Dendritic cells (DCs) are strong activators of primary T cell responses. Their priming ability is acquired upon encounter with maturation stimuli. To identify the genes that are differentially expressed upon maturation induced by exposure to Gram-negative bacteria, a kinetic study of DC gene expression was done with microarrays representing 11,000 genes and ESTs (expressed sequence tags). Approximately 3000 differentially expressed transcripts were identified. We found that functional interleukin 2 (IL-2) mRNA, which gave rise to IL-2 production, was transiently up-regulated at early time-points after bacterial encounter. In contrast, macrophages did not produce IL-2 upon bacterial stimulation. Thus, IL-2 is an additional key cytokine that confers unique T cell stimulatory capacity to DCs.
The conformational behavior of four [Ln(DOTA)(H(2)O)](-) systems (Ln = La, Gd, Ho, and Lu) has been characterized by means of ab initio calculations performed in vacuo and in aqueous solution, the latter by using the polarizable continuum model (PCM). Calculated molecular geometries and conformational energies of the [Ln(DOTA)(H(2)O)](-) systems, and interconversion mechanisms, barriers, and (13)C NMR spectra of the [Lu(DOTA)](-) complex are compared with experimental values. For each system, geometry optimizations, performed in vacuo and in solution at the HF/3-21G level and using a 46+4f(n) core electron effective core potential (ECP) for lanthanides, provide two minima corresponding to a square antiprismatic (A) and an inverted antiprismatic (IA) coordination geometry. All the systems are nonacoordinated, with the exception of the IA isomer of the Lu complex that, from in solution calculations, is octacoordinated, in agreement with experimental data. On comparing the in vacuo relative free energies calculated at different theory levels it can be seen that the nonacoordinated species dominates at the beginning of the lanthanide series while the octacoordinated one does so at the end. Furthermore, on passing along the series the IA isomer becomes less and less favored with respect to A and for the Lu complex a stabilization of the IAisomer is observed in solution (but not in vacuo), in agreement with the experimental data. Investigation of the A<-->IA isomerization process in the [Lu(DOTA)](-) system provides two different interconversion mechanisms: a single-step process, involving the simultaneous rotation of the acetate arms, and a multistep path, involving the inversion of the cyclen cycle configuration. While in vacuo the energy barrier for the acetate arm rotation is higher than that involved in the ring inversion (23.1 and 13.1 kcal mol(-)(1) at the B3LYP/6-311G level, respectively), in solution the two mechanisms present comparable barriers (14.7 and 13.5 kcal mol(-)(1)), in fairly good agreement with the experimental values. The NMR shielding constants for the two isomers of the [Lu(DOTA)](-) complex have been calculated by means of the ab initio GIAO and CSGT methods, and using a 46-core-electron ECP for Lu. The calculated (13)C NMR chemical shifts are in close agreement with the experimental values (rms 3.3 ppm, at the HF/6-311G level) and confirm the structural assignment of the two isomers based on experimental NMR spectra in solution. The results demonstrate that our computational approach is able to predict several physicochemical properties of lanthanide complexes, allowing a better characterization of this class of compounds for their application as contrast agents in medical magnetic resonance imaging (MRI).
A set of atomic radii used for the construction of solute cavities in the framework of the polarizable continuum model (PCM) is extended and validated with the aim of supporting the investigation of lanthanide(III) complexes in aqueous solution. The parameterization of the atomic radii for the whole Ln(III) series is performed by minimizing the differences between the experimental and the calculated standard hydration free energies of the ions calculated at the HF level. The optimized radii show a remarkable linear relationship with effective ionic radii and well reproduce the experimental hydration free energies also when electron correlation effects are included in the calculations. We have next validated a mixed discrete continuum model in which a supermolecule formed by the ion and by water molecules in the first hydration shell is immersed in a polarizable continuum. The molecular structures, the relative stability of the octa- with respect to the nonahydrated species, and the ion hydration free energies have been calculated for the neodymium(III) and ytterbium(III) aqueous ions. Results are in agreement with experimental evidence, both from structural and energetic standpoints. The molecular structures optimized including surrounding effects are in better agreement with the experimental structures than the in vacuo geometries. Moreover, the results show that the energetic properties of these systems in aqueous solution can be effectively calculated by using the structures optimized in vacuo, and including correlation effects in the gas-phase reaction of complex formation.
A double‐blind, randomized, controlled study was performed in 90 full term infants to evaluate dose‐related bifidogenic effects of a new synergistic mixture of galacto‐oligosaccharides (GOS) and fructo‐oligosacharides (FOS). The GOS/FOS mixture showed a dose‐dependent stimulatory effect on the intestinal growth of bifidobacteria. Also stool consistency and faecal pH were positively affected.
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