971 resultados para Fold interference


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The Lesser Himalayan fold-thrust belt on the south flank of the Jajarkot klippe in west central Nepal was mapped in detail between the Main Central thrust in the north and the Main Boundary thrust in the south. South of the Jajarkot klippe, the fold-thrust belt involves sandstone, shale and carbonate rocks that are unmetamorphosed in the foreland and increase in metamorphic grade with higher structural position to sub-greenschist facies towards the hinterland. The exposed stratigraphy is correlative with the Proterozoic Ranimata, Sangram, Galyang, Syangia Formations and Lakharpata Group of Western Nepal and overlain by the Paleozoic Tansen and Kali Gandaki Groups. Based on field mapping and cross-section construction, three distinct thrust sheets were identified separated by top-to-the-south thrust faults. From the foreland (south) to the hinterland (north), the first thrust sheet in the immediate hanging wall of the Main Boundary thrust defines an open syncline. The second thrust sheet contains a very broad synformal duplex, which is structurally stacked against the third thrust sheet containing a homoclinal panel of the oldest exposed Proterozoic stratigraphy. Outcrop scale folds throughout the study area are predominantly south vergent, open, and asymmetric reflecting the larger regional scale folding style, which corroborate the top-to-the-south deformation style seen in the faults of the region. Field techniques were complemented with microstructural and quartz crystallographic c-axis preferred orientation analyses using a petrographic microscope and a fabric analyzer, respectively. Microstructural analysis identified abundant strain-induced recrystallization textures and occasional occurrences of top-to-the-south shear-sense indicators primarily in the hinterland rocks in the immediate footwall of the Main Central Thrust. Top-to-the-south shearing is also supported by quartz crystallographic c-axis preferred orientations. Quartz recrystallization textures indicate an increase in deformation temperature towards the Main Central thrust. A line balance estimate indicates that approximately 15 km of crustal shortening was accommodated by folding and faulting in the fold-thrust belt south of the Jajarkot klippe. Additionally, estimations of shortening velocity suggest that the shortening velocity operating in this section of the fold-thrust belt between 23 to 14 Ma was slower than what is currently observed as a result of the ongoing deformation of the Sub-Himalayan fold-thrust belt.

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Despite the enormous economic importance of Neospora caninum related veterinary diseases, the number of effective therapeutic agents is relatively small. Development of new therapeutic strategies to combat the economic impact of neosporosis remains an important scientific endeavor. This study demonstrates molecular, structural and phenotypic evidence that N. caninum calcium-dependent protein kinase 1 (NcCDPK1) is a promising molecular target for neosporosis drug development. Recombinant NcCDPK1 was expressed, purified and screened against a select group of bumped kinase inhibitors (BKIs) previously shown to have low IC50s against Toxoplasma gondii CDPK1 and T. gondii tachyzoites. NcCDPK1 was inhibited by low concentrations of BKIs. The three-dimensional structure of NcCDPK1 in complex with BKIs was studied crystallographically. The BKI-NcCDPK1 structures demonstrated the structural basis for potency and selectivity. Calcium-dependent conformational changes in solution as characterized by small-angle X-ray scattering are consistent with previous structures in low Calcium-state but different in the Calcium-bound active state than predicted by X-ray crystallography. BKIs effectively inhibited N. caninum tachyzoite proliferation in vitro. Electron microscopic analysis of N. caninum cells revealed ultra-structural changes in the presence of BKI compound 1294. BKI compound 1294 interfered with an early step in Neospora tachyzoite host cell invasion and egress. Prolonged incubation in the presence of 1294 interfered produced observable interference with viability and replication. Oral dosing of BKI compound 1294 at 50 mg/kg for 5 days in established murine neosporosis resulted in a 10-fold reduced cerebral parasite burden compared to untreated control. Further experiments are needed to determine the PK, optimal dosage, and duration for effective treatment in cattle and dogs, but these data demonstrate proof-of-concept for BKIs, and 1294 specifically, for therapy of bovine and canine neosporosis.

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Owing to their pathogenical role and unique ability to exist both as soluble proteins and transmembrane complexes, pore-forming toxins (PFTs) have been a focus of microbiologists and structural biologists for decades. PFTs are generally secreted as water-soluble monomers and subsequently bind the membrane of target cells. Then, they assemble into circular oligomers, which undergo conformational changes that allow membrane insertion leading to pore formation and potentially cell death. Aerolysin, produced by the human pathogen Aeromonas hydrophila, is the founding member of a major PFT family found throughout all kingdoms of life. We report cryo-electron microscopy structures of three conformational intermediates and of the final aerolysin pore, jointly providing insight into the conformational changes that allow pore formation. Moreover, the structures reveal a protein fold consisting of two concentric β-barrels, tightly kept together by hydrophobic interactions. This fold suggests a basis for the prion-like ultrastability of aerolysin pore and its stoichiometry.

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Mode of access: Internet.

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Published also thesis (PH. D.) Columbia University, 1912.

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Cover title.