Failure to Preserve β-Cell Function With Mycophenolate Mofetil and Daclizumab Combined Therapy in Patients With New- Onset Type 1 Diabetes

OBJECTIVE This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in subjects with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test. RESULTS One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly. CONCLUSIONS Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process

A Live Zebrafish-Based Screening System for Human Nuclear Receptor Ligand and Cofactor Discovery

Nuclear receptors (NRs) belong to a superfamily of transcription factors that regulate numerous homeostatic, metabolic and reproductive processes. Taken together with their modulation by small lipophilic molecules, they also represent an important and successful class of drug targets. Although many NRs have been targeted successfully, the majority have not, and one third are still orphans. Here we report the development of an in vivo GFP-based reporter system suitable for monitoring NR activities in all cells and tissues using live zebrafish (Danio rerio). The human NR fusion proteins used also contain a new affinity tag cassette allowing the purification of receptors with bound molecules from responsive tissues. We show that these constructs 1) respond as expected to endogenous zebrafish hormones and cofactors, 2) facilitate efficient receptor and cofactor purification, 3) respond robustly to NR hormones and drugs and 4) yield readily quantifiable signals. Transgenic lines representing the majority of human NRs have been established and are available for the investigation of tissue- and isoform-specific ligands and cofactors

Tantalus, a Novel ASX-Interacting Protein with Tissue-Specific Functions

AbstractThe Drosophila trithorax- and Polycomb-group (trxG and PcG) proteins maintain activated and repressed transcriptional states at specific target gene loci. The Additional sex combs (Asx) gene is of particular interest as it appears to function in both protein complexes and yet its effects on target genes are more restricted. A novel protein, Tantalus (TAN), was identified in a yeast two-hybrid screen for ASX-interacting proteins that might confer tissue-specific ASX functions. TAN contains consensus nuclear localization sites and binds DNA in vitro. However, its subcellular localization varies in a tissue-specific fashion. In salivary glands, TAN is predominantly nuclear and associates with 66 euchromatic sites on polytene chromosomes, more than half of which overlap with ASX. These loci do not include the homeotic genes of the ANT and BX complexes bound by other PcG and trxG proteins. Rather, tan mutant defects are restricted to sensory organs. We show that one of these defects, shared by Asx, is genetically enhanced by Asx. Taken together, the data suggest that TAN is a tissue-specific cofactor for ASX, and that its activity may be partially controlled by subcellular trafficking

Towards an Explicit Model of D-brane Inflation

We present a detailed analysis of an explicit model of warped D-brane inflation, incorporating the effects of moduli stabilization. We consider the potential for D3-brane motion in a warped conifold background that includes fluxes and holomorphically-embedded D7-branes involved in moduli stabilization. Although the D7-branes significantly modify the inflaton potential, they do not correct the quadratic term in the potential, and hence do not cause a uniform change in the slow-roll parameter eta. Nevertheless, we present a simple example based on the Kuperstein embedding of D7-branes, z_1=constant, in which the potential can be fine-tuned to be sufficiently flat for inflation. To derive this result, it is essential to incorporate the fact that the compactification volume changes slightly as the D3-brane moves. We stress that the compactification geometry dictates certain relationships among the parameters in the inflaton Lagrangian, and these microscopic constraints impose severe restrictions on the space of possible models. We note that the shape of the final inflaton potential differs from projections given in earlier studies: in configurations where inflation occurs, it does so near an inflection point. Finally, we comment on the difficulty of making precise cosmological predictions in this scenario. This is the companion paper to arXiv:0705.3837.Comment: 68 pages, 6 figures; v2: fixed typos, added refs and clarifications; v3: expanded discussion of inflection point inflatio

Rituximab, B-lymphocyte depletion, and preservation of beta-cell function

BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition

Massive stars as thermonuclear reactors and their explosions following core collapse

Nuclear reactions transform atomic nuclei inside stars. This is the process of stellar nucleosynthesis. The basic concepts of determining nuclear reaction rates inside stars are reviewed. How stars manage to burn their fuel so slowly most of the time are also considered. Stellar thermonuclear reactions involving protons in hydrostatic burning are discussed first. Then I discuss triple alpha reactions in the helium burning stage. Carbon and oxygen survive in red giant stars because of the nuclear structure of oxygen and neon. Further nuclear burning of carbon, neon, oxygen and silicon in quiescent conditions are discussed next. In the subsequent core-collapse phase, neutronization due to electron capture from the top of the Fermi sea in a degenerate core takes place. The expected signal of neutrinos from a nearby supernova is calculated. The supernova often explodes inside a dense circumstellar medium, which is established due to the progenitor star losing its outermost envelope in a stellar wind or mass transfer in a binary system. The nature of the circumstellar medium and the ejecta of the supernova and their dynamics are revealed by observations in the optical, IR, radio, and X-ray bands, and I discuss some of these observations and their interpretations.Comment: To be published in " Principles and Perspectives in Cosmochemistry" Lecture Notes on Kodai School on Synthesis of Elements in Stars; ed. by Aruna Goswami & Eswar Reddy, Springer Verlag, 2009. Contains 21 figure