Influence of PEPT2 on the Regional Distribution Kinetics of Cefadroxil in Brain Using Intracerebral Microdialysis in Rats, Wildtype and PEPT2 Knockout mice

Peptide transporter 2 (PEPT2) is a member of proton-coupled oligopeptide transporter (POT) family that recognizes and transports di-/tri-peptides and peptide-like drugs across cell membranes, thus playing an important role in substrate pharmacokinetics. In brain, PEPT2 works to efflux substrates from cerebrospinal fluid (CSF) into choroid plexus, thus limiting the substrate distribution in CSF. However, PEPT2 does not reduce the distribution of substrate in brain parenchyma, which is believed to be a more relevant site for the neurological effects of most compounds. Moreover, this finding is not consistent with the observance that PEPT2 decreases the neurological effects of its substrates (e.g., kyotorphin and 5-aminolevulinic acid). Considering that the brain parenchyma consists of extracellular fluid (ECF) and intracellular fluid (ICF), we hypothesized that PEPT2 has an impact in reducing substrate distribution in brain ECF, which is the site of neurological effects of most compounds. In the present study, intracerebral microdialysis (the only method to directly monitor drug concentrations in brain ECF) was applied to rats, wildtype and Pept2 knockout mice in order to study the impact of PEPT2 on the brain distribution of cefadroxil, a substrate of PEPT2 with high affinity. Our findings demonstrated that cefadroxil concentration in brain ECF of Pept2 knockout mice was 2.3 fold higher as compared to wildtype mice, indicating that PEPT2 as an efflux transporter at choroid plexus does not only reduce cefadroxil concentrations in CSF but also in brain ECF. Moreover, the microdialysis study of cefadroxil in rats (± probenecid) demonstrated that other transporters (e.g., OATs, MRPs and/or OATPs) were also involved in the elimination of cefadroxil from brain. PEPT2 also functions as an uptake transporter at brain cells (e.g., neurons in neonate and adult, and astrocytes in neonate), which resulted in a higher cefadroxil level in brain ICF compared to brain ECF (i.e., higher unbound volume distribution Vu,brain). These results provided significant insight into the mechanism by which PEPT2 affected the distribution of its substrates in brain (brain cells, ECF, and CSF) and could have important implications in the design and delivery of peptide-like pharmaceuticals for brain diseases.PHDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/137151/1/xmchen_1.pd

Threshold Optimization of interference image of surface roughness measuring interferometer

In this paper, a brief and effective method-arithmatic mean thresholding is suggested for segmenting interference image of complex light interferometer used in automatic measurement of surface roughness. The roughness profile information extracted from binary image after thresholding and the calculated results by sampling enough height deviation data from roughness profile coinside with those charted and measured by TALYSURF 6 profilemeter. This thresholding method is also suitable for segmenting interference image of laser surface roughness interferometer

Risk Aversion, Prudence, and the Three-Moment Decision Model for Hedging

The linear two-moment mean-variance (MV) model has been widely used in finance and economic decision analysis as an approximation of Von Neumann-Morgenstern expected utility (EU) model. The introduction of third or higher moments not only can improve the accuracy of the approximation, but is also suitable to represent investors¡¯ skewness preference (prudence) with the latter supported by empirical evidence. The goal of this paper is to develop a general MVS model and compare it and the traditional MV model against the EU model in the setting of an individual producer hedging in the futures market. Results show: 1) the derived linear MVS model maintains the analytical convenience of MV model, 2) it can generate different results as MV, 3) it approximate EU better than MV, and 4) it is more flexible than MV.Risk and Uncertainty,

Production Risk and Crop Insurance Effectiveness: Organic Versus Conventional Apples

This paper empirically examines the income risks for Pacific Northwest apple growers, both conventional and organic. Current yield based apple production insurance, the Growers Yield Certification (GYC), and hypothesized revenue based insurance are also examined for their risk management effect on growers. Results show that organic apple production is more risky but has higher expected return than its conventional counterpart. The current GYC is subsidized and subsidized more for organic growers. However, the current low price selection levels prevent these programs from offering effective risk reducing effect, and they also prevent the hypothesized revenue insurance from showing its advantage over yield insurance as in the case of other major field crops.Risk and Uncertainty,

THE CROWDING OUT EFFECTS OF THE 2002 FARM BILL ON HEDGING: EVIDENCE FROM PACIFIC NORTHWEST GRAIN FARMS

The 2002 Food Security and Rural Investment (FSRI) Act introduced a price protection program called Counter Cyclical Payments (CCP) to major grain producers in the US. The CCP program is an addition to the Loan Deficiency Payment (LDP) and Direct Payment (DP) programs from the previous 1996 Federal Agriculture Improvement and Reform (FAIR) Act. At the same time, US federally subsidized crop revenue insurance programs also protect farmers from market and production risks. These government policy programs may crowd out the traditional price risk management role of hedging in commodity futures markets.Agricultural and Food Policy, Crop Production/Industries,