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101.
102.
X Chen DJ Kempf HL Sham BE Green A Molla M Korneyeva S Vasavanonda NE Wideburg A Saldivar KC Marsh E McDonald DW Norbeck 《Canadian Metallurgical Quarterly》1998,8(24):3531-3536
The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed. 相似文献
103.
104.
FG Gervais NA Thornberry SC Ruffolo DW Nicholson S Roy 《Canadian Metallurgical Quarterly》1998,273(27):17102-17108
Focal adhesion kinase (Fak) is a non-receptor protein-tyrosine kinase that stimulates cell spreading and motility by promoting the formation of contact sites between the cell and the extracellular matrix (focal adhesions). It suppresses apoptosis by transducing survival signals that emanate from focal adhesions via the clustering of transmembrane integrins by components of the extracellular matrix. We demonstrate that Fak is cleaved by caspases at two distinct sites during apoptosis. The sites were mapped to DQTD772, which was preferentially cleaved by caspase-3, and VSWD704, which was preferentially cleaved by caspase-6 and cytotoxic T lymphocyte-derived granzyme B. The cleavage of Fak during apoptosis separates the tyrosine kinase domain from the focal adhesion targeting (FAT) domain. The carboxyl-terminal fragments that are generated suppress phosphorylation of endogenous Fak and thus resemble a natural variant of Fak, FRNK, that inhibits Fak activity by preventing the localization of Fak to focal adhesions. The cleavage of Fak by caspases may thus play an important role in the execution of the suicide program by disabling the anti-apoptotic function of Fak. Interestingly, rodent Fak lacks an optimal caspase-3 consensus cleavage site although it is cleaved in murine cells undergoing apoptosis at an upstream site. This appears to be the first example of a caspase substrate where the cleavage sites are not conserved between species. 相似文献
105.
Damage to cochlear efferents in chinchillas was assessed using transmission electron microscopy following unilateral treatment with the cholinotoxin ethylcholine mustard aziridinium ion (AF64A). AF64A was diluted in artificial perilymph to concentrations ranging from 0.5 to 100 microM. Survival times ranged from 1 to 12 weeks. At concentrations above 10 microM, widespread damage was noted to efferent fibers within the inner spiral bundle (ISB), tunnel spiral bundle (TSB), tunnel radial fibers (TRF) and efferent terminals at the base of OHCs. This damage included degeneration of fibers and terminals, delamination of mitochondria, vacuolization, and loss of cell membrane. However, at high concentrations, non-specific damage was also noted as thinnings or discontinuities of the membrane of OHCs and afferent fibers. At concentrations between 3 and 10 microM, selective damage was observed to efferent fibers within the ISB, TSB, TRF, and to terminals at the base of the OHCs, with all other structures appearing normal. At concentrations of 0.5 and 1 microM, damage was limited to efferent fibers within the TSB and ISB below the inner hair cells. In general, insult was greatest to middle- and basal-turn efferents, and longer survival times did not produce greater damage to, or loss of, efferents. These data suggest that at low concentrations, AF64A produces a partial yet selective degeneration of cochlear efferents within both the medial and lateral tracts, and that at the lowest concentrations used in these studies, AF64A produces a preferential insult on lateral olivocochlear efferents. 相似文献
106.
107.
SA Petrill K Saudino SS Cherny RN Emde DW Fulker JK Hewitt R Plomin 《Canadian Metallurgical Quarterly》1998,69(1):68-74
Two definitions of normality ("isolated" or "correlated") are considered. The boundaries of "isolated" normality were determined by a statistical procedure, whereas the "correlated" approach was related to a clinical or predictive definition. In the latter case, the biological variations were considered abnormal if they implied a hazard with some significant future ailment as a risk factor. In this pragmatic approach, the upper limit of normal/abnormal variations is the point beyond which medical strategy is related to the most expected benefit when applied to a definite population or to an individual patient. The capacity of a diagnostic test to discriminate between patients with a defined risk and those without risk depends strictly on the value of the parameter chosen. In medical care for the prevention of vascular complications in diabetic patients or with foetal risks in pregnant women, the limits of the so-called normal range of glycaemia and other parameters should be determined according to the objective of the preventive and/or therapeutic measures to be prescribed. 相似文献
108.
109.
Neuropeptide Y(NPY) inhibits Ca2+-activated K+ channels reversibly in vascular smooth muscle cells from the rat tail artery. NPY (200 microM) had no effect in the absence of intracellular adenosine 5'-triphosphate (ATP) and when the metabolic poison cyanide-M-chlorophenyl hydrozone (10 microM) was included in the intracellular pipette solution. NPY was also not effective when ATP was substituted by the non-hydrolysable ATP analogue adenosine 5'-[beta gamma-methylene]-triphosphate (AMP-PCP). NPY inhibited Ca2+-activated K+ channel activity when ATP was replaced by adenosine 5'-O-(3-thiotriphosphate) (ATP [gamma-S]) and the inhibition was not readily reversed upon washing. Protein kinase inhibitor (1 microM), a specific inhibitor of adenosine 3', 5'-cyclic monophosphate-dependent protein kinase, had no significant effect on the inhibitory action of NPY. The effect of NPY on single-channel activity was inhibited by the tyrosine kinase inhibitor genistein (10 microM) but not by daidzein, an inactive analogue of genistein. These observations suggest that the inhibition by NPY of Ca2+-activated K+ channels is mediated by ATP-dependent phosphorylation. The inhibitory effect of NPY was antagonized by the tyrosine kinase inhibitor genistein. 相似文献
110.
Nuclear scintigraphy was used to assess digital perfusion before and after treatment in 10 horses with clinical and radiographic evidence of chronic laminitis. Horses were evaluated for lameness, degree of distal phalanx rotation, and heel-toe hoof wall growth ratio, and randomly divided into two treatment groups. Group 1 horses received only egg bar-heart bar shoeing; Group 2 underwent egg bar-heart bar shoeing and coronary grooving. Horses were re-evaluated for digital perfusion, lameness, degree of distal phalanx rotation, and hoof wall growth at 6 week intervals over the 18 week follow-up period. Prior to treatment, relative scintigraphic activity at the dorsal laminar area was decreased and relative scintigraphic activity at the toe and adjacent solar area was increased. Egg bar-heart bar shoeing was associated with significantly increased dorsal laminar scintigraphic activity and significantly decreased solar scintigraphic activity over the 18 week period. Coronary grooving, in combination with egg bar-heart bar shoeing, resulted in a significantly lower heel-toe hoof wall growth ratio but did not enhance digital perfusion. Seven of 10 (70%) horses were responsive to treatment, defined as an improvement in lameness by at least one grade. Horses that were refractory to treatment had significantly lower dorsal laminar scintigraphic activity and higher palmar coronary scintigraphic activity prior to treatment than horses that responded to treatment. Our results are the first to demonstrate that egg bar-heart bar shoeing is associated with improved dorsal laminar perfusion, and support the use of this technique. In addition, we found that pre-treatment nuclear scintigraphy was predictive of clinical outcome in horses with chronic laminitis treated with corrective shoeing. 相似文献