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Biomedical subjects

A Peyman

Publications and source records attributed to A Peyman.

28 records · Page 2Linked to original sources
PubMed1996

c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption.

The primary defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorption by osteoclasts. Osteoclasts express high levels of the c-Src protein and the defect responsible for the osteopetrotic phenotype of the c-src-deficient (src-) mouse is cell-autonomous and occurs in mature osteoclasts. However, the specific signalling pathways that require c-Src expression for normal osteoclast activity have not been elucidated. We report here that the proto-oncogene product c-Cbl is tyrosine-phosphorylated in a Src-dependent manner in osteoclasts, where the two proteins colocalize on some vesicular structures. In vitro bone resorption by osteoclast-like cells (OCLs) is inhibited by both c-src and c-cbl antisense oligonucleotides. Furthermore, tyrosine phosphorylation of c-Cbl and the localization of c-Cbl-containing structures to the peripheral cytoskeleton are impaired in resorption-deficient c-src- OCLs, as well as in wild-type OCLs that have been treated with c-src antisense oligonucleotides. These results indicate that c-Cbl may act downstream of c-Src in a signalling pathway that is required for bone resorption.

3T3 Cells↗
PubMed1996

Minimally modified oligonucleotides - combination of end-capping and pyrimidine-protection.

The nuclease resistance of an oligonucleotide sequence that was phosphorothioate (PS)-modified in various positions and patterns was examined. We present a new ¿minimal' protection strategy for antisense oligonucleotides which is a combination of the end-capping technique and the protection of internal pyrimidine residues which are the major sites of endonuclease degradation. This strategy reduces the number of modifications needed to make a nuclease resistant oligonucleotide and therefore should minimize the non-sequence-specific effects that are frequently observed with uniformly modified oligonucleotides.

Base Sequence↗
PubMed1995

HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols.

A detailed structure-activity relationship of C2-symmetric diol inhibitors of HIV-1 protease leads to inhibitor 6 (HOE/BAY 793) which is outstanding in the inhibition of the enzyme and in the inhibition of viral replication in HIV infected cell culture (IC50: 0.3 nM; EC50: 3 nM). There are well defined steric requirements for the design of the side chains P1-P3 of the inhibitors. In addition, all three side chains need to be lipophilic. While the enzyme tolerates hydrophilic substituents in some cases, drastic reductions in anti-HIV activity are observed in cell culture, most likely due to insufficient cell penetration.

Carbon↗
PubMed1995

Inhibition of viral growth by antisense oligonucleotides directed against the IE110 and the UL30 mRNA of herpes simplex virus type-1.

In the present work we elucidate that the identification of active sequences for a given target is one of the principle hurdles of antisense oligonucleotide therapeutics. A number of 100 oligonucleotides directed against different target genes of HSV-1 and different locations within those genes were screened for antiviral activity. To facilitate comparison, the same length and the same chemical modification were used for all oligonucleotides: 20mers with two phosphorothioate linkages at both the 5'- and the 3'-end. No sequence-independent effects were observed with this type of modification. Surprisingly, only six oligonucleotides did show significant antiviral activity, the most active one (#6) being directed against the translation initiation site of IE 110.

Base Sequence↗
PubMed1994

Inhibition of c-Fos protein expression in rat spinal cord by antisense oligodeoxynucleotide superfusion.

Peripheral noxious stimulation leads to a rapid and transient expression of c-fos, c-jun and other immediate-early genes (IEGs) in the spinal cord. However, the role of IEG encoded transcription factors in plasticity of spinal neurons remains speculative. In the present study we have shown that superfusion of rat spinal cord with antisense oligodeoxynucleotides complementary to c-fos mRNA suppresses heat-induced c-Fos protein expression without affecting other members of the Fos and Jun family, thus providing a technique to determine the function of IEGs in vivo.

Animals↗
PubMed1994

P2 functions as a spacer in the Tetrahymena ribozyme.

The function of the P2 stem-loop region in the group I catalytic intron from Tetrahymena thermophila has been investigated. A comprehensive mutation analysis suggests that the bottom base pair of the P2 stem and nucleotides in the loop L2 are involved in interactions elsewhere on the intron. In addition, the P2 stem can be varied only between 9 and 11 base pairs in length. Phylogenetic evidence (3) from a sub-class of group I introns supports a model in which the P1 and P2 stems are coaxially stacked. We found that variation of the length of P2 does not shift the sites of intron-catalyzed cleavage in P1 (9). This suggests that coaxial stacking of the P1 and P2 stems is unlikely in the Tetrahymena intron. A narrowing of the window for cleavage activity and a drop in cleavage efficiency are observed when substrates with an insertion in P2 are compared with those with a deletion. A possible explanation for this phenomenon is an unfavorable movement of P1 away from the active site as a result of the the lengthening of P2.

Animals↗
PubMed1990

Stabilization of a reaction intermediate as a catalytic device: definition of the functional role of the flexible loop in triosephosphate isomerase.

The function of the mobile loop of triosephosphate isomerase has been investigated by deleting four contiguous residues from the part of this loop that interacts directly with the bound substrate. From the crystal structure of the wild-type enzyme, it appears that this excision will not significantly alter the conformation of the rest of the main chain of the protein. The specific catalytic activity of the purified mutant enzyme is nearly 10(5)-fold lower than that of the wild type. Kinetic measurements and isotopic partitioning studies show that the decrease in activity is due to much higher activation barriers for the enolization of enzyme-bound substrate. Although the substrates bind somewhat more weakly to the mutant enzyme than to the wild type, the intermediate analogue phosphoglycolohydroxamate binds much less well (by 200-fold) to the mutant. It seems that the deleted residues of the loop contribute critically to the stabilization of the enediol phosphate intermediate. Consistent with this view, the mutant enzyme can no longer prevent the loss of the enediol phosphate from the active site and its rapid decomposition to methylglyoxal and inorganic phosphate. Indeed, when glyceraldehyde 3-phosphate is the substrate, the enediol phosphate intermediate is lost (and decomposes) 5.5 times faster than it reprotonates to form the product dihydroxyacetone phosphate.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbohydrate Epimerases↗
PubMedDate not supplied

3'-End conjugates of minimally phosphorothioate-protected oligonucleotides with 1-O-hexadecylglycerol: synthesis and anti-ras activity in radiation-resistant cells.

Activation of the ras oncogene has been implicated in many types of human tumors. It has been shown that downmodulation of ras expression can lead to the reversion of the transformed phenotype of these tumor cells. Antisense oligodeoxyribonucleotides (ODNs) can inhibit gene expression by hybridization to complementary mRNA sequences. To minimize toxicity associated with all-phosphorothioated ODNs and improve cellular uptake, we used partially phosphorothioate (PPS)-modified ODNs having an additional hydrophobic tail at the 3'-end (PPS-C(16)). The PPS ODNs are protected against degradation by PS internucleotide linkages at both the 3'- and 5'-ends and additionally stabilized at internal pyrimidine sites, which are the major sites of endonuclease cleavage. Here we show that anti-ras PPS-C(16) ODN retains the high sequence-specificity of PPS ODNs and provides maximal inhibition of Ras p21 synthesis with minimal toxicity even without the use of a cellular uptake enhancer. Moreover, treatment of T24, a radiation-resistant human tumor cell line that carries a mutant ras gene, with anti-ras PPS-C(16) ODN resulted in a reduction in the radiation resistance of the cells in vitro. We also demonstrate that the growth of RS504 (a human c-Ha-ras transformed NIH/3T3 cell line) mouse tumors was significantly inhibited by the combination of intratumoral injection of anti-ras PPS-C(16) ODN and radiation treatment. These findings indicate the potential of this combination of antisense and conventional radiation therapy as a highly effective cancer treatment modality.

3' Untranslated Regions↗
PubMedDate not supplied

A regression model for correcting intraocular lens power after refractive surgery independent of preoperative data.

PURPOSE: To find a method of calculating intraocular lens (IOL) power that may be independent of preoperative data in eyes that have previously undergone myopic laser in situ keratomileusis (LASIK). METHODS: In 148 eyes of 75 patients, before and 6 months after LASIK, IOL power was calculated with SRK/T formula utilizing the spherical equivalent as the desired target refraction. Assuming that LASIK does not alter the crystalline lens refractive properties, IOL calculation error (CER) was estimated with this formula: CER = [pre-LASIK IOL power]/[post-LASIK IOL power]. Then the authors used postoperative biometry and Orbscan II corneal topography data in multiple regression models to find the best variables to predict the CER. Predicted amount of error which is calculated independent of preoperative data could be used to correct the post-LASIK calculated IOL: [corrected post-LASIK IOL power] = CER x [post-LASIK IOL power]. RESULTS: A regression model with these predictors was found: axial length in millimeters (L), radius of the anterior corneal surface best fitted sphere in millimeters divided by radius of the posterior corneal surface best fitted sphere in millimeters (AntBFS/PostBFS), corneal central 5 millimeters mean power in diopters divided by corneal central 3 millimeters mean power in diopters (mean 5 mm/mean 3 mm), the post-LASIK IOL power, and the post-LASIK simulated K reading. The model R square was 0.88. CONCLUSIONS: There is correlation between post-LASIK biometry values and IOL power correction factor. This study presents a new model for further investigation.

Adult↗