Scaling planar silicon devices

The generation-over-generation scaling of critical CMOS technology parameters is ultimately bound by nonscalable limitations, such as the thermal voltage and the elementary electronic charge. Sustained improvement in performance and density has required the introduction of new device structures and materials. Partially depleted SOI, a most recent MOSFET innovation, has extended VLSI performance while introducing unique idiosyncrasies. Fully depleted SOI is one logical extension of this device design direction. Gate dielectric tunneling, device self-heating, and single-event upsets present developers of these next-generation devices with new challenges. Strained silicon and high-permittivity gate dielectric are examples of new materials that will enable CMOS developers to continue to deliver device performance enhancements in the sub-100 nm regime.     

Lorazepam-valproate interaction: studies in normal subjects and isolated perfused rat liver

Valproate (VPA) has been shown to interact with all the major antiepileptic drugs (AEDs) through two mechanisms of action: displacement from albumin binding sites and inhibition of drug metabolism. More recently, evidence showed that VPA inhibits the elimination of drugs metabolized by glucuronide conjugation. Lorazepam (LZP), which is primarily eliminated by conjugation with glucuronic acid, is administered concurrently with VPA both in treatment of epilepsy and in patients treated with VPA for psychiatric disorders. Therefore, a significant drug interaction is likely. We investigated such interaction both in in vitro isolated perfused rat liver (IPRL) and in normal subjects. LZP [2 mg, intravenous (i.v.) bolus] was administered to 8 normal volunteers before and after chronic dosing with VPA. In 6 of 8 subjects, VPA significantly decreased LZP plasma clearance by an average of 40% (p < 0.05) and increased LZP concentrations by decreasing formation clearance of the LZP glucuronide. In the IPRL studies, VPA also significantly decreased formation of LZP glucuronide (from 0.72 +/- 0.14 to 0.22 +/- 0.15 ml/h/kg, p < 0.05), indicating that IPRL is a useful tool for evaluation of the effect of VPA on drugs eliminated by glucuronide conjugation.     

The Role of the γ/ γeutectic and porosity on the tensile behavior of a single-crystal nickel-base superalloy

The microstructure of a single-crystal nickel-base superalloy, PWA 1480, has been varied by heat treatment and hot isostatic pressing in order to study the role of the γ/yγ′ eutectic and porosity on subsequent tensile behavior. The level of porosity was found not to affect any of the tensile properties, while the γ/γ′ eutectic strongly influenced ductility. Eliminating the γ/γ′ eutectic increased ductility which was attributed to the cleavage fracture of this constituent. It is proposed that such cleavage of the γ/γ′ eutectic is initiated by the stress created from impinging slip bands, promoting shear localization, and final fracture along {111} slip planes. The precise nature of this fracture process is discussed with emphasis on the role of the γ/′ micro-structure. The deformation structure of PWA 1480 was also studied, and while different in some respects from many other single-crystal superalloys, its fracture process appears to be similar. Formerly Graduate Student, Department of Metallurgical Engineering and Materials Science, Carnegie Mellon University.     

Identification of a gene that causes primary open angle glaucoma

Glaucoma is a major cause of blindness and is characterized by progressive degeneration of the optic nerve and is usually associated with elevated intraocular pressure. Analyses of sequence tagged site (STS) content and haplotype sharing between families affected with chromosome 1q-linked open angle glaucoma (GLC1A) were used to prioritize candidate genes for mutation screening. A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping. Thirteen glaucoma patients were found to have one of three mutations in this gene (3.9 percent of the population studied). One of these mutations was also found in a control individual (0.2 percent). Identification of these mutations will aid in early diagnosis, which is essential for optimal application of existing therapies.     

Wooden sticks as the source of a pseudoepidemic of infection with Rhizopus microsporus var. rhizopodiformis among immunocompromised patients

Wooden sticks used to suspend feces obtained for surveillance cultures were found to be the source of Rhizopus microsporus var. rhizopodiformis causing a pseudo-outbreak among 17 immunocompromised patients cared for in three different wards. Nonsterile wooden products should therefore not be used for collecting, handling, and processing specimens for microbiological examination.     

Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT1 receptor

Angiotensin II is the effector molecule of the renin-angiotensin system. Virtually all of its biochemical actions are mediated through a single class of cell-surface receptors called AT1. These receptors contain the structural features of the seven-transmembrane, G-protein-coupled receptor superfamily. Angiotensin II, acting through the AT1 receptor, also stimulates the Jak/STAT pathway by inducing ligand-dependent Jak2 tyrosine phosphorylation and activation. Here, we show that a glutathione S-transferase fusion protein containing the carboxyl-terminal 54 amino acids of the rat AT1A receptor physically binds to Jak2 in an angiotensin II-dependent manner. Deletional analysis, using both in vitro protocols and cell transfection analysis, showed that this association is dependent on the AT1A receptor motif YIPP (amino acids 319-322). The wild-type AT1A receptor can induce Jak2 tyrosine phosphorylation. In contrast, an AT1A receptor lacking the YIPP motif is unable to induce ligand-dependent phosphorylation of Jak2. Competition experiments with synthetic peptides suggest that each of the YIPP amino acids, including tyrosine 319, is important in Jak2 binding to the AT1A receptor. The binding of the AT1A receptor to the intracellular tyrosine kinase Jak2 supports the concept that the seven-transmembrane superfamily of receptors can physically associate with enzymatically active intracellular proteins, creating a signaling complex mechanistically similar to that observed with growth factor and cytokine receptors.     

Temporal order and functional analysis of mutations within the Fli-1 and p53 genes during the erythroleukemias induced by F-MuLV

The erythroleukemias induced by Friend murine leukemia virus (F-MuLV) result from the accumulation of a number of genetic changes, including activation of the Fli-1 proto-oncogene and inactivation of the p53 tumor suppressor gene. We have determined the temporal order of mutation of the genes involved in this multistage malignancy, by serial in vivo transplantation of F-MuLV induced primary erythroleukemias into syngenic Balb/c mice. These primary tumors are capable of growing when transplanted into syngenic mice, but die after several days of in vitro culture. From the transplanted tumors grown in syngenic mice, erythropoietin-dependent cell lines were established in culture that are clonally related to cells in the primary tumors. We show that retroviral insertional activation of the Fli-1 ets family member is the first detectable genetic event in F-MuLV induced primary erythroleukemias. Mutations in the p53 gene were observed in the Epo-dependent cell lines but not in the transplanted erythroleukemias used to establish these cell lines in culture. These data suggest that activation of Fli-1 plays an important role in the early stages of F-MuLV-induced leukemia, perhaps by altering the self-renewal probabilities of erythroid progenitor cells and that p53 mutations immortalize these cells, enabling them to grow in vitro in the presence of Epo.