Celiac disease: how complicated can it get?

In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4+ T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4+ T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma

Inhibitor of antagonist binding to the muscarinic receptor is elevated in Alzheimer’s brain.

The 100,000×g supernatant fraction of human brain contains endogenous inhibitors of antagonist binding to the muscarinic receptor. Significantly greater inhibition was observed with Alzheimer's than non-demented control supernatant fractions. Low molecular weight inhibitor was separated from larger inhibitor species by membrane dialysis (3,500 dalton cut-off). The activity of low molecular weight inhibitor was greatly increased by sulfhydryl reducing agents. While the low molecular weight inhibitor was stable to heat, acid and base for short time periods (< 20 min), it was inactivated by acid hydrolysis (50% loss after 16 h, 100% loss after 96 h). The low molecular weight inhibitor activity is elevated approximately three-fold in Alzheimer's brain. The low molecular weight inhibitor from Alzheimer's brain was found to be a non-competitive inhibitor. This is the first report of endogenous inhibitors in human brain of ligand binding to the muscarinic receptor and of increased inhibitor activity in Alzheimer's disease

Wafer-level SLID bonding for MEMS encapsulation

Hermetic packaging is often an essential requirement to enable proper functionality throughout the device's lifetime and ensure the optimal performance of a micro electronic mechanical system (MEMS) device. Solid-liquid interdiffusion (SLID) bonding is a novel and attractive way to encapsulate MEMS devices at a wafer level. SLID bonding utilizes a low-melting-point metal to reduce the bonding process temperature; and metallic seal rings take out less of the valuable surface area and have a lower gas permeability compared to polymer or glass-based sealing materials. In addition, ductile metals can adopt mechanical and thermo-mechanical stresses during their service lifetime, which improves their reliability. In this study, the principles of Au-Sn and Cu-Sn SLID bonding are presented, which are meant to be used for wafer-level hermetic sealing of MEMS resonators. Seal rings in 15.24 cm silicon wafers were bonded at a width of 60 µm, electroplated, and used with Au-Sn and Cu-Sn layer structures. The wafer bonding temperature varied between 300 °C and 350 °C, and the bonding force was 3.5 kN under the ambient pressure, that is, it was less than 0.1 Pa. A shear test was used to compare the mechanical properties of the interconnections between both material systems. In addition, important factors pertaining to bond ring design are discussed according to their effects on the failure mechanisms. The results show that the design of metal structures can significantly affect the reliability of bond rings