Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1.

Transporter-mediated drug-drug interactions (DDIs) are a major cause of drug toxicities. Using published genome-wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10-8 ). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q-value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter-mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established.

Emerging transporters of clinical importance: an update from the International Transporter Consortium.

The International Transporter Consortium (ITC) has recently described seven transporters of particular relevance to drug development. Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds, and drug-drug interactions (DDIs) in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal DDIs. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. In addition, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition.

Securin degradation is mediated by fzy and fzr, and is required for complete chromatid separation but not for cytokinesis.

We have studied the ubiquitination and degradation patterns of the human securin/PTTG protein. We show that, in contrast to budding yeast pds1, securin degradation is catalyzed by both fzy (fizzy/cdc20) and fzr (fizzy-related/cdh1/hct1). Both fzy and fzr also induce the APC/C to ubiquitinate securin in vitro. Securin degradation is mediated by an RXXL destruction box and a KEN box, and is inhibited only when both sequences are mutated. Interestingly, the non-degradable securin mutant is also partially ubiquitinated by fzy and fzr in vitro. Expressing the non-degradable securin mutant in cells frequently resulted in incomplete chromatid separation and gave rise to daughter cells connected by a thin chromatin fiber, presumably of chromosomes that failed to split completely. Strikingly, the mutant securin did not prevent the majority of sister chromatids from separating completely, nor did it prevent mitotic cyclin degradation and cytokinesis. This phenotype, reminiscent of the fission yeast cut (cells untimely torn) phenotype, is reported here for the first time in mammals.

Older people's driving habits, visual abilities, and subjective assessment of daily visual functioning.

OBJECTIVES: To explore the relationship between the status of daily visual functions, as measured by Mangione et al.'s (1992) ADVS, and: (a) visual functions that are related to driving; (b) the tendency of elderly people to drive in different visual conditions; and (c) the reasons older people give for limiting their driving under different conditions. STUDY DESIGN: The subjects were 80 elderly people, ages 64-85. Seventy three of these people still drove and seven had quit driving. Each participant was individually administered (a) a subjective questionnaire containing the ADVS and questions from the Established Populations for the Epidemiological Studies of the Elderly (EPESE); (b) objective measures of visual performance including visual acuity, contrast sensitivity, and visual search speed. RESULTS: Strong correlations were obtained between the responses to the subjective questionnaire and the objective measures of visual skills. Most subjects were cognizant of the changes in their quality of vision and changed their driving habits accordingly by avoiding driving at dark, on unfamiliar roads, and on long trips. There were also significant associations between the changes in driving behavior and performance on the vision tests. CONCLUSION: The ADVS can be used as a self-administered test of driving-related visual functioning, and is most relevant to self-restrictions in night driving.

The nutritional value of high-oil corn for broiler chicks.

A variety of corn (Natan) with high fat and protein contents (6.7 and 9.8%, respectively) was developed at Newe Ya'ar, Israel. The nutritive value of this corn for broiler chicks from 7 to 28 d of age was evaluated in two experiments. In the first experiment, Natan and a local conventional corn variety (LCC-2.9% fat and 7.2% protein) were incorporated in a relatively low-protein diet designated for the determination of AMEn by the substitution method. The AMEn content of Natan was found to be 3,658 kcal/kg, whereas that of LCC was 3,437 kcal/kg. There were no differences in feed intake or weight gain between chicks fed the two corn varieties, but feed efficiency of those fed the diet containing Natan was improved (P < .05). In the second experiment, the effects on the performance of chicks of diets adequate in protein and containing either imported conventional corn (ICC), or Natan, or ICC-enriched with corn oil and soybean meal (to equalize its fat and protein content to that of the diet containing Natan), were compared. There were no differences in feed intake or weight gain among chicks fed the three diets and in feed efficiency among chicks fed the diet containing Natan and those fed the other two diets, whereas, the enrichment of the ICC-containing diet significantly improved feed efficiency. It was concluded, therefore, that in spite of the high nutritional value of the high-oil corn, its effect on improving the performance of chicks, when replacing a conventional corn in a well-balanced diet, was not pronounced.

Nonuniform temperature distribution monitoring with an IR fiber-optic radiometer.

A fiber-optic radiometric system based on IR AgB(x)Cl(1)-(x), fiber was developed and different nonuniform temperature distributions have been investigated. Experimental results show agreement with the theoretical model. The developed system enables us to monitor nonuniform surface temperature distribution with an accuracy of δT = ±0.1 ° C.

Theory of noncontact point thermal sensing by fiber-optic radiometry.

This paper formulates a theory of noncontact point thermal sensing by fiber-optic radiometry. This theory covers the field of mid- and far-infrared fibers that are suitable for low-temperature radiometry. However, new problems arise in the infrared range, the emission of thermal radiation from the fiber itself due to infrared absorption introduces perturbations into the radiometry, and this must be taken into consideration. The model presented is based on three-dimensional optical geometry of bounded and tunneling skew rays and yields an analytical expression for the inclination and the skewness angle distribution of the guided power collected by the fiber from various layers of a thermal body. The effective field of view, the surface resolution, and the temperature resolution of fiber-optic radiometry are discussed. Thermal sensing by direct coupling is shown to have an advantage over the coupling of a focusing lens located behind the fiber tip. A formulation of fiber emissivity is presented that quantifies the suppression of radiometric perturbations in fiber-optic thermal sensing. Bulk and surface absorption in the fiber core and cladding absorption are all taken into consideration deriving emissivity. Combining the transmissivity and emissivity of the fiber, we propose a measurable criterion, a figure of merit, for fiber-optic radiometry.

Theory of fiber optic radiometry, emissivity of fibers, and distributed thermal sensors.

This paper formulates a general radiometric theory of multimode step index fibers, covering in particular the region of mid- and far IR fibers. The optical fiber is treated both as a passive waveguide, guiding the external radiation injected into it, as well as an active waveguide, generating internal thermal radiation which is guided to both fiber endfaces. Several fiber absorption profiles are considered. In other words, the thermal radiation sources coupling radiation into the guided modes of the fiber are in one case considered to be distributed in the core, and in another, to be distributed in the cladding. The model is based on 3-D optical geometry of bounded and tunneling skew rays and yields an analytical expression for the angular power distribution along the length of the fiber. The radiation emissivity of multimode fibers is formulated. Based on the model, the theory of a new fiber optic distributed thermal sensor is presented. This sensor needs no external source of radiation for its operation and is based on the self-generation of thermal radiation in a modified IR fiber. Such a sensor can be produced by deliberately inducing surface or bulk absorption in the fiber core or coating (cladding) a bare fiber core with an IR absorbing material.

Infrared fibers for radiometer thermometry in hypothermia and hyperthermia treatment.

Hypothermia is a condition which results from prolonged exposure to a cold environment. Rapid and efficient heating is needed to rewarm the patient from 32-35 degrees C to normal body temperature. Hyperthermia in cancer treatment involves heating malignant tumors to 42.5-43.0 degrees C for an extended period (e.g., 30 min) in an attempt to obtain remission. Microwave or radio frequency heating is often used for rewarming in hypothermia or for temperature elevation in hyperthermia treatment. One severe problem with such heating is the accurate measurement and control of temperature in the presence of a strong electromagnetic field. For this purpose, we have developed a fiberoptic radiometer system which is based on a nonmetallic, infrared fiber probe, which can operate either in contact or noncontact mode. In preliminary investigations, the radiometer worked well in a strong microwave or radiofrequency field, with an accuracy of +/- 0.5 degrees C. This fiberoptic thermometer was used to control the surface temperature of objects within +/- 2 degrees C.

Fibers for low-temperature radiometric measurements.

Theoretical calculations are presented for the performance of a fiber-optic radiometer which makes use of infrared transmitting fibers to measure low temperatures (near room temperature). We calculate the radiometer spatial resolution, the dependence of the radiometer signal on the surface temperature, and the minimum resolvable temperature difference (MRDeltaAT) of the radiometer. The performance of the fiber-optic radiometer is compared with a conventional optical (thin lens) radiometer.