneuropathies and Encephalopathy in the BB/Wor-rat

Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN. The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide. Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity. A significant abnormality in type 1 DPN is nodal degeneration. In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect. It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration. Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits. It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction. Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes

Preparation and Characteristic of Dextran-BSA Antibody and Establishment of it’s Elisa Immunoassay

The enzyme linked immunosorbent assay (ELISA) is a potential tool for the determination of dextran. In this study, dextran–BSA antigens were prepared by Reductive amination method, and were confirmed by SDS-PAGE and free amino detection. The effects of coupled reaction conditions such as different oxidation degree of dextran, the reaction time were investigated and the immunity of the resulting dextran- BSA neoglycoprotein antigens were evaluated through the interaction with standard dextran antibody. The immunogen was immunized with white rabbits to obtained polyclonal antibody respectively. A general and broad class-specific Elisa detection method was developed according to Elisa theory. The method was put to use for quantitative analysis of dextran in practical saccharose samples

The separability of tripartite Gaussian state with amplification and amplitude damping

Tripartite three mode Gaussian state undergoes parametric amplification and amplitude damping as well as thermal noise is studied. In the case of a state totally symmetrically interacting with the environment, the time dependent correlation matrix of the state in evolution is given. The conditions for fully separability and fully entanglement of the final tripartite three mode Gaussian state are worked out.Comment: 9 pages, 3 figure

Wolf-Rayet Galaxies in the Sloan Digital Sky Survey: the metallicity dependence of the initial mass function

We use a large sample of 174 Wolf-Rayet (WR) galaxies drawn from the Sloan Digital Sky Survey to study whether and how the slope of the stellar initial mass function depends on metallicity. We calculate for each object its oxygen abundance according to which we divide our sample into four metallicity subsamples. For each subsample, we then measure three quantities: the equivalent width of \hb emission line, the equivalent width of WR bump around 4650\AA, and the WR bump-to-\hb intensity ratio, and compare to the predictions of the same quantities by evolutionary synthesis models of Schaerer & Vacca. Such comparisons lead to a clear dependence of the slope of initial mass function ($\alpha$) on metallicity in that galaxies at higher metallicities tend to have steeper initial mass functions, with the slope index ranging from $\alpha\sim$1.00 for the lowest metallicity of $Z=0.001$ to $\alpha\sim$3.30 for the highest metallicity $Z=0.02$. We have carefully examined the possible sources of systematic error either in models or in our observational measurements and shown that these sources do not change this result.Comment: 12 pages, 6 figures, ApJ accepte