Tephra-linked peat humification records from Irish ombrotrophic bogs question nature of solar forcing at 850 cal. yr BC.

This paper investigates evidence for palaeoclimatic changes during the period ca. 1500-500 cal. yr BC through peat humification studies on seven Irish ombrotrophic bogs. The sites are well-correlated by the identification of three mid-first millennium BC tephras, which enable the humification records at specific points in time to be directly compared. Phases of temporarily increased wetness are suggested at ca. 1300-1250 cal. yr BC, ca. 1150-1050 cal. yr BC, ca. 940 cal. yr BC and ca. 740 cal. yr BC. The last of these is confirmed to be synchronous at five sites, suggesting external forcing on a regional scale. The timing of this wet-shift is constrained by two closely dated tephras and is demonstrated to be distinct from the widely reported changes to cooler/wetter conditions associated with a solar minimum at 850-760 cal. yr BC, at which time the Irish sites appear instead to experience drier conditions. The results suggest the possibility of either non-uniform responses to solar forcing in northwest Europe at this time, or the existence of unrelated climate events in the early first millennium BC. The findings caution against the correlation of loosely dated palaeoclimate data if the effects of forcing mechanisms are to be understood.

New mustard-linked 2-aryl-bis-benzimidazoles with anti-proliferative activity

We describe new methodology for the synthesis of symmetric bis-benzimidazole carrying 2-aryl moieties, including 2-[4-3'-aminopropoxy)phenyl] and 2-[4-(3'-aminopropanamido)pheny] substituents, together with the synthesis of novel hybrid molecules comprising bis-benzimidazoles in ester and amide combination with the N-mustard chlorambucil. The in vitro activities of these compounds against five cancer cell lines are also provided.

Molecular basis for estrogen receptor alpha deficiency in BRCA1-linked breast cancer

Background BRCA1-mutant breast tumors are typically estrogen receptor alpha (ER alpha) negative, whereas most sporadic tumors express wild-type BRCA1 and are ER alpha positive. We examined a possible mechanism for the observed ER alpha-negative phenotype of BRCA1-mutant tumors.

Methods We used a breast cancer disease-specific microarray to identify transcripts that were differentially expressed between paraffin-embedded samples of 17 BRCA1-mutant and 14 sporadic breast tumors. We measured the mRNA levels of estrogen receptor 1 (ESR1) ( the gene encoding ER alpha), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ER alpha protein expression was assessed in human breast cancer HCC1937 cells that were stably reconstituted with wild-type BRCA1 expression construct and in human breast cancer T47D and MCF-7 cells transiently transfected with BRCA1-specific short-interfering RNA ( siRNA). Chromatin immunoprecipitation assays were performed to determine if BRCA1 binds the ESR1 promoter and to identify other interacting proteins. Sensitivity to the antiestrogen drug fulvestrant was examined in T47D and MCF-7 cells transfected with BRCA1-specific siRNA. All statistical tests were two-sided.

Results Mean ESR1 gene expression was 5.4-fold lower in BRCA1-mutant tumors than in sporadic tumors ( 95% confidence interval [CI]=2.6-fold to 40.1-fold, P =.0019). The transcription factor Oct-1 recruited BRCA1 to the ESR1 promoter, and both BRCA1 and Oct-1 were required for ER alpha expression. BRCA1-depleted breast cancer cells expressing exogenous ER alpha were more sensitive to fulvestrant than BRCA1-depleted cells transfected with empty vector ( T47D cells, the mean concentration of fulvestrant that inhibited the growth of 40% of the cells [IC40] for empty vector versus ER alpha: > 10(-5) versus 8.0 x 10(-9) M [ 95% CI=3.1x10(-10) to 3.2 x 10(-6) M]; MCF-7 cells, mean IC40 for empty vector versus ER alpha : > 10(-5) versus 4.9 x 10(-8) M [ 95% CI=2.0 x 10(-9) to 3.9 x 10(-6) M]).

Conclusions BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ER alpha expression.

Two functionally linked amino acids in the stem 2 region of measles virus haemagglutinin determine infectivity and virulence in the rodent central nervous system.

Rodent brain-adapted measles virus (MV) strains, such as CAM/RB and recombinant MVs based on the Edmonston strain containing the haemagglutinin (H) of CAM/RB, cause acute encephalitis after intracerebral infection of newborn rodents. We have demonstrated that rodent neurovirulence is modulated by two mutations at amino acid positions 195 and 200 in the H protein, one of these positions (200) being a potential glycosylation site. In order to analyse the effects of specific amino acids at these positions, we introduced a range of individual and combined mutations into the open reading frame of the H gene to generate a number of eukaryotic expression plasmids. The functionality of the mutant H proteins was assessed in transfected cells and by generating recombinant viruses. Interestingly, viruses caused acute encephalitis only if the amino acid Ser at position 200 was coupled with Gly at position 195, whereas viruses with single or combined mutations at these positions, including glycosylation at position 200, were attenuated. Neurovirulence was associated with virus spread and induction of neuronal apoptosis, whereas attenuated viruses failed to infect brain cells. Similar results were obtained by using primary brain-cell cultures. Our findings indicate that a structural alteration in the stem 2 region of the H protein at position 195 or 200 interferes with infectivity of rodent neurons, and suggest that the interaction of the viral attachment protein with cellular receptors on neurons is affected.