Stochastic Models for Pad Structure and Pad Conditioning Used in Chemical-Mechanical Polishing

Stochastic models are presented for the structure and conditioning of pads used in chemical-mechanical polishing of wafers. First the one-dimensional distribution function of surface depth in the case of a conditioned solid pad is described. Then, for characterizing the structure of a foamed pad, the theory of random closed sets is applied. An important distributional characteristic of a random closed set, the linear contact distribution function, yields the contribution to surface depth resulting from pores. As a special example the Boolean model is considered. This leads to a formula that describes the variability of the surface of a conditioned foamed pad after a certain time. Simulations and experimental data show a good agreement between theory and reality.     

Fluid-Induced Seismicity: Theory, Modeling, and Applications

Operations including borehole fluid injections are typical for exploration and development of hydrocarbon or geothermic reservoirs. Microseismicity occurring during such operations has a large potential for understanding physics of the seismogenic process as well as in obtaining detailed information about reservoirs at locations as far as several kilometers from boreholes. We propose that the phenomenon of microseismicity triggering by borehole fluid injections is related to the process of the Frenkel–Biot slow wave propagation. In the low-frequency range (hours or days of fluid injection durations) this process reduces to the pore-pressure diffusion. We search for diffusion-related features of induced microseismicity. Two types of such signatures are considered. The first one is related to the geometry of microseismic clouds. Another type of signature is related to the probability of microearthquakes. On this basis we introduce a concept for interpretation of microseismic data which provides a possibility to infer information about hydraulic properties of rocks. Such information can be of significant importance for industrial applications and for understanding physical properties of geological structures.     

Efficient query execution on broadcasted index tree structures

The continuous broadcast of data together with an index structure is an effective way of disseminating data in a wireless mobile environment. The index allows a mobile client to tune in only when relevant data is available on the channel and leads to reduced power consumption for the clients. This paper investigates the execution of queries on broadcasted index trees when query execution corresponds to a partial traversal of the tree. Queries exhibiting this behavior include range queries and nearest neighbor queries. We present two broadcast schedules for index trees and two query algorithms executed by mobile clients. Our solutions simultaneously minimize tuning time and latency and adapt to the client’s available memory. Experimental results using real and synthetic data compare results for a broadcast with node repetition to one without node repetition and they show how a priority-based data management can help reduce tuning time and latency.     

Whole Exome Sequencing Identifies a Heterozygous Variant in the Cav1.3 Gene CACNA1D Associated with Familial Sinus Node Dysfunction and Focal Idiopathic Epilepsy

Cav1.3 voltage-gated L-type calcium channels (LTCCs) are involved in cardiac pacemaking, hearing and hormone secretion, but are also expressed postsynaptically in neurons. So far, homozygous loss of function mutations in CACNA1D encoding the Cav1.3 α₁-subunit are described in congenital sinus node dysfunction and deafness. In addition, germline mutations in CACNA1D have been linked to neurodevelopmental syndromes including epileptic seizures, autism, intellectual disability and primary hyperaldosteronism. Here, a three-generation family with a syndromal phenotype of sinus node dysfunction, idiopathic epilepsy and attention deficit hyperactivity disorder (ADHD) is investigated. Whole genome sequencing and functional heterologous expression studies were used to identify the disease-causing mechanisms in this novel syndromal disorder. We identified a heterozygous non-synonymous variant (p.Arg930His) in the CACNA1D gene that cosegregated with the combined clinical phenotype in an autosomal dominant manner. Functional heterologous expression studies showed that the CACNA1D variant induces isoform-specific alterations of Cav1.3 channel gating: a gain of ion channel function was observed in the brain-specific short CACNA1D isoform (Cav1.3_S), whereas a loss of ion channel function was seen in the long (Cav1.3_L) isoform. The combined gain-of-function (GOF) and loss-of-function (LOF) induced by the R930H variant are likely to be associated with the rare combined clinical and syndromal phenotypes in the family. The GOF in the Cav1.3_S variant with high neuronal expression is likely to result in epilepsy, whereas the LOF in the long Cav1.3_L variant results in sinus node dysfunction.     

Establishment and Characterization of Novel Human Intestinal In Vitro Models for Absorption and First-Pass Metabolism Studies

Commonly used intestinal in vitro models are limited in their potential to predict oral drug absorption. They either lack the capability to form a tight cellular monolayer mimicking the intestinal epithelial barrier or the expression of cytochrome P450 3A4 (CYP3A4). The aim of this study was to establish a platform of colorectal cancer patient-derived cell lines for evaluation of human intestinal drug absorption and metabolism. We characterized ten 2D cell lines out of our collection with confluent outgrowth and long-lasting barrier forming potential as well as suitability for high throughput applications with special emphasis on expression and inducibility of CYP3A4. By assessment of the transepithelial electrical resistance (TEER) the cells barrier function capacity can be quantified. Very high TEER levels were detected for HROC60. A high basal CYP3A4 expression and function was found for HROC32. Eight cell lines showed higher CYP3A4 induction by stimulation via the vitamin D receptor compared to Caco-2 cells (5.1- to 16.8-fold change). Stimulation of the pregnane X receptor led to higher CYP3A4 induction in two cell lines. In sum, we identified the two cell lines HROC183 T0 M2 and HROC217 T1 M2 as useful tools for in vitro drug absorption studies. Due to their high TEER values and inducibility by drug receptor ligands, they may be superior to Caco-2 cells to analyze oral drug absorption and intestinal drug–drug interactions. Significance statement: Selecting appropriate candidates is important in preclinical drug development. Therefore, cell models to predict absorption from the human intestine are of the utmost importance. This study revealed that the human cell lines HROC183 T0 M2 and HROC217 T1 M2 may be better suited models and possess higher predictive power of pregnane X receptor- and vitamin D-mediated drug metabolism than Caco-2 cells. Consequently, they represent useful tools for predicting intestinal absorption and simultaneously enable assessment of membrane permeability and first-pass metabolism.     

Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects

The voltage-dependent L-type calcium channel isoform Ca_V1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the Ca_V1.2 α₁-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified Ca_V1.2^L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.     

Effects of organic and conventional growth systems on the content of carotenoids in carrot roots, and on intake and plasma status of carotenoids in humans

BACKGROUND: The demand for organic food products has increased during the last decades due to their probable health effects, among others. A higher content of secondary metabolites such as carotenoids in organic food products has been claimed, though not documented, to contribute to increased health effects of organic foods. The aim was to study the impact of organic and conventional agricultural systems on the content of carotenoids in carrots and human diets. In addition, a human cross‐over study was performed, measuring the plasma status of carotenoids in humans consuming diets made from crops from these agricultural systems. RESULTS: The content of carotenoids in carrot roots and human diets was not significantly affected by the agricultural production system or year, despite differences in fertilisation strategy and levels. The plasma status of carotenoids increased significantly after consumption of the organic and conventional diets, but no systematic differences between the agricultural production systems were observed. CONCLUSION: The expected higher content of presumed health‐promoting carotenoids in organic food products was not documented in this study. Copyright © 2011 Society of Chemical Industry     

Sulfur in wheat gluten: In situ analysis by X-ray absorption near edge structure (XANES) spectroscopy

The sulfur containing gluten proteins largely determine the baking quality of wheat. In order to probe the speciation of sulfur, gluten proteins [gliadin, high molecular weight (HMW) and low molecular weight (LMW) subunits of glutenin], stored glutenin subunits as well as flour were investigated in situ by S K-edge X-ray near edge absorption structure (XANES) spectroscopy. The spectra confirmed the existence of disulfide bonds in oxidised (oxygen stream) glutenin subunits, supporting their significance for the formation of gluten networks. Additionally, glutenin subunits, which were stored under ambient air and temperature conditions, predominantly contained sulfur of higher oxidation states (sulfoxide, sulfonic acid). The disulfide state and also sulfoxide and sulfonic acid states were detected after reoxidation of glutenin subunits with potassium bromate.