Asynchrony in key Holocene chronologies: Evidence from Irish bog pines

The Greenland Ice Core Chronology 2005 (GICC05) and the radiocarbon calibration curve (IntCal) are the foremost time scales used in paleoclimatic and paleoenvironmental studies of the most recent 10 k.y. Due to varying and often insufficient dating resolution, opportunities to test the synchrony of these two influential chronologies are rare. Here we present evidence for a phase of major pine recruitment on Irish bogs at ca. 8160 yr B.P. Dendrochronological dating of subfossil trees from three sites reveals synchronicity in germination across the study area, indicative of a regional forcing. The concurrent colonization of pine on peatland is interpreted in terms of drier surface conditions and provides the first substantive proxy data in support of a significant hydroclimatic change in the north of Ireland accompanying the 8.2 ka climate cooling event. The date of pine establishment does not overlap with the GICC05 age range for the event, and possible lags between responses are unlikely to explain the full difference. In light of recent studies highlighting a possible offset in GICC05 and IntCal dates, the Irish pine record supports the notion of ice core dates being too early during the period of study. If the suggested discrepancy in timing is an artifact of chronological error, it is likely to have affected interpretations of previous proxy comparisons and alignments.

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.