A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds ...are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.
...every Passion which doth rise Is as the several Atomes lies. ...Sicknesse, Health, and Peace, and War, Are alwaies as the several Atomes are.12 Cavendish's atomic determinism was a threat to other ...seventeenth-century conceptions of order that rely heavily on the mind, or soul, as evidence and expression of immanent order. ...order for Cavendish is not absolute, or even rational in a Hobbesian sense, but contingent on the interplay of autonomous, independent forces.14 Cavendish suggests that her brain is one such provisionally ordered system. Cavendish sees not only her own, but other people's ideas as physical, self-reflexive objects. ...Dioptrics," or science that makes use of magnifying lenses, is a "brittle art," and the arcane theory that the world was formed from circular motions of air is a "giddy and Dissie opinion. Perhaps not surprisingly, most new philosophers embraced a version of the Cartesian notion of the immaterial soul. ...many women writers used the notion of the immaterial soul to legitimize their work, arguing that if discourse is the product of an immaterial soul, sex ought not interfere with one's ability to write sensibly.
A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV ...replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50 (HIV-1) = 80 nM) containing P1/P1 benzyl and P2/P2 Boc substituents. Compound 9a is a selective inhibitor of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs. After i.v. and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40%) and a promising plasma elimination half-life (4 h).
This study discusses the importance of the idea of the material soul in the writings of Margaret Cavendish and, more broadly, in the literature of early modern England, showing that the seemingly ...arcane notion that discourse is the product of the psychic mechanism was central to Cavendish's works. I suggest that cultural proscriptions against early modern women's discourse were more complex than has been recognized. These proscriptions were both supported and made problematic by conflicting ideas about the nature of the soul. I argue that, in engaging these conflicting ideas, Cavendish exhibits not her personal inadequacies as a writer as has often been thought, but rather, simultaneously, a highly self-conscious strategy of self-representation and a sophisticated materialist psychology. In so doing, my study provides a new perspective on a tradition of early modern women's literature concerned with psychic development and management of the passions and shows that Cavendish responded to epistemological and class conflict in a singularly resourceful manner.
The basic disregard for the simplest ethical and social values is seen among collegiate student-athletes on an almost daily basis. Such negative national attention continues to erode the limited ...credibility of competitive athletics as a legitimate part of higher education. The NCAA has responded to the needs of collegiate student-athletes (and to a large extent the mounting criticism) with the development of the CHAMPS/Life Skills Program. The CHAMPS/Life Skills Program is without question an impressive, yet equally enormous, educational undertaking by the NCAA. Its stated goals and objectives are admirable (and perhaps achievable). However, no valid and reliable measure of the program's objectives currently exists, nor has there been any serious moral inquiry into the program's development. The current study was undertaken with these concerns in mind. Specifically, the purposes of this descriptive study were to develop a valid and reliable instrument to measure cognitive moral judgements; and to compare the cognitive moral judgements of general students and student-athletes at selected NCAA Division I institutions on issues of social responsibility, commonly addressed by CHAMPS/Life Skills Programs. Four hundred and fifteen subjects were utilized in data analysis. The convenience sample consisted of 202 general students and 213 student-athletes; 159 males and 256 females. A 5 x 2 x 3 x 3 Factorial Analysis of Variance (ANOVA) using the general linear model (GLM) was utilized to analyze the data. The basic differences (p < .05) noted between groups included: (1) females had significantly higher cognitive moral judgement scores than did males; (2) team sport athletes had significantly lower cognitive moral judgement scores than did non-athletes or individual sport athletes; and (3) revenue producing sport athletes had significantly lower cognitive moral judgement scores than did non-athletes or non-revenue producing sport athletes. These results support previous research concluding that competitive athletics, as currently practiced in America, negatively affects the moral reasoning/moral development of participants. Disturbingly, however, the present study finds that the lowered reasoning scores are not limited to the competitive context, but also appear on a measure of social responsibility.
On the Presence of Fixed Ammonium in Rocks Stevenson, F. J.
Science (American Association for the Advancement of Science),
1959-Jul-24, Volume:
130, Issue:
3369
Journal Article
Peer reviewed
From one-fourth to one-half of the nitrogen in some granite rocks, and up to two-thirds of that in some paleozoic shales, occurred as ammonium ions held within the lattice structure of silicate ...minerals. The results provide greater insight into the origin of the earth's atmosphere.
The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate ...compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.
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