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Human kininogen belongs to the plasma kallikreinkinin system. High molecular weight kininogen is the precursor for two-chain kinin-free kininogen and bradykinin. It has been shown that the two-chain kinin-free kininogen has the properties of anti-adhesion, anti-platelet aggregation, and anti-thrombosis, whereas bradykinin is a potent vasodilator and mediator of inflammation. In this study we show that the human kininogen gene is strongly up-regulated by agonists of the farnesoid X receptor (FXR), a nuclear receptor for bile acids. In primary human hepatocytes, both the endogenous FXR agonist chenodeoxycholate and synthetic FXR agonist GW4064 increased kininogen mRNA with a maximum induction of 8-10-fold. A more robust induction of kininogen expression was observed in HepG2 cells, where kininogen mRNA was increased by chenodeoxycholate or GW4064 up to 130-140-fold as shown by real time PCR. Northern blot analysis confirmed the up-regulation of kininogen expression by FXR agonists. To determine whether kininogen is a direct target of FXR, we examined the sequence of the kininogen promoter and identified a highly conserved FXR response element (inverted repeat, IR-1) in the proximity of the kininogen promoter (-66/-54). FXR/RXRalpha heterodimers specifically bind to this IR-1. A construct of a minimal promoter with the luciferase reporter containing this IR-1 was transactivated by FXR. Deletion or mutation of this IR-1 abolished FXR-mediated promoter activation, indicating that this IR-1 element is responsible for the promoter transactivation by FXR. We conclude that kininogen is a novel and direct target of FXR, and bile acids may play a role in the vasodilation and anti-coagulation processes.

Ligands for peroxisome proliferator activated receptors (PPARs) are used as hypolipidemic agents and for the treatment of type II diabetes, PPARa and PPARg, respectively. PPARs are members of the nuclear receptor family of ligand activated transcription factors which exert their effects primarily by regulating gene transcription. We have used gene microarrays to characterize PPAR ligands (profiling) and to investigate their mechanism of action. Compound profiles based on gene expression allow for novel ligand groupings when compared with groupings based on compound structure or on the results from single variable assays.

3,4-Epoxy-1-butene (I), prepared by the selective oxidation of butadiene, is an unusual difunctional monomer containing polymerizable vinyl and epoxy groups. As expected, free radical homopolymerization of I and its cyclic ketal derivatives was found to be very sluggish, as expected, for the allylic monomer structures. However, I was found to form alternating copolymers with maleic anhydride with both 1,2- and 1,5- enchainment observed. The structures of the alternating copolymers were observed to be solvent dependent with the in situ formation of cyclic ketals and their incorporation into the copolymers in polymerizations done in ketone solvents. Various cyclic ketal monomers derived from I readily formed alternating copoymers with maleic anhydride. Thermally activated self-crosslinking of these resins was observed.

A new method is described for the synthesis of polyimides utilizing bis(o-iodo esters) and primary diamines in the presence of carbon monoxide (CO) and a palladium catalyst. A goal of isolating the intermediate poly(amide esters) from these reactions was not realized. Under all conditions examined in the model systems, neutralizing bases suitable for promoting the carbonylation reaction also induced cyclization to the fully imidized product; intermediate amide esters were not observed. Hydrogen iodide traps such as olefins were also examined, but did not give the desired amide esters. Polyimides formed by this method were fully imidized and had thermal stability commensurate with conventionally prepared polymers. However, the synthetic scope of this method was limited to fully imidized polymers that were soluble in dipolar aprotic solvents

High molecular weight poly(imide-amides) can be readily formed by the palladium-mediated carbonylation and condensation reactions of activated chlorophthalimide monomers and aromatic diamines. The presence of iodide ion greatly accelerates the rate of reaction and increases the ultimate molecular weight of the polymer. Polymerizations proceed best using a protocol of high CO pressure (90 psig) for 2-4 h, followed by lower CO pressure (20 psig) in DMAc or NMPfor 24-48 h at 100°C using 0.3-3.0% PdCl 2 L 2 (L=PPh 3 ) as the catalyst with 2-6 equiv of PPh 3 /Pd and 0.3-1.0 equiv of an iodide/ chloro group

NMR View is a computer program designed for the visualization and analysis of NMR data. It allows the user to interact with a practically unlimited number of 2D, 3D and 4D NMR data files. Any number of spectral windows can be displayed on the screen in any size and location. Automatic peak picking and facilitated peak analysis features are included to aid in the assignment of complex NMR spectra. NMR View provides structure analysis features and data transfer to and from structure generation programs, allowing for a tight coupling between spectral analysis and structure generation. Visual correlation between structures and spectra can be done with the Molecular Data Viewer, a molecular graphics program with bidirectional communication to NMR View. The user interface can be customized and a command language is provided to allow for the automation of various tasks.

High molecular weight poly(imide-amides) can be readily formed by the palladium-mediated carbonylation and condensation reactions of diiodo imide monomers and aromatic diamines. Reaction conditions for polymerization are 100-120°C, 90 psig CO, 3-6% PdCl 2 L 2 (L=PPh 3 ), and 2.4 equiv of DBU for 2-4h in DMAc or NMP. This route offers the flexibility of incorporating different ratios of amide and imide groups in the polymer backbone in a controlled manner. The imide moiety is preformed, which eliminates the possibility of postpolymerization curing

High molecular weight aromatic polyamides can be synthesized by the palladium-catalyzed carbonylation and condensation of diiodoaromatics and aromatic diamines. This process is tolerant of a variety of functionality and, in one optimized system, was found to work best sligth a slight excess of the diamine monomer. At elevated CO pressures, a dramatic difference in reactivity between the m-diiodobenzene monomer and the corresponding bromo analogue was observed. In the former case, high molecular weight aromatic polyamide was formed in 1 h, and in the latter, only oligomers were isolated after 24 h

Wholly aromatic polyamides, including poly(1,4-phenyleneisophthalamide) and poly(1,4-phenyleneterephthalamide) are N-methylated to render them soluble in N,N-dimethylformamide, a common size-exclusion chromatography eluent. The procedure N-methylates 50–55% of the total amide linkages in these two examples, permitting reproducible measurement of their absolute molecular weight distributions using differential viscometry detection. There is no observable degradation in molecular weight resulting from the N-methylation, provided the excess methylating reagent is destroyed shortly after completion of the derivatization by quenching with potassium acetate. The validity of the molecular weight data obtained by the method is confirmed by light-scattering measurements on derivatized polymer and by comparison to the molecular weight of underivatized polymer that can be approximated from the intrinsic viscosity in concentrated sulfuric acid. The method is applicable to a variety of wholly aromatic polyamide structures. Examples are given.

The analysis of matrix-assisted laser desorption ionization post-source decay (MALDI-PSD) mass spectra of peptides by using the cross-correlation method for database searching is illustrated. MALDI-PSD mass spectra are shown to contain sufficient fragmentation information to uniquely identify the correct amino acid sequence from large protein databases (approximately 160,000 entries). A search employing the MALDI-PSD mass spectrum of a phosphorylated peptide that correctly identifies the amino acid sequence and the site of phosphorylation is also illustrated.

Copolymers of allyl methacrylate and propargyl methacrylate have very high speed as electron-beam and x-ray resists. They produce polymers of a structural complexity not often encountered in addition polymerization. The structural variety available in allyl methacrylate polymers gives them unusual properties, which consequently enhance their microlithographic performance.

A new application program, the BIOINFORMATICS PROFILER, is described which simplifies the analysis of new genome sequence information appearing on a daily basis. Control tasks are defined through an intuitive graphical user interface and are executed at user defined nightly intervals. Electronic mail is sent to indicate that search results have been found. All task output is presented to users in the form of hypertext (HTML), allowing easy browsing. Currently supported tasks include BLAST and FastA sequence searching, keyword based searching of network news articles and WAIS databases, examination of GenBank sequence entries using regular expressions and boolean operations and protein sequence motif searching.