Characterization of Apo-Form Selective Inhibition of Indoleamine 2,3-Dioxygenase**

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.     

Identification of Tumor Antigens in Ovarian Cancers Using Local and Circulating Tumor-Specific Antibodies

Ovarian cancers include several disease subtypes and patients often present with advanced metastatic disease and a poor prognosis. New biomarkers for early diagnosis and targeted therapy are, therefore, urgently required. This study uses antibodies produced locally in tumor-draining lymph nodes (ASC probes) of individual ovarian cancer patients to screen two separate protein microarray platforms and identify cognate tumor antigens. The resulting antigen profiles were unique for each individual cancer patient and were used to generate a 50-antigen custom microarray. Serum from a separate cohort of ovarian cancer patients encompassing four disease subtypes was screened on the custom array and we identified 28.8% of all ovarian cancers, with a higher sensitivity for mucinous (50.0%) and serous (40.0%) subtypes. Combining local and circulating antibodies with high-density protein microarrays can identify novel, patient-specific tumor-associated antigens that may have diagnostic, prognostic or therapeutic uses in ovarian cancer.     

Comparison of methods to determine the endogenous amino acid flow at the terminal ileum of the growing rat

The aim was to compare a recently developed peptide alimentation method and the protein-free and regression methods for determining endogenous ileal nitrogen (N) and amino acid excretion in the rat, and to apply the endogenous loss estimates to determine the true ileal digestibility of a meat and bone meal (MBM). Preliminary investigations determined the effect of the time of sampling of digesta after a meal (slaughter method) for rats given a protein-free or an enzymically hydrolysed casein (EHC) based diet, on ileal digesta and endogenous N excretion. There was a significant (P < 0.05) effect of the time of sampling on the amount of digesta collected and the endogenous N excretion for both the EHC and protein-free fed rats. The amount of digesta collected from the terminal 20 cm of ileum and the endogenous N excretion for both the EHC and protein-free fed rats were greatest and least variable at 3 h post-feeding. In the main study, endogenous ileal amino acid excretions were determined in the growing rat fed an EHC-based diet (n = 6) and with subsequent treatment of the digesta using ultrafiltration or in six rats given a protein-free diet or by extrapolation from data for 30 animals given five diets which contained graded levels of MBM as the sole protein source. For the EHC treatment, the ileal digesta precipitate plus retentate was used to determine the endogenous flows. The ultrafiltration step excludes unabsorbed dietary amino acids from the measure of endogenous loss. Chromic oxide was the reference marker in all diets. The endogenous N flows determined by the protein-free and regression methods were similar but both significantly (P < 0.01) lower than those for rats fed the EHC-based diet. The mean endogenous ileal N flows determined by the peptide alimentation method, the protein-free and regression approaches were 1866, 1103 and 1019 μg g^?1 freeze dry matter intake, respectively. The endogenous amino acid flows at the terminal ileum were lower when determined using the traditional protein-free or regression methods. The true ileal digestibility coefficients for MBM were considerably higher based on the EHC versus protein-free endogenous flows.     

Landscape features control river's confluences water quality and tributary fish composition

Rivers networks represent hierarchical dendritic habitats within terrestrial landscapes and differences in connectivity and land use influence dispersal, and consequently biodiversity patterns. We, therefore, measured variation in water chemistry and fish abundance and related these to a number of landscape characteristics (e.g., wetland, urban, wooded, and agricultural) in the River Klarälven and its 30 permanently flowing tributaries. We hypothesized that these environmental attributes would differ between tributary and main stem habitat and that these differences would be driven by landscape attributes including land use. We found considerable intertributary variation in temperature and nutrient levels, and between the tributaries and the main stem. Generally, water temperature was lower in the tributaries, whereas nutrient levels were higher in the tributaries. The lower water temperature has implications for coldwater fishes, and we found two fishes, burbot and lamprey, associated with coldwater tributaries. We also found an inverse relationship between water quality and anthropogenic land use. Protecting tributaries with low anthropogenic impact will likely become increasingly important with ongoing global warming as they can function as thermal refugia for coldwater fishes. Hence, this study underscores the need to evaluate water courses at regional scales to identify spatial refuges and ensure connectivity.     

Preparation and characterization of biodiesel produced from fish oil

This study evaluated the production of biodiesel using fish oil as raw material. Two-stage alkaline-catalysis transesterification was performed with 6/1 molar ratio of methanol to oil at 55°C in the presence of 1 wt. % base amount of potassium hydroxide (KOH). The fuel properties of the biodiesel were further analyzed. The characterizations of the produced biodiesel showed that it met ASTM D 6751 standard with respect to acid number, flash point, water and sediment, free and total glycerin, sulfur content, distillation temperature, etc. It was found that cold soak and oxidative stability were out spec due to the high amount of polyunsaturated fatty acid present in the fish oil. However, through blending with used cooking oil biodiesel, in spec biodiesel fuel could be achieved.     

Using bald eagles to indicate the health of the Great Lakes' environment

The bald eagle (Haliaeetus leucocephalus) is one of the most studied birds of North America, and a great amount of natural life‐history information, including the response of various stressors on the eagles' ability to reproduce, are well known. In Michigan, the eagle has been chosen to track the trends of bioaccumulative compounds of concern across watersheds in the state. The state has been divided into major watersheds, and 20% of these are surveyed each year. A control area in northern Minnesota, Voyageurs National Park, is also sampled annually. We report here on the methods used, the preliminary results of the 1999 field season, and how differences in mercury concentrations varied over a 10‐year period. Mercury in feathers of nestling eagles declined over time only in Lakes Michigan and Huron, but have not decreased among other subpopulations in Michigan. Concentrations of polychlorinated biphenyls (PCBs) and 4,4′‐DDE in blood plasma from nestling eagles have declined over time for most subpopulations; however, they remain greater for breeding areas associated with the Great Lakes' food web. Sea eagles of the genus Haliaeetus are a good sentinel species to track trends in bioaccumulative compounds in aquatic systems.     

AN EXAMINATION OF ASTM PROCEDURES FOR DETERMINING SULFUR FORMS IN COAL

Several raw coals of various ranks were used to examine the effects of some of the variations in ASTM procedures on analytical results obtained for total sulfur and sulfur forms. ASTM procedures were also used to determine pyritic sulfur in two coals cleaned by selective agglomeration processes.In addition, organic sulfur values obtained by the indirect ASTM procedure were compared to those obtained directly by leaching coal with hot HNO3 followed by total sulfur determinations on the coal residue.

Differences in the ASTM leaching procedure with HNO3 did not significantly affect the pyritic sulfur results for any of the coals. However, small differences between the referee (leaching coal with HNO3) versus alternate (leaching coal ash with HCl) ASTM procedures for determining pyritic sulfur were observed.Neithei: procedure was consistently higher than the other.     

电缆与连接器（七）

（上接2008年第6期92页）3．3滤波器的安装滤波器在实际应用环境中的工作性能完全取决于其安装的方式,尤其是射频参考地的阻抗和滤波器到射频地的搭接阻抗。这些阻抗必须远远低于滤波器内并联电容的阻抗,同时,滤波器内部与外部的共模表面电流也必须具有最佳的返回路径。