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71.
Mona Saleh Shaun Abbott Valérie Perron Caroline Lauzon Christopher Penney Boulos Zacharie 《Bioorganic & medicinal chemistry letters》2010,20(3):945-949
A series of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines (1) and (2) were synthesized and evaluated for their antimicrobial activity against three representative gram-positive bacteria and two fungi. The structure–activity relationship (SAR) demonstrates that the 3- or 4-fluorophenyl component attached directly to the triazine ring was essential for activity. Of these compounds, 14, 15, and 25 demonstrated significant activity against all selected organisms compared to control. These compounds were generally nontoxic and may prove useful as antimicrobial agents. 相似文献
72.
Lipovsek D Lippow SM Hackel BJ Gregson MW Cheng P Kapila A Wittrup KD 《Journal of molecular biology》2007,368(4):1024-1041
The 10th human fibronectin type III domain ((10)Fn3) is one of several protein scaffolds used to design and select families of proteins that bind with high affinity and specificity to macromolecular targets. To date, the highest affinity (10)Fn3 variants have been selected by mRNA display of libraries generated by randomizing all three complementarity-determining region -like loops of the (10)Fn3 scaffold. The sub-nanomolar affinities of such antibody mimics have been attributed to the extremely large size of the library accessible by mRNA display (10(12) unique sequences). Here we describe the selection and affinity maturation of (10)Fn3-based antibody mimics with dissociation constants as low as 350 pM selected from significantly smaller libraries (10(7)-10(9) different sequences), which were constructed by randomizing only 14 (10)Fn3 residues. The finding that two adjacent loops in human (10)Fn3 provide a large enough variable surface area to select high-affinity antibody mimics is significant because a smaller deviation from wild-type (10)Fn3 sequence is associated with a higher stability of selected antibody mimics. Our results also demonstrate the utility of an affinity-maturation strategy that led to a 340-fold improvement in affinity by maximizing sampling of sequence space close to the original selected antibody mimic. A striking feature of the highest affinity antibody mimics selected against lysozyme is a pair of cysteines on adjacent loops, in positions 28 and 77, which are critical for the affinity of the (10)Fn3 variant for its target and are close enough to form a disulfide bond. The selection of this cysteine pair is structurally analogous to the natural evolution of disulfide bonds found in new antigen receptors of cartilaginous fish and in camelid heavy-chain variable domains. We propose that future library designs incorporating such an interloop disulfide will further facilitate the selection of high-affinity, highly stable antibody mimics from libraries accessible to phage and yeast surface display methods. 相似文献
73.
Comparison of heterologous neutralizing antibody responses of human immunodeficiency virus type 1 (HIV-1)- and HIV-2-infected Senegalese patients: distinct patterns of breadth and magnitude distinguish HIV-1 and HIV-2 infections 下载免费PDF全文
Rodriguez SK Sarr AD MacNeil A Thakore-Meloni S Gueye-Ndiaye A Traoré I Dia MC Mboup S Kanki PJ 《Journal of virology》2007,81(10):5331-5338
Neutralizing antibody responses against heterologous isolates in human immunodeficiency virus type 1 (HIV-1) and HIV-2 infections were compared, and their relationships with established clinical markers of progression were examined. Neutralizing responses against 7 heterologous primary isolates and 1 laboratory strain were compared between 32 untreated HIV-1-infected subjects and 35 untreated HIV-2-infected subjects using a pseudotyped reporter virus assay. The breadth of the neutralizing response, defined as the proportion of panel viruses positively neutralized by patient plasma, was significantly greater among HIV-2-infected subjects than among HIV-1-infected subjects. Notably, for fully one-third of HIV-2 subjects, all viruses were effectively neutralized in our panel. Magnitudes of responses, defined as reciprocal 50% inhibitory concentration (IC(50)) titers for positive reactions, were significantly greater among HIV-1-infected subjects than among HIV-2-infected subjects. When plasma samples from HIV-1 patients were tested for cross-neutralization of HIV-2 and vice versa, we found that these intertype responses are very rare and their prevalences comparable in both HIV-1 and HIV-2 infection. The significantly higher magnitude of heterologous responses for HIV-1 compared to HIV-2 prompted us to examine associations with viremia, which is known to be significantly higher in HIV-1 infection. Importantly, there was a significant positive correlation between the IC(50) titer and viral load within both the HIV-1 and HIV-2 groups, suggesting heterologous antibodies may be driven by viral replication. We conclude that HIV-2 infection is characterized by a broad, low-magnitude intratype neutralization response, while HIV-1 is characterized by a narrower but higher-magnitude intratype response and that a significant positive association between the IC(50) titer and viremia is common to both HIV-1 and HIV-2 infections. 相似文献
74.
PLINK: a tool set for whole-genome association and population-based linkage analyses 总被引:63,自引:0,他引:63 下载免费PDF全文
Purcell S Neale B Todd-Brown K Thomas L Ferreira MA Bender D Maller J Sklar P de Bakker PI Daly MJ Sham PC 《American journal of human genetics》2007,81(3):559-575
Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis. 相似文献
75.
Comerford I Litchfield W Harata-Lee Y Nibbs RJ McColl SR 《BioEssays : news and reviews in molecular, cellular and developmental biology》2007,29(3):237-247
Directed cell migration is a fundamental component of numerous biological systems and is critical to the pathology of many diseases. Although the importance of secreted chemoattractant factors in providing navigational cues to migrating cells bearing specific chemoattractant receptors is now well-established, how the function of these factors is regulated is not so well understood and may be of key importance to the design of new therapeutics for numerous human diseases. While regulation of migration clearly takes place on a number of different levels, it is becoming clear that so-called 'atypical' receptors play a role in scavenging, or altering the localisation of, chemoattractant molecules such as chemokines and complement components. These receptors do this through binding and/or internalising their chemoattractant ligands without activating signal transduction cascades leading to cell migration. The atypical chemokine receptor family currently comprises the receptors D6, DARC and CCX-CKR. In this review, we discuss the evidence from in vitro and in vivo studies that these receptors play a role in regulating cell migration, and speculate that other orphan receptors may also belong to this family. Furthermore, with the advent of gene therapy on the horizon, the therapeutic potential of these receptors in human disease is also considered. 相似文献
76.
Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members 下载免费PDF全文
Goetz R Beenken A Ibrahimi OA Kalinina J Olsen SK Eliseenkova AV Xu C Neubert TA Zhang F Linhardt RJ Yu X White KE Inagaki T Kliewer SA Yamamoto M Kurosu H Ogawa Y Kuro-o M Lanske B Razzaque MS Mohammadi M 《Molecular and cellular biology》2007,27(9):3417-3428
Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/betaKlotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FGF23 in complex with sucrose octasulfate, a disaccharide chemically related to heparin. The conformation of the heparin-binding region between beta strands 10 and 12 in FGF19 and FGF23 diverges completely from the common conformation adopted by paracrine-acting FGFs. A cleft between this region and the beta1-beta2 loop, the other heparin-binding region, precludes direct interaction between heparin/heparan sulfate and backbone atoms of FGF19/23. This reduces the heparin-binding affinity of these ligands and confers endocrine function. Klotho/betaKlotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -21, and -23 to their cognate receptors. 相似文献
77.
Formation of Tellurium Nanocrystals during Anaerobic Growth of Bacteria That Use Te Oxyanions as Respiratory Electron Acceptors 总被引:2,自引:1,他引:1 下载免费PDF全文
Shaun M. Baesman Thomas D. Bullen James Dewald Donghui Zhang Seamus Curran Farhana S. Islam Terry J. Beveridge Ronald S. Oremland 《Applied microbiology》2007,73(7):2135-2143
Certain toxic elements support the metabolism of diverse prokaryotes by serving as respiratory electron acceptors for growth. Here, we demonstrate that two anaerobes previously shown to be capable of respiring oxyanions of selenium also achieve growth by reduction of either tellurate [Te(VI)] or tellurite [Te(IV)] to elemental tellurium [Te(0)]. This reduction achieves a sizeable stable-Te-isotopic fractionation (isotopic enrichment factor [] = −0.4 to −1.0 per ml per atomic mass unit) and results in the formation of unique crystalline Te(0) nanoarchitectures as end products. The Te(0) crystals occur internally within but mainly externally from the cells, and each microorganism forms a distinctly different structure. Those formed by Bacillus selenitireducens initially are nanorods (~10-nm diameter by 200-nm length), which cluster together, forming larger (~1,000-nm) rosettes composed of numerous individual shards (~100-nm width by 1,000-nm length). In contrast, Sulfurospirillum barnesii forms extremely small, irregularly shaped nanospheres (diameter < 50 nm) that coalesce into larger composite aggregates. Energy-dispersive X-ray spectroscopy and selected area electron diffraction indicate that both biominerals are composed entirely of Te and are crystalline, while Raman spectroscopy confirms that they are in the elemental state. These Te biominerals have specific spectral signatures (UV-visible light, Raman) that also provide clues to their internal structures. The use of microorganisms to generate Te nanomaterials may be an alternative for bench-scale syntheses. Additionally, they may also generate products with unique properties unattainable by conventional physical/chemical methods. 相似文献
78.
The accumulation of polymers of the microtubule associated protein tau is correlative with increased neurodegeneration in Alzheimer's disease and other related tauopathies. In vitro models have been developed in order to investigate molecular mechanisms that regulate the polymerization of tau. Arachidonic acid and heparin have been proposed to induce tau polymerization via a ligand dependent nucleation-elongation mechanism. However, certain aspects of these in vitro results are inconsistent with a classic nucleation-elongation mechanism. Using steady state and kinetic analyses of tau polymerization at a variety of protein and inducer concentrations, we have found that the thermodynamic barrier for nucleation in the presence of inducers is negligible, which was manifested by increases in protein polymerization at low tau concentrations and very rapid kinetics of polymerization. However, the mechanism of polymerization is complicated by the observation that high concentrations of inducer molecules result in the inhibition of tau fibril formation through different mechanisms for arachidonic acid and heparin. These observations indicate that the molar ratio of inducer to protein is a greater determinant of the rate and extent of tau polymerization than the concentration of tau itself. Our results are therefore not consistent with a canonical nucleation-elongation reaction but rather are more consistent with an allosteric regulation model in which the presence of small molecules induce a conformational change in the protein that decreases the thermodynamic barrier for polymerization essentially to zero. 相似文献
79.
Susan M. Theiss Thomas J. Lisney Shaun P. Collin Nathan S. Hart 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2007,193(1):67-79
Relatively little is known about the physical structure and ecological adaptations of elasmobranch sensory systems. In particular,
elasmobranch vision has been poorly studied compared to the other senses. Virtually nothing is known about whether elasmobranchs
possess multiple cone types, and therefore the potential for colour vision, or how the spectral tuning of their visual pigments
is adapted to their different lifestyles. In this study, we measured the spectral absorption of the rod and cone visual pigments
of the blue-spotted maskray, Dasyatis kuhlii, using microspectrophotometry. D. kuhlii possesses a rod visual pigment with a wavelength of maximum absorbance (λmax) at 497 nm and three spectrally distinct cone types with λmax values at 476, 498 and 552 nm. Measurements of the spectral transmittance of the ocular media reveal that wavelengths below
380 nm do not reach the retina, indicating that D. kuhlii is relatively insensitive to ultraviolet radiation. Topographic analysis of retinal ganglion cell distribution reveals an
area of increased neuronal density in the dorsal retina. Based on peak cell densities and using measurements of lens focal length
made using laser ray tracing and sections of frozen eyes, the estimated spatial resolving power of D. kuhlii is 4.10 cycles per degree. 相似文献
80.
The treatment of myeloid leukaemia has progressed in recent years with the advent of donor leukocyte infusions (DLI), haemopoietic
stem cell transplants (HSCTs) and targeted therapies. However, relapse has a high associated morbidity rate and a method for
removing diseased cells in first remission, when a minimal residual disease state is achieved and tumour load is low, has
the potential to extend remission times and prevent relapse especially when used in combination with conventional treatments.
Acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are heterogeneous diseases which lack one common molecular
target while chronic myeloid leukaemia (CML) patients have experienced prolonged remissions through the use of targeted therapies
which remove BCR-ABL+ cells effectively in early chronic phase. However, escape mutants have arisen and this therapy has little effectivity in
the late chronic phase. Here we review the immune therapies which are close to or in clinical trials for the myeloid leukaemias
and describe their potential advantages and disadvantages. 相似文献