Calculation of higher protonation states and of a new resting state for vanadium chloroperoxidase using QM/MM, with an Atom-in-Molecules analysis.

Earlier QM/MM studies of the resting state of vanadium chloroperoxidase (VCPO) focused on the diprotonated states of the vanadate cofactor. Herein, we report a new extensive QM/MM study that includes the tri- and quadprotonated states of VCPO at neutral pH. We identify certain di- and triprotonated states as being candidates for the resting state based on a comparison of relative energies.

Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics.

Background: Vascular patterning depends on coordinated timing of arteriovenous specification of endothelial cells and the concomitant hemodynamic forces supplied by the onset of cardiac function. Using a combination of 3D imaging by OPT and embryo registration techniques, we sought to identify structural differences between three different mouse models of cardiovascular perturbation.

Results: Endoglin mutant mice shared a high degree of similarity to Mlc2a mutant mice, which have been shown to have a primary developmental heart defect causing secondary vessel remodeling failures.

3D imaging, registration, and analysis of the early mouse embryonic vasculature.

Background: Cardiovascular development requires the input of a large number of molecular signaling molecules, and undergoes tightly regulated, three-dimensional developmental patterning. Conventional developmental biology techniques have successfully identified many of the signaling cascades and molecular cues necessary for proper cardiovascular development, which has furnished us with a wealth of biochemical, molecular, and biologically functional information on how tightly linked cardiac and vascular development are. Still missing, however, is a genuine appreciation of the three-dimensional (3D) nature of these important developmental steps.

Hedgehog regulates distinct vascular patterning events through VEGF-dependent and -independent mechanisms.

Despite the clear importance of Hedgehog (Hh) signaling in blood vascular development as shown by genetic analysis, its mechanism of action is still uncertain. To better understand the role of Hh in vascular development, we further characterized its roles in vascular development in mouse embryos and examined its interaction with vascular endothelial growth factor (VEGF), a well-known signaling pathway essential to blood vascular development. We found that VEGF expression in the mouse embryo depended on Hh signaling, and by using genetic rescue approaches, we demonstrated that the role of Hh both in endothelial tube formation and Notch-dependent arterial identity was solely dependent on its regulation of VEGF.

Endoglin is dispensable for angiogenesis, but required for endocardial cushion formation in the midgestation mouse embryo.

Vascular patterning depends on precisely coordinated timing of endothelial cell differentiation and onset of cardiac function. Endoglin is a transmembrane receptor for members of the TGF-beta superfamily that is expressed on endothelial cells from early embryonic gestation to adult life. Heterozygous loss of function mutations in human ENDOGLIN cause Hereditary Hemorrhagic Telangiectasia Type 1, a vascular disorder characterized by arteriovenous malformations that lead to hemorrhage and stroke.

Prostatic extramedullary leukemia as a first site of relapse of acute nonlymphocytic leukemia.

Extramedullary leukemia (EML) is an uncommon clinical diagnosis in patients with acute nonlymphocytic leukemia (ANLL). Prostatic EML as a first site of ANLL relapse is even more rare. To our knowledge, only three cases have been reported.