Annihilation of positrons trapped at the (100) and (111) surfaces of Si

We present results of theoretical studies of positron surface states and positron annihilation characteristics at the clean non reconstructed (100) and (111) surfaces of Si performed within the modified atomistic, superposition method. It is found that in the case of non reconstructed semiconductor surfaces, the positron surface state is localized mainly on the vacuum side of the topmost layer. The computed positron surface state energies Eb at the (100) and (111) surfaces of Si are -2.81 and -2.69 eV. In addition, calculations of the positron work functions with respect to the vacuum for bulk Si(100) and Si(111) yielded 2.34 and 2.23 eV, respectively demonstrating the stability of positron surface state on these surfaces. The positron surface state lifetime as well as probabilities for a positron trapped in a surface state to annihilate with relevant core-level electrons are computed for both surfaces, and compared with available experimental data

Theoretical study of the positron surface state at an alkali-metal surface

We present a quantum mechanical analysis of positrons trapped in a bound state at the (100) surface of bulk Cs, based on the treatment of a positron as a single charged particle trapped in an image potential-correlation well in the proximity of the surface atoms. The image-potential-induced positron surface state is calculated using the corrugated-mirror model in full three-dimensional geometry. Calculations show that the positron bound state is delocalized in the surface plane, but is strongly localized perpendicular to the surface mainly in the region between the top and the second layers of Cs atoms. The positron binding energy Eb in the surface state is computed to be 4.92 eV. Calculations on the positron annihilation rates for different Cs core levels are performed using the independent particle model. The positron surface state lifetime is calculated using the local density approximation method. The annihilation probabilities of a positron trapped at the Cs(100) surface with Cs 4p and 4d core electron levels are computed to be 0.065% and 0.22%, respectively. © 1995

Study of positron surface states on the alkali-metal-covered transition-metal surface

We present a first-principles study of annihilation probabilities of surface trapped positrons with core electrons at the Cu(100) surface with sub-monolayers of Cs adsorbed. Image-potential-induced positron surface states are calculated using a corrugated-mirror model in a full three-dimensional geometry. These states are studied for various arrangements of Cs atoms below and above the critical alkali-metal coverage of approximately 0.7 physical monolayer. Computer simulations of the deposition of Cs atoms are used to show that hexagonal close-packed Cs islands are formed at about 0.7 physical monolayer coverage of Cs. It is found that the abrupt decrease in the positron annihilation rate with Cu 3p electrons observed experimentally results from a metallization of the Cs islands. This causes a shift in the localization of the positron bound state from the Cs Cu interface to the vacuum side of the Cs overlayer, with the corresponding abrupt decrease in the positron annihilation probability with Cu electrons. Annihilation probabilities for positrons with Cs electrons are also computed and compared with experiment. © 1995

Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier–Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system’s components taken in isolation

Characteristics of the Early Immune Response Following Transplantation of Mouse ES Cell Derived Insulin-Producing Cell Clusters

Background The fully differentiated progeny of ES cells (ESC) may eventually be used for cell replacement therapy (CRT). However, elements of the innate immune system may contribute to damage or destruction of these tissues when transplanted. Methodology/Principal Findings Herein, we assessed the hitherto ill-defined contribution of the early innate immune response in CRT after transplantation of either ESC derived insulin producing cell clusters (IPCCs) or adult pancreatic islets. Ingress of neutrophil or macrophage cells was noted immediately at the site of IPCC transplantation, but this infiltration was attenuated by day three. Gene profiling identified specific inflammatory cytokines and chemokines that were either absent or sharply reduced by three days after IPCC transplantation. Thus, IPCC transplantation provoked less of an early immune response than pancreatic islet transplantation. Conclusions/Significance Our study offers insights into the characteristics of the immune response of an ESC derived tissue in the incipient stages following transplantation and suggests potential strategies to inhibit cell damage to ensure their long-term perpetuation and functionality in CRT

Eigenvalue Problem in Two Dimensions for an Irregular Boundary II: Neumann Condition

We formulate a systematic elegant perturbative scheme for determining the eigenvalues of the Helmholtz equation (\bigtriangledown^{2} + k^{2}){\psi} = 0 in two dimensions when the normal derivative of {\psi} vanishes on an irregular closed curve. Unique feature of this method, unlike other perturbation schemes, is that it does not require a separate formalism to treat degeneracies. Degenerate states are handled equally elegantly as the non-degenerate ones. A real parameter, extracted from the parameters defining the irregular boundary, serves as a perturbation parameter in this scheme as opposed to earlier schemes where the perturbation parameter is an artificial one. The efficacy of the proposed scheme is gauged by calculating the eigenvalues for elliptical and supercircular boundaries and comparing with the results obtained numerically. We also present a simple and interesting semi-empirical formula, determining the eigenspectrum of the 2D Helmholtz equation with the Dirichlet or the Neumann condition for a supercircular boundary. A comparison of the eigenspectrum for several low-lying modes obtained by employing the formula with the corresponding numerical estimates shows good agreement for a wide range of the supercircular exponent.Comment: 26 pages, 12 figure

Centrosome clustering and Cyclin D1 gene amplification in double minutes are common events in chromosomal unstable bladder tumors

Background: Aneuploidy, centrosome abnormalities and gene amplification are hallmarks of chromosome instability (CIN) in cancer. Yet there are no studies of the in vivo behavior of these phenomena within the same bladder tumor. Methods: Twenty-one paraffin-embedded bladder tumors were analyzed by conventional comparative genome hybridization and fluorescence in situ hybridization (FISH) with a cyclin D1 gene (CCND1)/centromere 11 dual-color probe. Immunofluorescent staining of α, β and γ tubulin was also performed. Results: Based on the CIN index, defined as the percentage of cells not displaying the modal number for chromosome 11, tumors were classified as CIN-negative and CIN-positive. Fourteen out of 21 tumors were considered CIN-positive. All T1G3 tumors were included in the CIN-positive group whereas the majority of Ta samples were classified as CIN-negative tumors. Centrosome clustering was observed in six out of 12 CIN-positive tumors analyzed. CCND1 amplification in homogeneously staining regions was present in six out of 14 CIN-positive tumors; three of them also showed amplification of this gene in double minutes. Conclusions: Complex in vivo behavior of CCND1 amplicon in bladder tumor cells has been demonstrated by accurate FISH analysis on paraffin-embedded tumors. Positive correlation between high heterogeneity, centrosome abnormalities and CCND1 amplification was found in T1G3 bladder carcinomas. This is the first study to provide insights into the coexistence of CCND1 amplification in homogeneously staining regions and double minutes in primary bladder tumors. It is noteworthy that those patients whose tumors showed double minutes had a significantly shorter overall survival rate (p < 0.001)

Novel Functional MAR Elements of Double Minute Chromosomes in Human Ovarian Cells Capable of Enhancing Gene Expression

Double minute chromosomes or double minutes (DMs) are cytogenetic hallmarks of extrachromosomal genomic amplification and play a critical role in tumorigenesis. Amplified copies of oncogenes in DMs have been associated with increased growth and survival of cancer cells but DNA sequences in DMs which are mostly non-coding remain to be characterized. Following sequencing and bioinformatics analyses, we have found 5 novel matrix attachment regions (MARs) in a 682 kb DM in the human ovarian cancer cell line, UACC-1598. By electrophoretic mobility shift assay (EMSA), we determined that all 5 MARs interact with the nuclear matrix in vitro. Furthermore, qPCR analysis revealed that these MARs associate with the nuclear matrix in vivo, indicating that they are functional. Transfection of MARs constructs into human embryonic kidney 293T cells showed significant enhancement of gene expression as measured by luciferase assay, suggesting that the identified MARS, particularly MARs 1 to 4, regulate their target genes in vivo and are potentially involved in DM-mediated oncogene activation

Point Mutations in c-Myc Uncouple Neoplastic Transformation from Multiple Other Phenotypes in Rat Fibroblasts

Deregulation of c-Myc (Myc) occurs in many cancers. In addition to transforming various cell types, Myc also influences additional transformation-associated cellular phenotypes including proliferation, survival, genomic instability, reactive oxygen species production, and metabolism. Although Myc is wild type in most cancers (wtMyc), it occasionally acquires point mutations in certain lymphomas. Some of these mutations confer a survival advantage despite partially attenuating proliferation and transformation. Here, we have evaluated four naturally-occurring or synthetic point mutations of Myc for their ability to affect these phenotypes, as well as to promote genomic instability, to generate reactive oxygen species and to up-regulate aerobic glycolysis and oxidative phosphorylation. Our findings indicate that many of these phenotypes are genetically and functionally independent of one another and are not necessary for transformation. Specifically, the higher rate of glucose metabolism known to be associated with wtMyc deregulation was found to be independent of transformation. One mutation (Q131R) was greatly impaired for nearly all of the studied Myc phenotypes, yet was able to retain some ability to transform. These findings indicate that, while the Myc phenotypes examined here make additive contributions to transformation, none, with the possible exception of increased reliance on extracellular glutamine for survival, are necessary for achieving this state