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[en] Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments. Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM. Treatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10–20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells. The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs
[en] The properties of hammerhead ribozymes are described. Various hammerhead ribozyme constructs for target RNA cleavage were considered. Approaches to enhancement of the stability of artificial ribozymes in biological media and to regulation of the catalytic activity of hammerhead ribozymes using effector molecules are described. The effect of ribozymes on extended structured natural RNAs is discussed. Applications of artificial hammerhead ribozymes as inhibitors of gene expression at matrix RNA level were considered.
[en] The unordered N-termini of parvovirus capsid proteins (Nt) are translocated through a channel at the icosahedral five-fold axis to serve for virus traffick. Heterologous peptides were genetically inserted at the Nt of MVM to study their functional tolerance to manipulations. Insertion of a 5T4-single-chain antibody at VP2-Nt (2Nt) yielded chimeric capsid subunits failing to enter the nucleus. The VEGFR2-binding peptide (V1) inserted at both 2Nt and VP1-Nt efficiently assembled in virions, but V1 disrupted VP1 and VP2 entry functions. The VP2 defect correlated with restricted externalization of V1-2Nt out of the coat. The specific infectivity of MVM and wtVP-pseudotyped mosaic MVM-V1 virions, upon heating and/or partial 2Nt cleavage, demonstrated that some 2Nt domains become intracellularly translocated out of the virus shell and cleaved to initiate entry. The V1 insertion defines a VP2-driven endosomal enlargement of the channel as an essential structural rearrangement performed by the MVM virion to infect.
[en] A series of functionalized furans were synthesized by way of a palladium -catalyzed coupling reaction of 2,3,5-tri substituted furans with aryl chlorides through C-H bond cleavages at C-4 position. The feature of the reaction was facilitative preparation of furan derivatives with good functional group tolerance. All reactions gave the desired products in moderate to good yields in the presences of BuAd2P and t-BuOK in DMF at 120 .deg. C after 15 h
[en] The peptidyl-tRNA hydrolase from M. tuberculosis has been crystallized in three closely related forms, two orthorhombic and one monoclinic, and X-ray diffraction data have been collected from them. Peptidyl-tRNA hydrolase catalyses the cleavage of the ester link between the peptide and the tRNA in peptidyl-tRNAs that, for various reasons, have dropped off the translating ribosomes. This enzyme from Mycobacterium tuberculosis has been crystallized in three related but distinct forms: P212121, unit-cell parameters a = 36.30, b = 61.85, c = 73.97 Å, P21, a = 35.83, b = 73.79, c = 59.79 Å, β = 92.3°, and P212121, a = 35.84, b = 57.06, c = 72.59 Å. X-ray data have been collected from all three forms
[en] The maturation of many small nuclear RNAs is dependent on RNase III-like endonuclease mediated cleavage, which generates a loading site for the exosome complex that trims the precursor at its 3' end. Using a temperature sensitive Pac1 nuclease, here we show that the endonuclease cleavage is equally important in terminating the transcription of the U2 snRNA in Schizosaccharomyces pombe. Using a temperature sensitive Dhp1p 5' → 3' exonuclease, we demonstrate that it also is an essential component of the termination pathway. Taken together the results support a 'reversed torpedoes' model for the termination and maturation of the U2 snRNA; the Pac1 endonuclease cleavage provides entry sites for the 3' and 5' exonuclease activities, leading to RNA maturation in one direction and transcript termination in the other.
[en] The results of studies of RNA bulge structures are reviewed. Cleavage of the phosphodiester bonds within RNA bulges is considered. Attention is focused on the factors influencing the cleavage efficiency. The state-of-the-art of the problem of targeted RNA cleavage induced by various reagents is discussed.
[en] The predicted Env protein of insect retroviruses (errantiviruses) is related to the envelope fusion protein of a major division of the Baculoviridae. The highest degree of homology is found in a region that contains a furin cleavage site in the baculovirus proteins and an adjacent sequence that has the properties of a fusion peptide. In this investigation, the homologous region in the Env protein of the gypsy retrovirus of Drosophila melanogaster (DmegypV) was investigated. Alteration of the predicted DmegypV Env proteinase cleavage site from RIAR to AIAR significantly reduced cleavage of Env in both Spodoptera frugiperda (Sf-9) and D. melanogaster (S2) cell lines. When the predicted DmegypV Env cleavage site RIAR was substituted for the cleavage sequence RRKR in the Lymantria dispar nucleopolyhedrovirus fusion protein (LD130) sequence, cleavage of the hybrid LD130 molecules still occurred, although at a reduced level. The conserved 21-amino acid sequence just downstream of the cleavage site, which is thought to be the fusion peptide in LD130, was also characterized. When this sequence from DmegypV Env was substituted for the homologous sequence in LD130, cleavage still occurred, but no fusion was observed in either cell type. In addition, although a DmegypV-Env-green fluorescent protein construct localized to cell membranes, no cell fusion was observed