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91.
To date, there are no vaccines against any of the major parasitic diseases, and chemotherapy is the main weapon in our arsenal. There is an urgent need for better drugs against Leishmania. With the completion of the human genome sequence and soon that of Leishmania, for the first time we have the opportunity to identify novel chemotherapeutic treatments. This requires the exploitation of a variety of technologies. The major challenge is to take the process from discovery of drug candidates all the way along the arduous path to the marketplace. A crucial component will be the forging of partnerships between the pharmaceutical industry and publicly funded scientists to ensure that the promise of the current revolution in biology lives up to our hopes and expectations. 相似文献
92.
Vanessa Capone Emanuela Clemente Elena Restelli Antonella Di Campli Samantha Sperduti Francesca Ornaghi Laura Pietrangelo Feliciano Protasi Roberto Chiesa Michele Sallese 《生物化学与生物物理学报:疾病的分子基础》2018,1864(10):3164-3180
Loss-of-function mutations in the SIL1 gene are linked to Marinesco-Sjögren syndrome (MSS), a rare multisystem disease of infancy characterized by cerebellar and skeletal muscle degeneration. SIL1 is a ubiquitous adenine nucleotide exchange factor for the endoplasmic reticulum (ER) chaperone BiP. The complexity of mechanisms by which loss of SIL1 causes MSS is not yet fully understood. We used HeLa cells to test the hypothesis that impaired protein folding in the ER due to loss of SIL1 could affect secretory trafficking, impairing the transport of cargoes essential for the function of MSS vulnerable cells. Immunofluorescence and ultrastructural analysis of SIL1-knocked-down cells detected ER chaperone aggregation, enlargement of the Golgi complex, increased autophagic vacuoles, and mitochondrial swelling. SIL1-interefered cells also had delayed ER-to-plasma membrane transport with retention of Na+/K+-ATPase and procollagen-I in the ER and Golgi, and increased apoptosis. The PERK pathway of the unfolded protein response was activated in SIL1-interfered cells, and the PERK inhibitor GSK2606414 attenuated the morphological and functional alterations of the secretory pathway, and significantly reduced cell death. These results indicate that loss of SIL1 is associated with alterations of secretory transport, and suggest that inhibiting PERK signalling may alleviate the cellular pathology of SIL1-related MSS. 相似文献
93.
Pedemonte N Caci E Sondo E Caputo A Rhoden K Pfeffer U Di Candia M Bandettini R Ravazzolo R Zegarra-Moran O Galietta LJ 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(8):5144-5153
SCN(-) (thiocyanate) is an important physiological anion involved in innate defense of mucosal surfaces. SCN(-) is oxidized by H(2)O(2), a reaction catalyzed by lactoperoxidase, to produce OSCN(-) (hypothiocyanite), a molecule with antimicrobial activity. Given the importance of the availability of SCN(-) in the airway surface fluid, we studied transepithelial SCN(-) transport in the human bronchial epithelium. We found evidence for at least three mechanisms for basolateral to apical SCN(-) flux. cAMP and Ca(2+) regulatory pathways controlled SCN(-) transport through cystic fibrosis transmembrane conductance regulator and Ca(2+)-activated Cl(-) channels, respectively, the latter mechanism being significantly increased by treatment with IL-4. Stimulation with IL-4 also induced the strong up-regulation of an electroneutral SCN(-)/Cl(-) exchange. Global gene expression analysis with microarrays and functional studies indicated pendrin (SLC26A4) as the protein responsible for this SCN(-) transport. Measurements of H(2)O(2) production at the apical surface of bronchial cells indicated that the extent of SCN(-) transport is important to modulate the conversion of this oxidant molecule by the lactoperoxidase system. Our studies indicate that the human bronchial epithelium expresses various SCN(-) transport mechanisms under resting and stimulated conditions. Defects in SCN(-) transport in the airways may be responsible for susceptibility to infections and/or decreased ability to scavenge oxidants. 相似文献
94.
Coquelle N Fioravanti E Weik M Vellieux F Madern D 《Journal of molecular biology》2007,374(2):547-562
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate with concomitant oxidation of NADH during the last step in anaerobic glycolysis. In the present study, we present a comparative biochemical and structural analysis of various LDHs adapted to function over a large temperature range. The enzymes were from Champsocephalus gunnari (an Antarctic fish), Deinococcus radiodurans (a mesophilic bacterium) and Thermus thermophilus (a hyperthermophilic bacterium). The thermodynamic activation parameters of these LDHs indicated that temperature adaptation from hot to cold conditions was due to a decrease in the activation enthalpy and an increase in activation entropy. The crystal structures of these LDHs have been solved. Pairwise comparisons at the structural level, between hyperthermophilic versus mesophilic LDHs and mesophilic versus psychrophilic LDHs, have revealed that temperature adaptation is due to a few amino acid substitutions that are localized in critical regions of the enzyme. These substitutions, each having accumulating effects, play a role in either the conformational stability or the local flexibility or in both. Going from hot- to cold-adapted LDHs, the various substitutions have decreased the number of ion pairs, reduced the size of ionic networks, created unfavorable interactions involving charged residues and induced strong local disorder. The analysis of the LDHs adapted to extreme temperatures shed light on how evolutionary processes shift the subtle balance between overall stability and flexibility of an enzyme. 相似文献
95.
96.
In the Bifrons to Aalensis Ammonite Zones of the Vrines section (Toarcian stratotype), woody phytoclasts, nonsaccate pollen grains, and marine assemblages (dinoflagellate cysts, acritarchs, and foraminiferal linings) dominate the palynofacies. The dinoflagellate cyst assemblage is cosmopolitan with minor Boreal influences, characterized by relatively high quantities of Micrhystridium, Baltisphaeridium, Mendicodinium spinosum, Nannoceratopsis, and the Parvocysta suite, dominating in turn the marine assemblages. Marine assemblage compositions, both dinoflagellate cysts and acritarchs, and calcareous nannofossil abundances are different in marl and limestone lithotypes of the Vrines section. Calcareous nannofossils are generally more abundant in marls than in limestones, they display however a cyclic pattern of semiquantitative abundances in phase with lithological cycles. Although a diagenetic overprint cannot be completely excluded to explain such a difference, it seems likely that these dissimilarities are in part primary, the results of variations in terms of proximality-distality, and climatic fluctuations. A mean duration of 117.6 Kyr per marl-limestone alternation, and the stacking of four marl-limestone alternations for 470.6 Kyr, suggest a control by the Earth's two orbital eccentricity cycles. It is likely that the palaeoenvironmental conditions, which influenced the formation of marl-limestone alternations, also controlled the variations in marine phytoplankton assemblages. 相似文献
97.
Franceschin M Alvino A Casagrande V Mauriello C Pascucci E Savino M Ortaggi G Bianco A 《Bioorganic & medicinal chemistry》2007,15(4):1848-1858
In developing G-quadruplex interactive telomerase inhibitors two main features have to be taken into account: the hydrophobic interactions with the G-quartet plane and the electrostatic interactions with the negatively charged phosphates of the four grooves. In this paper, we report the synthesis of four hydrosoluble coronene derivatives, which are characterized by a large hydrophobic aromatic core and four orthogonal hydrophilic side chains. We have studied their ability to induce both inter- and intramolecular G-quadruplex structures and found a significant selectivity of all the coronene derivatives for the intramolecular G-quadruplex. The efficiency in inhibiting human telomerase has been evaluated in a cell-free system and the experimental results correlate with the relative affinities of these compounds for the G-quadruplex monomeric structure, as derived by molecular modelling simulations. Thus, the coronene derivatives can be considered as a new class of telomerase inhibitors, although further investigations are surely necessary to fully exploit their features. 相似文献
98.
Debiaggi M Canducci F Terulla C Sampaolo M Marinozzi MC Alessandrino PE Colombo AA Caldera D Bragotti LZ Migliavacca R Bianchi E Romero E Clementi M 《The new microbiologica》2007,30(3):255-258
From October 2004 through October 2006 a study was performed to evaluate the prevalence of human Metapneumovirus (hMPV) infection in adult hematopoietic stem cell transplant (HSCT) recipients. Sequential nasopharyngeal aspirates (NPA) were collected independently from respiratory symptoms and evaluated for hMPV-RNA by polymerase chain reaction (PCR) and sequence analysis. Results indicate epidemiological and molecular differences between the 2004-2005 and 2005-2006 periods and that hMPV seems not to symptomatically affect HSCT patients or cause late respiratory sequelae. In addition, data collected suggest a hospital origin of hMPV infection in most HSCT patients during the 2004-2005 period. 相似文献
99.
Balbis E Patriarca S Furfaro AL Cottalasso D Pronzato MA Carlier P Botta F Marinari UM Fontana L Traverso N 《Redox report : communications in free radical research》2007,12(1):59-62
Results on oxidative markers during ageing are not consistent throughout the scientific literature; however, successful ageing may depend on better ability to cope with oxidative stress. A previous study of ours showed that successful ageing could actually be related to enhanced response to oxidatively modified proteins. In this study, a healthy nonagenarian population (OVER-90) was examined for various blood oxidative biomarkers and compared with a healthy population of blood donors (age range, 23-66 years). Blood glutathione, both total (tGSH) and oxidised (GSSG), and total plasmatic antioxidant status were maintained in the OVER-90 at a level similar to the control population. Sulphydryl (sulfhydryl) groups and glutathione peroxidase (GPx) were instead decreased. The results are discussed in a possible unifying view: the OVER-90 population could possess a globally preserved antioxidant ability, though some signs of oxidative damage are present and some structures could be 'sacrificed' in order to keep the redox equilibrium. 相似文献
100.
The 16S-23S rRNA gene internal transcribed spacer region (ITS1) from 34 strains of Pseudomonas avellanae and some strains of Pseudomonas syringae pathovars was amplified and assessed by restriction fragment length polymorphism (RFLP) using 10 restriction enzymes. In addition, the ITS1 region of four representative P. avellanae strains was sequenced and compared by the neighbour-joining algorithm with that of P. syringae pathovars. Two main groups of P. avellanae strains were observed that did not correlate with their origin. The ITS1 region sequencing revealed a high similarity with the P. syringae complex. One group of P. avellanae strains showed high similarity to P. s. pv. actinidiae and P. s. pv. tomato; another group showed similarity with P. s. pv. tabaci and P. s. pv. glycinea. Two strains clustered with P. s. pv. pisi. The difficulties to unambiguously classify the strains associated with hazelnut decline in Greece and Italy are discussed. 相似文献