Shedding light on the elusive role of endothelial cells in cytomegalovirus dissemination.

Cytomegalovirus (CMV) is frequently transmitted by solid organ transplantation and is associated with graft failure. By forming the boundary between circulation and organ parenchyma, endothelial cells (EC) are suited for bidirectional virus spread from and to the transplant. We applied Cre/loxP-mediated green-fluorescence-tagging of EC-derived murine CMV (MCMV) to quantify the role of infected EC in transplantation-associated CMV dissemination in the mouse model. Both EC- and non-EC-derived virus originating from infected Tie2-cre(+) heart and kidney transplants were readily transmitted to MCMV-naïve recipients by primary viremia. In contrast, when a Tie2-cre(+) transplant was infected by primary viremia in an infected recipient, the recombined EC-derived virus poorly spread to recipient tissues. Similarly, in reverse direction, EC-derived virus from infected Tie2-cre(+) recipient tissues poorly spread to the transplant. These data contradict any privileged role of EC in CMV dissemination and challenge an indiscriminate applicability of the primary and secondary viremia concept of virus dissemination

Vital Rates from the Action of Mutation Accumulation

New models for evolutionary processes of mutation accumulation allow hypotheses about the age-specificity of mutational effects to be translated into predictions of heterogeneous population hazard functions. We apply these models to questions in the biodemography of longevity, including proposed explanations of Gompertz hazards and mortality plateaus

A model for antagonistic pleiotropic gene action for mortality and advanced age.

Association or linkage studies involving control and long-lived populations provide information on genes that influence longevity. However, the relationship between allele-specific differences in survival and the genetic structure of aging cohorts remains unclear. We model a heterogeneous cohort comprising several genotypes differing in age-specific mortality. In its most general form, without any specific assumption regarding the shape of mortality curves, the model permits derivation of a fundamental property underlying abrupt age-related changes in the composition of a cohort. The model is applied to sex-specific survival curves taken from period life tables, and Gompertz-Makeham mortality coefficients are calculated for the French population. Then, adjustments are performed under Gompertz-Makeham mortality functions for three genotypes composing a heterogeneous cohort, under the constraint of fitting the resultant mortality to the real French population mortality obtained from life tables. Multimodal curves and divergence after the 8th decade appear as recurrent features of the frequency trajectories. Finally, a fit to data previously obtained at the angiotensin-converting-enzyme locus is realized, explaining what had seemed to be paradoxical results-namely, that the frequency of a genotype known as a cardiovascular risk factor was increased in centenarians. Our results help explain the well-documented departure from Gompertz-Makeham mortality kinetics at older ages. The implications of our model are discussed in the context of known genetic effects on human longevity and age-related pathologies. Since antagonistic pleiotropy between early and late survival emerges as a general rule, extrapolating the effects measured for a gene in a particular age class to other ages could be misleading

Mutators, population size, adaptive landscape and the adaptation of asexual populations of bacteria.

Selection of mutator alleles, increasing the mutation rate up to 10, 000-fold, has been observed during in vitro experimental evolution. This spread is ascribed to the hitchhiking of mutator alleles with favorable mutations, as demonstrated by a theoretical model using selective parameters corresponding to such experiments. Observations of unexpectedly high frequencies of mutators in natural isolates suggest that the same phenomenon could occur in the wild. But it remains questionable whether realistic in natura parameter values could also result in selection of mutators. In particular, the main parameters of adaptation, the size of the adapting population and the height and steepness of the adaptive peak characterizing adaptation, are very variable in nature. By simulation approach, we studied the effect of these parameters on the selection of mutators in asexual populations, assuming additive fitness. We show that the larger the population size, the more likely the fixation of mutator alleles. At a large population size, at least four adaptive mutations are needed for mutator fixation; moreover, under stronger selection stronger mutators are selected. We propose a model based on multiple mutations to illustrate how second-order selection can optimize population fitness when few favorable mutations are required for adaptation

New group 4 organometallic and imido compounds of diamide-diamine and related dianionic O2N2-donor ligands

New group 4 compounds supported by the tetradentate diamide-diamine ligand N2NN′ are reported (N2NN′ = (2-C 5H4N)CH2N(CH2CH 2NSiMe3)2) along with some comparative studies with the new bis(alkoxide)-diamine ligand O2NN′ (O 2NN′ = (2-C5H4N)CH2N(CH 2-CMe2O)2). Reaction of the previously described ZrCl2(N2NN′) (1) with 2 equiv of MeLi or PhCH2MgCl gave ZrR2(N2NN′) (R = Me (2) or CH2Ph (3)). Reaction of 1 with 1 equiv of RCH2MgCl gave the monoalkyl analogues ZrCl(R)(N2NN′) (R = CH2Ph (6) or CH2SiMe3 (7)). Reaction of Zr(CH2R) 4 (R = SiMe3 or CMe3) with H2N 2NN′ in C6D6 gave the corresponding Zr(CH2R)2(N2NN′), but these decomposed over several hours. Reaction of 1 with allylmagnesium chloride gave ZrCl{(2-NC5(6-C3H5)H4)CH 2N(CH2CH2NSiMe3)2}, in which the pyridyl group has undergone nucleophilic attack. Reaction of 2 with BArF3 (ArF = C6F5) in benzene led to the cyclometalated cation [Zr{(2-NC5H 4)CH2N(CH2CH2NSiMe 3)(CH2CH2NSiMe2CH 2-)}]+ via SiMe3 group C-H activation, but in the presence of THF the methyl cation [ZrMe-(THF)(N2NN′)] + was formed. Reaction of 6 with BAr3F gave the chloride cation [ZrCl(N2-NN′)]+. Reaction of Li2N2NN′ with Ti(NR)Cl2(py)3 gave the five-coordinate imides Ti(NR)(N2NN′) (R = tBu or Ar (15), Ar = 2,6-C6H3iPr2). Zirconium imides Zr(NAr)(N2NN′) and Zr(NtBu)-(py)(N2NN′) (18) were prepared by sequential reaction of 1 with LiCH2SiMe3 (2 equiv) and the appropriate amine and pyridine for the latter. Reaction of 1 with LiNH tBu (2 equiv) gave Zr(NHtBu)2(N 2NN′). Reaction of 18 with piperidine gave Zr(NH tBu)(NC5H10)(N2NN′) (19) via N-H bond activation. For comparative purposes the group 5 imides M(N tBu)Cl(N2NN′) (M = Nb (20) or Ta (21)) were prepared from Li2N2NN′ and the corresponding M(N t-Bu)Cl3(py)2. Reaction of 2- aminomethylpyridine with an excess of isobutylene oxide afforded H 2O2NN′ (22). Reaction of H2O 2NN′ (1 or 2 equiv) with Ti(NMe2)4 gave Ti(O2NN′)2, which reacted with TiCl 4(THF)2 to form TiCl2(O2NN′). Reaction of H2O2NN′ with Zr(CH2SiMe 3)2-Cl2(Et2O)2, Zr(NMe2)4, or Zr(CH2SiMe3) 4 gave ZrX2(O2NN′) (X = Cl, NMe 2, or CH2SiMe3 (27)). Reaction of 27 with BAr3F in the presence of THF formed [Zr(CH 2SiMe3)(THF)(O2NN′)]+, but in the absence of a Lewis base the μ-alkoxide-bridged dimer [Zr 2(CH2SiMe3)2(O2NN′) 2]2+ was formed. The compounds 3, 6, 15, 19, 21, 22, and 27 were crystallographically characterized. © 2005 American Chemical Society