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91.
Perni RB Pitlik J Britt SD Court JJ Courtney LF Deininger DD Farmer LJ Gates CA Harbeson SL Levin RB Lin C Lin K Moon YC Luong YP O'Malley ET Rao BG Thomson JA Tung RD Van Drie JH Wei Y 《Bioorganic & medicinal chemistry letters》2004,14(6):1441-1446
The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed. 相似文献
92.
During nervous system development stem cell daughters must exit the proliferative cycle to adopt specific neural and glial fates and they must do so in the correct positions. Cell proliferation in the central nervous system occurs in neuroepithelia such as the neural retina and the ventricular zones. As cells are assigned specific fates they migrate out of the plane of the epithelium to form higher layers. Recent evidence from the Drosophila compound eye suggests that a novel mode of Ras pathway regulation may be crucial in both cell-cycle exit and neural patterning: "MAP Kinase cytoplasmic hold". 相似文献
93.
Maternal and perinatal morbidity and mortality rates are significantly higher in pregnancies complicated by preterm labor, pre-eclampsia and fetal growth restriction. Decades of research have not translated into a clear understanding of the underlying pathophysiologies or effective identification of women who are at high risk of developing these complications. Often the severity of these diseases does not correlate with the clinical symptoms, and current diagnostic methods are unable to accurately predict the conditions prior to clinical presentation. Though several potential markers have been proposed for each of these disorders, to date none have proven clinical utility. Emerging proteomic technology is only beginning to be employed in pregnancy research. A comprehensive analysis of gestational tissues can be expected to contribute to the elucidation of the complex molecular mechanisms of pregnancy and related complications. Comparison of the expression profiles of normal and pathogenic tissues and biofluids may also highlight novel candidate marker proteins that have so far remained undetected. More interestingly, rapidly evolving technologies using sophisticated bioinformatic tools are demonstrating their potential in disease diagnostics by using overall protein profiles to detect diseases. The clinical significance of these methodological advances is enormous. Early diagnosis together with improved understanding of underlying molecular mechanisms can enhance outcomes and increase effective management and therapeutic options. 相似文献
94.
Fernández CA Butterfield C Jackson G Moses MA 《The Journal of biological chemistry》2003,278(42):40989-40995
Tissue inhibitors of metalloproteinases (TIMPs) regulate tumor growth, progression, and angiogenesis in a variety of experimental cancer models and in human malignancies. Results from numerous studies have revealed important differences between TIMP family members in their ability to inhibit angiogenic processes in vitro and angiogenesis in vivo despite their universal ability to inhibit matrix metalloproteinase (MMP) activity. To address these differences, a series of structure-function studies were conducted to identify and to characterize the anti-angiogenic domains of TIMP-2, the endogenous MMP inhibitor that uniquely inhibits capillary endothelial cell (EC) proliferation as well as angiogenesis in vivo. We demonstrate that the COOH-terminal domain of TIMP-2 (T2C) inhibits the proliferation of capillary EC at molar concentrations comparable with those previously reported for intact TIMP-2, while the NH2-terminal domain (T2N), which inhibits MMP activity, has no significant anti-proliferative effect. Interestingly, although both T2N and T2C inhibited embryonic angiogenesis, only T2C resulted in the potent inhibition of angiogenesis driven by the exogenous addition of angiogenic mitogen, suggesting that MMP inhibition alone may not be sufficient to inhibit the aggressive neovascularization characteristic of aberrant angiogenesis. We further mapped the anti-proliferative activity of T2C to a 24-amino acid peptide corresponding to Loop 6 of TIMP-2 and show that Loop 6 is a potent inhibitor of both embryonic and mitogen-stimulated angiogenesis in vivo. These findings demonstrate that TIMP-2 possesses two distinct types of anti-angiogenic activities which can be uncoupled from each other, the first represented by its MMP-dependent inhibitory activity which can inhibit only embryonic neovascularization and the second represented by an MMP-independent activity which inhibits both normal angiogenesis and mitogen-driven angiogenesis in vivo. In addition, we report, for the first time, the discovery of Loop 6 as a novel and potent inhibitor of angiogenesis. 相似文献
95.
This experiment tested the hypothesis that using near-infrared (IR) imaging spectrometry on tablets through blister packs
permits the identification and composition of multiple individual tablets to be determined simultaneously. Aspirin was selected
for this study because its breakdown mechanism is well understood. Near-IR cameras were used to collect thousands of spectra
simultaneously from a field of packaged aspirin tablets. Tablets were selected by a principal component analysis selection
alogorithm. Graphs of the columns of the transformation matrix showed that salicylic acid and acetylsalicylic acid in the
samples were modeled by the principal components. The bootstrap error-adjusted single-sample technique chemometric-imaging
algorithm was used to draw probability-density contour plots that revealed tablet composition. Choice of color was used to
represent constituent identity, whereas intensity represented concentration. The percentage of usable pixels in the indium
antimonide (InSb) array was 99.9%. The SEP was 0.06% of the tablet mass for both water uptake and salicylic acid production.
The number of tablets that a typical near-IR camera can currently analyze simultaneously was also estimated to be approximately
1300. 相似文献
96.
Baldridge BR Burgess DE Zimmerman EE Carroll JJ Sprinkle AG Speakman RO Li SG Brown DR Taylor RF Dworkin S Randall DC 《American journal of physiology. Regulatory, integrative and comparative physiology》2002,283(3):R748-R756
This experiment quantified the initial disruption and subsequent adaptation of the blood pressure (BP)-heart rate (HR) relationship after spinal cord transection (SCT). BP and HR were recorded for 4 h via an implanted catheter in neurally intact, unanesthetized rats. The animals were then anesthetized, and their spinal cords were severed at T(1)-T(2) (n = 5) or T(4)-T(5) (n = 6) or sham lesioned (n = 4). BP was recorded for 4 h daily over the ensuing 6 days. The neurally intact rat showed a positive cross correlation, with HR leading BP at the peak by 1.8 +/- 0.8 (SD) s. The cross correlation in unanesthetized rats (n = 2) under neuromuscular blockade was also positive, with HR leading. After SCT at T(1)-T(2), the cross correlation became negative, with BP leading HR, and did not change during the next 6 days. The cross correlation also became negative 1-3 days after SCT at T(4)-T(5), but in four rats by day 6 and thereafter the cross correlation progressively reverted to a positive value. We propose that the positive cross correlation with HR leading BP in the intact rat results from an open-loop control that depends on intact supraspinal input to sympathetic preganglionic neurons in the spinal cord. After descending sympathetic pathways were severed at T(1)-T(2), the intact vagal pathway to the sinoatrial node dominated BP regulation via the baroreflex. We suggest that reestablishment of the positive correlation after SCT at T(4)-T(5) was attributable to the surviving sympathetic outflow to the heart and upper vasculature reasserting some effective function, perhaps in association with decreased spinal sympathetic hyperreflexia. The HR-BP cross correlation may index progression of sympathetic dysfunction in pathological processes. 相似文献
97.
Two types of xylanase gene, XYN11A (XYL1) and XYN11B (XYL2), were amplified by PCR and partially sequenced in four phytopathogenic species of the ascomycete fungal genus Cochliobolus (anamorph genus Bipolaris). Three of the species, C. heterostrophus (B. maydis), C. sativus (B. sorokiniana), and Bipolaris sorghicola (no teleomorph known), are interrelated; the fourth, C. spicifer (B. spicifera), was found, through analysis of the 5.8S RNA and internal transcribed spacer (ITS) sequences of its ribosomal DNA, to be
more distantly related to the other three. Isolates from all four species contain orthologous XYN11A and XYN11B genes, but a set of laboratory strains of C. heterostrophus gave no product corresponding to the XYN11B gene. The patterns of evolution of the two xylanase genes and ribosomal DNA sequences are mutually consistent; the results
indicate that the two genes were present in the common ancestor of all Cochliobolus species and are evolving independently of each other.
Received: 12 July 2001 / Accepted: 6 March 2002 相似文献
98.
Kiakos K Howard TT Lee M Hartley JA McHugh PJ 《The Journal of biological chemistry》2002,277(46):44576-44581
Nucleotide excision repair (NER) is the primary pathway for the removal of DNA adducts that distort the double helix. In the yeast Saccharomyces cerevisiae the RAD6 epistasis group defines a more poorly characterized set of DNA damage response pathways, believed to be distinct from NER. Here we show that the elimination of the DNA minor groove adducts formed by an important class of anticancer antibiotic (CC-1065 family) requires NER factors in S. cerevisiae. We also demonstrate that the elimination of this class of minor groove adduct from the active MFA2 gene depends upon functional Rad18 and Rad6. This is most clear for the repair of adducts on the transcribed strand, where an absolute requirement for Rad6 and Rad18 was seen. Further experiments revealed that a specific RAD6-RAD18-controlled subpathway, the RAD5 branch, mediates these events. Cells disrupted for rad5 are highly sensitive to this minor groove binding agent, and rad5 cells exhibit an in vivo adduct elimination defect indistinguishable from that seen in rad6 and rad18 cells as well as in NER-defective cells. Our results indicate that the RAD5 subpathway may interact with NER factors during the repair of certain DNA adducts. 相似文献
99.
Lin X Njenga MK Johnson AJ Pavelko KD David CS Pease LR Rodriguez M 《Journal of virology》2002,76(15):7799-7811
We investigated the role of the immune system in protecting against virus-induced demyelination by generating lines of transgenic B10 (H-2(b)) congenic mice expressing three independent contiguous coding regions of the Theiler's murine encephalomyelitis virus (TMEV) under the control of a class I major histocompatibility complex (MHC) promoter. TMEV infection of normally resistant B10 mice results in virus clearance and development of inflammatory demyelination in the spinal cord. Transgenic expression of the viral capsid genes resulted in inactivation of virus-specific CD8(+) T lymphocytes (class I MHC immune function) directed against the relevant peptides, but it did not affect production of virus capsid-specific antibodies or lymphocyte proliferation to the virus antigen (class II MHC immune functions). Following intracerebral infection with TMEV, all three lines of mice survived the acute encephalitis but transgenic mice expressing VP1 (or the cluster of virus capsid proteins [VP4, VP2, and VP3] mapping to the left of VP1 in the TMEV genome) developed virus persistence and subsequent demyelination in spinal cord white matter. Transgenic mice expressing noncapsid proteins mapping to the right of VP1 (2A, 2B, 2C, 3A, 3B, 3C, and 3D) cleared the virus and did not develop demyelination. These results are consistent with the hypothesis that virus capsid gene products of TMEV stimulate class I-restricted CD8(+) T-cell immune responses, which are important for virus clearance and for protection against myelin destruction. Presented within the context of self-antigens, inactivation of these cells by ubiquitous expression of relevant virus capsid peptides partially inhibited resistance to virus-induced demyelination. 相似文献
100.
Maneesha E. Andrews Julia P. Moses S. Sendhil C. Rakkappan Rajadas Jayakumar 《Letters in Peptide Science》2002,9(4-5):167-172
Density and sound velocity measurements and 1H NMR investigations were carried out in aqueous solution at various temperatures for determining the adiabatic compressibility () and hydration of the tetrapeptide, TFA. Tyr-Gly-Phe-Ala-Obz I. The present investigation showed changes in the temperature coefficient of adiabatic compressibility at 40 °C. 1H NMR studies indicated the inverse temperature transition in the concentration range studied. 相似文献