Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109769/1/cptclpt201378.pd

PKCθ Regulates T Cell Motility via Ezrin-Radixin-Moesin Localization to the Uropod

Cell motility is a fundamental process crucial for function in many cell types, including T cells. T cell motility is critical for T cell-mediated immune responses, including initiation, activation, and effector function. While many extracellular receptors and cytoskeletal regulators have been shown to control T cell migration, relatively few signaling mediators have been identified that can modulate T cell motility. In this study, we find a previously unknown role for PKCθ in regulating T cell migration to lymph nodes. PKCθ localizes to the migrating T cell uropod and regulates localization of the MTOC, CD43 and ERM proteins to the uropod. Furthermore, PKCθ-deficient T cells are less responsive to chemokine induced migration and are defective in migration to lymph nodes. Our results reveal a novel role for PKCθ in regulating T cell migration and demonstrate that PKCθ signals downstream of CCR7 to regulate protein localization and uropod formation.</p

Hierarchical Equations of Motion Approach to Quantum Thermodynamics

We present a theoretical framework to investigate quantum thermodynamic processes under non-Markovian system-bath interactions on the basis of the hierarchical equations of motion (HEOM) approach, which is convenient to carry out numerically "exact" calculations. This formalism is valuable because it can be used to treat not only strong system-bath coupling but also system-bath correlation or entanglement, which will be essential to characterize the heat transport between the system and quantum heat baths. Using this formalism, we demonstrated an importance of the thermodynamic effect from the tri-partite correlations (TPC) for a two-level heat transfer model and a three-level autonomous heat engine model under the conditions that the conventional quantum master equation approaches are failed. Our numerical calculations show that TPC contributions, which distinguish the heat current from the energy current, have to be take into account to satisfy the thermodynamic laws.Comment: 9 pages, 4 figures. As a chapter of: F. Binder, L. A. Correa, C. Gogolin, J. Anders, and G. Adesso (eds.), "Thermodynamics in the quantum regime - Recent Progress and Outlook", (Springer International Publishing

Decoherence-assisted initialization of a resident hole spin polarization in a two-dimensional hole gas

We investigate spin dynamics of resident holes in a p-modulation-doped GaAs/Al$_{0.3}$Ga$_{0.7}$As single quantum well. Time-resolved Faraday and Kerr rotation, as well as resonant spin amplification, are utilized in our study. We observe that nonresonant or high power optical pumping leads to a resident hole spin polarization with opposite sign with respect to the optically oriented carriers, while low power resonant optical pumping only leads to a resident hole spin polarization if a sufficient in-plane magnetic field is applied. The competition between two different processes of spin orientation strongly modifies the shape of resonant spin amplification traces. Calculations of the spin dynamics in the electron--hole system are in good agreement with the experimental Kerr rotation and resonant spin amplification traces and allow us to determine the hole spin polarization within the sample after optical orientation, as well as to extract quantitative information about spin dephasing processes at various stages of the evolution.Comment: 10 pages, 6 figures; moderate modifications, one new figur

Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver

Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed

The Phylogenetic Structure of Reptile, Avian and Uropathogenic Escherichia coli with Particular Reference to Extraintestinal Pathotypes

The impact of the Gram-negative bacterium Escherichia coli (E. coli) on the microbiomic and pathogenic phenomena occurring in humans and other warm-blooded animals is relatively well-recognized. At the same time, there are scant data concerning the role of E. coli strains in the health and disease of cold-blooded animals. It is presently known that reptiles are common asymptomatic carriers of another human pathogen, Salmonella, which, when transferred to humans, may cause a disease referred to as reptile-associated salmonellosis (RAS). We therefore hypothesized that reptiles may also be carriers of specific E. coli strains (reptilian Escherichia coli, RepEC) which may differ in their genetic composition from the human uropathogenic strain (UPEC) and avian pathogenic E. coli (APEC). Therefore, we isolated RepECs (n = 24) from reptile feces and compared isolated strains’ pathogenic potentials and phylogenic relations with the aforementioned UPEC (n = 24) and APEC (n = 24) strains. To this end, we conducted an array of molecular analyses, including determination of the phylogenetic groups of E. coli, virulence genotyping, Pulsed-Field Gel Electrophoresis-Restriction Analysis (RA-PFGE) and genetic population structure analysis using Multi-Locus Sequence Typing (MLST). The majority of the tested RepEC strains belonged to nonpathogenic phylogroups, with an important exception of one strain, which belonged to the pathogenic group B2, typical of extraintestinal pathogenic E. coli. This strain was part of the globally disseminated ST131 lineage. Unlike RepEC strains and in line with previous studies, a high percentage of UPEC strains belonged to the phylogroup B2, and the percentage distribution of phylogroups among the tested APEC strains was relatively homogenous, with most coming from the following nonpathogenic groups: C, A and B1. The RA-PFGE displayed a high genetic diversity among all the tested E. coli groups. In the case of RepEC strains, the frequency of occurrence of virulence genes (VGs) was lower than in the UPEC and APEC strains. The presented study is one of the first attempting to compare the phylogenetic structures of E. coli populations isolated from three groups of vertebrates: reptiles, birds and mammals (humans).</jats:p

The mechanical response of a uranium-nobium alloy: a comparison of cast versus wrought processing

A rigorous experimentation and validation program is being undertaken to create constitutive models that elucidate the fundamental mechanisms controlling plasticity in uranium-6 wt.% niobium alloys (U-6Nb). The first, 'wrought', material produced by processing a cast ingot I'ia forging and forming into plate was studied. The second material investigated is a direct cast U-6Nb alloy. The purpose of the investigation is to detennine the principal differences, or more importantly, similarities, between the two materials due to processing. It is well known that parameters like grain size, impurity size and chemistry affect the deformation and failure characteristics of materials. Metallography conducted on these materials revealed that the microstructures are quite different. Characterization techniques like tension, compression, and shear were performed to find the principal differences between the materials as a function of stress state. Dynamic characterization using a split Hopkinson pressure bar in conjunction with Taylor impact testing was conducted to derive and thereafter validate constitutive material models. The Mechanical Threshold Strength Model is shown to accurately capture the constitutive response of these materials and Taylor cylinder tests are used to provide a robust way to verify and validate the constitutive model predictions of deformation by comparing finite element simulations with the experimental results. The primary differences between the materials will be described and predictions about material behavior will be made

Thermodynamic resource theories, non-commutativity and maximum entropy principles

We discuss some features of thermodynamics in the presence of multiple conserved quantities. We prove a generalisation of Landauer principle illustrating tradeoffs between the erasure costs paid in different ‘currencies’. We then show how the maximum entropy and complete passivity approaches give different answers in the presence of multiple observables. We discuss how this seems to prevent current resource theories from fully capturing thermodynamic aspects of non-commutativity

Synthesis and Characterization of Nonbanded U-Nb Plate Material

This report describes the synthesis and characterization of four plates, two each of U-5.5Nb and U-7.5Nb (nominal wt%) for aging studies described elsewhere. The plates were induction melted and cast into graphite molds that were unheated and {approx}0.5 inches thick to maximize the cooling rate and minimize large length-scale Nb segregation (banding). Microstructural images and electron microprobe traces observed after various processing stages, including casting, hot rolling, and homogenizing are documented. The as-cast microsegregation assumed the form of an isotropic cellular structure, with an amplitude of 3-15 wt% Nb and 40-50 micron-length scales. Subsequent thermomechanical processing was shown to be sufficient to attain Nb compositional homogeneity on local scales of hundreds of microns. The results of chemical analysis and other characterization methods are given. The principal impurity elements (of the 40+ elements measured) were carbon, boron, oxygen, tantalum, and iron. In all four plates, after homogenization, the Nb distribution across the entire plate cross-section showed minima at the plate faces and a broad maximum in the center, the differential being 0.5-0.7 wt% in U-7.5Nb and 0.2-0.5 wt% in U-5.5Nb. None of the impurity elements showed statistically significant variations between the center 50% of the plate volume vs the outer 25%. These plates were considered nonbanded and compositionally homogeneous for their proposed use because the required tensile, metallographic, and dilatometer specimens could be extracted from the fairly homogeneous center portion of the plate cross-section. Characterization of the phases and their transition temperatures by x-ray diffraction and dilatometry in rapidly quenched specimens from the final product confirmed that the microstructure of this plate material was suitable for the intended aging studies. The as-quenched tensile response from multiple specimens taken from each plate showed some variability, especially in the ultimate tensile strength and elongation to failure. In general, U-5.5Nb has higher strength and less ductility than U-7.5Nb, though both alloys exhibited the double yield behavior characteristic of banded U-6Nb