Indiana University-Purdue University Indianapolis (IUPUI) / Pompe disease (PD) is a rare metabolic myopathy characterized by loss of acid alpha-glucosidase (GAA), the enzyme responsible for breaking down glycogen to glucose within the lysosomes. PD cells accumulate massive quantities of glycogen within their lysosomes, and as such, PD is classified as a “lysosomal storage disease” (LSD). GAA-deficient cells also exhibit accumulation of autophagic debris. Symptoms of severe infantile PD include extreme muscle weakness, hypotonia, and hypertrophic cardiomyopathy, resulting in death before one year of age. Certain LSDs are currently being successfully treated with enzyme replacement therapy (ERT), which involves intravenous infusion of a recombinant enzyme to counteract the endogenous deficiency. ERT has been less successful in PD, however, due to ineffective delivery of the recombinant enzyme. Alternatively, specific genes deletion may reduce lysosomal glycogen load, and could thus be targeted in PD therapy development. Absence of malin (EPM2B) or laforin (EPM2A) has been proposed to impair autophagy, which could reduce lysosomal glycogen levels. Additionally, deficiency of Stbd1 has been postulated to disable lysosomal glycogen import. Furthermore, Ptg deficiency was previously reported to abrogate Lafora body formation and correct neurological abnormalities in Lafora disease mouse models and could have similar effects on PD pathologies. The goal of this study was to characterize the effects of homozygous disruption of Epm2a, Epm2b, Stbd1, and Ptg loci on total glycogen levels in PD mouse model heart tissue, as in severe infantile PD, it is accumulation of glycogen in the heart that results in fatal hypertrophic cardiomyopathy. Gaa-/- mice were intercrossed with Epm2a-/-, Epm2b-/-, Stbd1-/-, and Ptg-/- mice to generate wildtype (WT), single knockout, and double knockout mice. The results indicated that Gaa-/- hearts accumulated up to 100-fold more glycogen than the WT. These mice also displayed cardiac hypertrophy. However, deficiency of Epm2a, Epm2b, Stbd1, or PTG in the Gaa-/- background did not reveal changes of statistical significance in either heart glycogen or cardiac hypertrophy. Nevertheless, since total glycogen was measured, these deficiencies should not be discarded in future discussions of PD therapy, as increasing sample sizes and/or distinguishing cytosolic from lysosomal glycogen content may yet reveal differences of greater significance.

Undoped body multi gate (MG) Metal Oxide Semiconductor Field Effect Transistors (MOSFET) are appearing as replacements for single gate bulk MOSFET in forthcoming sub-45nm technology nodes. It is therefore extremely necessary to develop compact models for MG transistors in order to use them in nano-scale integrated circuit design and simulation. There is however a sharp distinction between the electrostatics of traditional bulk transistors and undoped body devices. In bulk transistor, where the substrate is sufficiently doped, the inversion charges are located close to the surface and hence the surface potential solely controls the electrostatic integrity of the device. However, in undoped body devices, gate electric field penetrates the body center, and inversion charge exists throughout the body. In contrast to the bulk transistors, depending on device geometry, the potential of the body center of undoped body devices could be higher than the surface in weak inversion regime and the current flows through the center-part of the device instead of surface. Several crucial parameters (e.g. Sub-threshold slope) sometimes become more dependable on the potential of body center rather than the surface. Hence the body-center potential should also be modeled correctly along with the surface-potential for accurate calculation of inversion charge, threshold voltage and other related parameters of undoped body multi-gate transistors. Although several potential models for MG transistors have been proposed to capture the short channel behavior in the subthreshold regime but most of them are based on the crucial approximation of coverting the 2D Poisson’s equation into Laplace equation. This approximation holds good only at surface but breaks down at body center and in the moderate inversion regime. As a result all the previous models fail to capture the potential of body center Correctly and remain valid only in weak-inversion regime. In this work we have developed semiclassical compact models for potential distribution for double gate (DG) and cylindrical Gate-All-Around (GAA) transistors. The models are based on the analytical solution of 2D Poisson’s equation in the channel region and valid for both: a) weak and strong inversion regimes, b) long channel and short channel transistors, and, c) body surface and center. Using the proposed model, for the first time, it is demonstrated that the body potential versus gate voltage characteristics for the devices having equal channel lengths but different body thicknesses pass through a single common point (termed as crossover point). Using the concept of “crossover point” the effect of body thickness on the threshold voltage of undoped body multi-gate transistors is explained. Based on the proposed body potential model, a new compact model for the subthreshold swing is formulated. Some other parameters e.g. inversion charge, threshold voltage roll-off etc are also studied to demonstrate the impact of body center potential on the electrostatics of multi gate transistor. All the models are validated against professional numerical device simulator.