Solution and solid phase synthetic methods leading to the rapid, stereocontrolled construction of highly functionalized fused bicyclic amino acid derivatives have been developed. The key step ...involves a unique application of the intramolecular Pauson-Khand cyclization for the construction of hexahydro-1H-2pyrindinone ring systems. Further modifications which demonstrate the potential for combinatorial library generation are also disclosed.
Longitudinal studies require high follow-up rates in order to maintain statistical power, reduce bias, and enhance the generalizability of results. This study reports on locating and survey ...completion for a 10-year follow-up of the Focus on Families project, an investigation of 130 families headed by parents who were enrolled in methadone treatment for opiate addiction. Despite having no contact with participants in the study for at least 10 years, the project successfully located nearly 99% of parent participants and 98% of their children. Twenty-four percent of the parents and one child had died before the follow-up. Of the surviving sample, 91% of parents and 86% of the children completed the follow-up interview. Multiple techniques were used to locate study participants, including internet searches, researching court and public records, collaborating with government and service agencies, and contacting family and social networks. For more than half of the sample, costly efforts were required to locate individual participants.
The antibacterial target enoyl-acyl carrier protein (ACP) reductase is a homotetrameric enzyme that catalyzes the last reductive step of fatty acid biosynthesis. In the present paper, four ...2-(2-hydroxyphenoxy)phenol inhibitors, wherein the 4-position substituent varied from H to n-propyl, were studied to determine the contribution of the aliphatic chain to the binding to the wild-type (wt) enoyl-ACP reductase from Escherichia coli (FabI) and a drug-resistant mutant, (F203L)FabI, in which phenylalanine 203 is mutated to leucine. Thermodynamic parameters of ternary complex formation (enzyme−NAD+−inhibitor) were determined by isothermal titration calorimetry. The inhibitor affinity to wt FabI and (F203L)FabI increases with increasing aliphatic chain length, although the corresponding affinity for (F203L)FabI is lower, and also, it shows no detectable binding to the 4-H inhibitor. A distinguishing feature of inhibitor binding to either binary enzyme−NAD+ complex is the apparent negative cooperativity for binding to the tetramer with half-site occupancy. For both enzymes, binding is enthalpy, ΔH, driven. However, binding ΔH becomes less favorable with increasing aliphatic chain length. Increases in affinity are found to be exclusively due to favorable changes in solvation entropy. Incremental changes in thermodynamic parameters within the series of inhibitors binding to wt FabI and (F203L)FabI are approximately the same. However, absolute differences between the two enzymes for binding to a given inhibitor are significant, suggesting different binding modes. This finding, coupled with a binding site conformation that is likely to be more rigid in the mutant, appears to result in the drug resistance of (F203L)FabI.
Poly(ethylene terephthalate) (PET) was treated with supercritical fluid (SCF) carbon dioxide to study crystallization of this polymer under SCF conditions. Solid state NMR spectroscopy and wide angle ...X-ray diffraction (WAXD) detected dramatic changes in the PET molecular structure and motion after treatment. To fit WAXD data, the powder diffraction pattern for crystalline PET was calculated and is reported here for the first time. The WAXD results indicate an increase in crystallinity from essentially zero in the as-received sample to 62% in the SCF-treated sample. This large increase in the crystallinity of the SCF-treated PET was verified by the NMR relaxation measurements. The X-ray crystallite size, obtained from WAXD, was compared with those obtained from NMR proton spin diffusion measurements. The 13C signals for aliphatic carbons (centered at 61.5 ppm) in the PET crystalline domain were resolved for the first time in a 13C cross polarization/magic angle spinning spectrum (CP/MAS) due to the SCF treatment. The 13C chemical shift tensors for PET were determined experimentally and were also compared to theoretical ab initio calculations. The anisotropic chemical shift data were then interpreted in terms of changes in the molecular conformation in PET as a result of SCF CO2 treatment. It was found that the SCF CO2 treatment is an effective method for enhancing the crystallinity of PET. These results in PET strongly support the previously proposed model for the existence of three motional regimes; crystalline, rigid amorphous, and mobile amorphous.
Macrophage accumulation is not only a characteristic hallmark but also a critical component of pulmonary artery (PA) remodeling associated with pulmonary hypertension (PH). However, the cellular and ...molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Utilizing multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, as well as primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive Pas (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL4/IL13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation while complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, while deficiency in C/EBPβ or HIF1 attenuated fibroblast driven macrophage activation. These findings challenge the current paradigm of IL4/IL13-STAT6 mediated alternative macrophage activation as the sole driver of vascular remodeling in PH and uncover a crosstalk between adventitial fibroblasts and macrophages in which paracrine IL6 activated STAT3, HIF1, and C/EBPβ signaling is critical for macrophage activation and polarization. Thus, targeting IL6 signaling in macrophages by completely inhibiting C/EBPβ, HIF1a or partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL6 and absent IL4/IL13 signaling.
The biological behavior of human polyclonal immunoglobulin G (IgG), radiolabeled with 99mTc via a nicotinyl hydrazine derivative (99mTc-HYNIC-IgG), was evaluated in normal human subjects.
Initial ...biodistribution and dosimetry studies were performed in six normal male volunteers. Additionally, 99mTc-IgG and 111In-DTPA-IgG were co-injected into six subjects and scintillation camera images were acquired at 6 and 18 hr later and serial blood and urine samples were collected. Biodistribution of both radiopharmaceuticals were measured by region of interest analysis. In the dual-injection group, images were crossover-corrected.
All subjects tolerated injection of the radiolabeled IgG preparations without apparent ill effects. Biodistribution of the two antibody preparations were remarkably similar with an increase in liver and abdominal activity for the 111In preparation. Linear correlation of the tissue-to-blood ratios of 99mTc and 111In-labeled IgG was observed at both times (r2 > 0.98). The slopes of the regression line were 0.97 and 0.76 at 6 and 18 hr, respectively. The beta phase of the blood clearance of 99mTc-HYNIC-IgG was significantly delayed (p < 0.01) compared with 111In-IgG (t1/2: 51.9 +/- 6.5 versus 35.3 +/- 3.4 hr). In contrast, the volumes of redistribution and urinary excretions of the radiopharmaceuticals were not significantly different.
These studies establish that the biodistribution of 99mTc-HYNIC-IgG in normal human subjects is nearly identical to 111In-DTPA-IgG.
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