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941.
Magdalena Valldosera Marta Monsò Catarina Xavier Paula Raposinho João D. G. Correia Isabel Santos Paula Gomes 《International journal of peptide research and therapeutics》2008,14(3):273-281
The synthesis of a cyclic melanocortin analogue (H-pz-βAla-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2), where the Boc-protected derivative of a metal-chelating pyrazolyl ligand (pz) was inserted as N-terminal residue, was addressed
by several different Fmoc/tBu and Boc/Bzl solid-phase strategies. On-resin cyclization was achieved immediately following
incorporation of Asp, by condensation of the Asp side chain carboxyl with the Lys side chain primary amine after selective
and simultaneous removal of side chain protecting groups. The success of the synthesis was highly dependent on the chemical
strategy employed, with Boc/Bzl chemistry giving the best results. On the light of our findings, Fmoc/tBu strategies are not
advantageous for the solid-phase synthesis of this particular type of lactam-bridged peptides. Last, but not least, the target
peptide was recently found to have promising tumor-seeking properties (J Biol Inorg Chem 13:449–459, 2008). 相似文献
942.
César Menor‐Salván Marta Ruiz‐Bermejo Susana Osuna‐Esteban Guillermo Muñoz‐Caro Sabino Veintemillas‐Verdaguer 《化学与生物多样性》2008,5(12):2729-2739
The recent evidences of presence of subsurface oceans of liquid water and ice on Saturn's moons, and the possible presence and astrobiological importance of polycyclic aromatic hydrocarbons (PAHs) in these environments, provide strong motivation for the exploration of the prebiotic chemistry in ice and to test if PAHs could be experimentally synthesized in ice surfaces under atmospheres containing methane as carbon source. In this work, we present a new design for prebiotic‐chemistry experiments in ice matrix. Using this design, a mixture of products including PAHs, polar aromatic compounds, and hydrophilic acetylene‐based polymers was obtained. We propose that acetylene generation in a methane/nitrogen atmosphere and subsequent polymerization to PAHs and polyynes could be a favored pathway in the presence of water freeze–melt cycles. These results shed light on the processes involved in PAH synthesis in icy environments and on the physical factors that drive the different competing pathways in methane/nitrogen atmospheres. 相似文献
943.
The capsid protein of HIV-1 (p24) (CA) forms the mature capsid of the human immunodeficiency virus. Capsid assembly involves hexamerization of the N-terminal domain and dimerization of the C-terminal domain of CA (CAC), and both domains constitute potential targets for anti-HIV therapy. CAC homodimerization occurs mainly through its second helix, and it is abolished when its sole tryptophan is mutated to alanine. This mutant, CACW40A, resembles a transient monomeric intermediate formed during dimerization. Its tertiary structure is similar to that of the subunits in the dimeric, non-mutated CAC, but the segment corresponding to the second helix samples different conformations. The present study comprises a comprehensive examination of the CACW40A internal dynamics. The results obtained, with movements sampling a wide time regime (from pico- to milliseconds), demonstrate the high flexibility of the whole monomeric protein. The conformational exchange phenomena on the micro-to-millisecond time scale suggest a role for internal motions in the monomer-monomer interactions and, thus, flexibility of the polypeptide chain is likely to contribute to the ability of the protein to adopt different conformational states, depending on the biological environment. 相似文献
944.
Morphogen gradients, which specify different fates for cells in a direct concentration‐dependent manner, are a highly influential framework in which pattern formation processes in developmental biology can be characterized. A common analysis approach is combining experimental and theoretical strategies, thereby fostering relevant data on the dynamics and transduction of gradients. The mechanisms of morphogen transport and conversion from graded information to binary responses are some of the topics on which these combined strategies have shed light. Herein, we review these data, emphasizing, on the one hand, how theoretical approaches have been helpful and, on the other hand, how these have been combined with experimental strategies. In addition, we discuss those cases in which gradient formation and gradient interpretation at the molecular and/or cellular level may influence each other within a mutual feedback loop. To understand this interplay and the features it yields, it becomes essential to take system‐level approaches that combine experimental and theoretical strategies. 相似文献
945.
Hypertext atlas of fetal and neonatal pathology is a free resource for pregraduate students of medicine, pathologists and other health professionals dealing with prenatal medicine. The atlas can be found at http://www.muni.cz/atlases. The access is restricted to registered users. Concise texts summarize the gross and microscopic pathology, etiology, and clinical signs of both common and rare fetal and neonatal conditions. The texts are illustrated with over 300 images that are accompanied by short comments. The atlas offers histological pictures of high quality. Virtual microscope interface is used to access the high-resolution histological images. Fetal ultrasound video clips are included. Case studies integrate clinical history, prenatal ultrasonographic examination, gross pathology and histological features. The atlas is available in English (and Czech) and equipped with an active index. The atlas is suitable both for medical students and pathologists as a teaching and reference tool. The atlas is going to be further expanded while keeping the high quality of the images. 相似文献
946.
Villalobos-Comparán M Teresa Flores-Dorantes M Teresa Villarreal-Molina M Rodríguez-Cruz M García-Ulloa AC Robles L Huertas-Vázquez A Saucedo-Villarreal N López-Alarcón M Sánchez-Muñoz F Domínguez-López A Gutiérrez-Aguilar R Menjivar M Coral-Vázquez R Hernández-Stengele G Vital-Reyes VS Acuña-Alonzo V Romero-Hidalgo S Ruiz-Gómez DG Riaño-Barros D Herrera MF Gómez-Pérez FJ Froguel P García-García E Teresa Tusié-Luna M Aguilar-Salinas CA Canizales-Quinteros S 《Obesity (Silver Spring, Md.)》2008,16(10):2296-2301
Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals. 相似文献
947.
Teegarden D White KM Lyle RM Zemel MB Van Loan MD Matkovic V Craig BA Schoeller DA 《Obesity (Silver Spring, Md.)》2008,16(7):1566-1572
Objective: The purpose of this study was to investigate the impact of dietary calcium or dairy product intake on total energy expenditure (TEE), fat oxidation, and thermic effect of a meal (TEM) during a weight loss trial. Methods and Procedures: The intervention included a prescribed 500‐kcal deficit diet in a randomized placebo‐controlled calcium or dairy product intervention employing twenty‐four 18 to 31‐year‐old (22.2 ± 3.1 years, mean ± s.d.) overweight women (75.5 ± 9.6 kg). TEM and fat oxidation were measured using respiratory gas exchange after a meal challenge, and TEE was measured by doubly labeled water. Fat mass (FM) and lean mass (fat‐free mass (FFM)) were measured by dual‐energy X‐ray absorptiometry. Subjects were randomized into one of these three intervention groups: (i) placebo (<800 mg/day calcium intake); (ii) 900 mg/day calcium supplement; (iii) three servings of dairy products/day to achieve an additional 900 mg/day. Results: There were no group effects observed in change in TEE; however, a group effect was observed for fat oxidation after adjusting for FFM (P = 0.02). The treatment effect was due to an increase in fat oxidation in the calcium‐supplemented group of 1.5 ± 0.6 g/h, P = 0.02. Baseline 25‐hydroxyvitamin D (25OHD) was positively correlated with TEM (R = 0.31, P = 0.004), and trended toward a correlation with fat oxidation (P = 0.06), independent of group assignment. Finally, the change in log parathyroid hormone (PTH) was positively correlated with the change in trunk FM (R = 0.27, P = 0.03). Discussion: These results support that calcium intake increases fat oxidation, but does not change TEE and that adequate vitamin D status may enhance TEM and fat oxidation. 相似文献
948.
949.
Mastroianni M Watanabe K White TB Zhuang F Vernon J Matsuura M Wallingford J Lambowitz AM 《PloS one》2008,3(9):e3121
Background
Mobile group II introns insert site-specifically into DNA target sites by a mechanism termed retrohoming in which the excised intron RNA reverse splices into a DNA strand and is reverse transcribed by the intron-encoded protein. Retrohoming is mediated by a ribonucleoprotein particle that contains the intron-encoded protein and excised intron RNA, with target specificity determined largely by base pairing of the intron RNA to the DNA target sequence. This feature enabled the development of mobile group II introns into bacterial gene targeting vectors (“targetrons”) with programmable target specificity. Thus far, however, efficient group II intron-based gene targeting reactions have not been demonstrated in eukaryotes.Methodology/Principal Findings
By using a plasmid-based Xenopus laevis oocyte microinjection assay, we show that group II intron RNPs can integrate efficiently into target DNAs in a eukaryotic nucleus, but the reaction is limited by low Mg2+ concentrations. By supplying additional Mg2+, site-specific integration occurs in up to 38% of plasmid target sites. The integration products isolated from X. laevis nuclei are sensitive to restriction enzymes specific for double-stranded DNA, indicating second-strand synthesis via host enzymes. We also show that group II intron RNPs containing either lariat or linear intron RNA can introduce a double-strand break into a plasmid target site, thereby stimulating homologous recombination with a co-transformed DNA fragment at frequencies up to 4.8% of target sites. Chromatinization of the target DNA inhibits both types of targeting reactions, presumably by impeding RNP access. However, by using similar RNP microinjection methods, we show efficient Mg2+-dependent group II intron integration into plasmid target sites in zebrafish (Danio rerio) embryos and into plasmid and chromosomal target sites in Drosophila melanogster embryos, indicating that DNA replication can mitigate effects of chromatinization.Conclusions/Significance
Our results provide an experimental foundation for the development of group II intron-based gene targeting methods for higher organisms. 相似文献950.
Pires de Miranda M Alenquer M Marques S Rodrigues L Lopes F Bustelo XR Simas JP 《PloS one》2008,3(2):e1654
To establish latent infections in B-cells, gammaherpesviruses express proteins in the infected B-cells of the host that spuriously activate signalling pathways located downstream of the B-cell receptor. One such protein is M2, a murine gammaherpesvirus 68-encoded molecule that activates the Vav1/Rac1 pathway via the formation of trimolecular complexes with Scr family members. Previous reports have shown that the formation of this heteromolecular complex involves interactions between a proline rich region of M2 and the Vav1 and Fyn SH3 domains. Here, we show that the optimal association of these proteins requires a second structural motif encompassing two tyrosine residues (Tyr120 and 129). These residues are inducibly phosphorylated by Fyn in non-hematopoietic cells and constitutively phosphorylated in B-cells. We also demonstrate that the phosphorylation of Tyr120 creates specific docking sites for the SH2 domains of both Vav1 and Fyn, a condition sine qua non for the optimal association of these two signalling proteins in vivo. Interestingly, signaling experiments indicate that the expression of M2 in B-cells promotes the tyrosine phosphorylation of Vav1 and additional signaling proteins, a biological process that requires the integrity of both the M2 phosphotyrosine and proline rich region motifs. By infecting mice with viruses mutated in the m2 locus, we show that the integrity of each of these two M2 docking motifs is essential for the early steps of murine gammaherpesvirus-68 latency. Taken together, these results indicate that the M2 phosphotyrosine motif and the previously described M2 proline rich region work in a concerted manner to manipulate the signaling machinery of the host B-cell. 相似文献