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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.

Silk is a protein fiber used to weave fabrics and as a biomaterial in medical applications. Recently, genetically modified silks have been produced from transgenic silkworms. In the present study, transgenic silkworms for the mass production of three colors of fluorescent silks, (green, red, and orange) are generated using a vector originating from the fibroin H chain gene and a classical breeding method. The suitability of the recombinant silks for making fabrics is investigated by harvesting large amounts of the cocoons, obtained from rearing over 20 thousand silkworms. The application of low temperature and a weakly alkaline solution for cooking and reeling enables the production of silk fiber without loss of color. The maximum strain tolerated and Young's modulus of the fluorescent silks are similar to those of ordinary silk, although the maximum stress value of the recombinant silk is slightly lower than that of the control. Fabrics with fluorescent color are demonstrated using the recombinant silk, with the color persisting for over two years. The results indicate that large amounts of genetically modified silk can be made by transgenic silkworms, and the silk is applicable as functional silk fiber for making fabrics and for use in medical applications.

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To establish objective criteria for "grade 3" (G3) in T1 (TNM staging) colorectal cancer (CRC), a total of 296 T1 CRC cases were reviewed. The incidence of nodal involvement differed most greatly between G3 and non-G3 (21/27 [27%] and 6/162 [3.7%], respectively; P < .0001), when G3 was applied to tumors containing either or both of the following: (1) 10 or more solid cancer nests in the microscopic field of a 4x objective lens and (2) a mucin-producing component fully occupied the microscopic field of a 40x objective lens. Regarding G3, vascular invasion, and tumor budding as indicating the risk of metastasis, nodal involvement rate was 21.0% in the tumors with 1 or more risk factors, whereas it was only 1.7% in the no-risk tumors (P < .0001). In patients treated with local excision only, nodal recurrence occurred in 3 (20%) of 15 risk-positive patients, whereas none of 42 patients without risk factors had nodal recurrence (P = .016). In cases of locally excised T1 CRC, G3 as determined by the proposed criteria, vascular invasion, and budding would comprise a useful combination of parameters for determining the indication for additional laparotomy.