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.

Ca(2+)-activated transbilayer movement of plasma membrane phospholipids in Leishmania donovani during ionomycin or thapsigargin stimulation

The protozoan parasite Leishmania causes serious infections in humans all over the world. After being inoculated into the skin through the bite of an infected sandfly, Leishmania promastigotes must gain entry into macrophages to initiate a successful infection. Specific, surface exposed phospholipids have been implicated in Leishmania-macrophage interaction but the mechanisms controlling and regulating the plasma membrane lipid distribution remains to be elucidated. Here, we provide evidence for Ca(2+)-induced phospholipid scrambling in the plasma membrane of Leishmania donovani. Stimulation of parasites with ionomycin increases intracellular Ca(2+) levels and triggers exposure of phosphatidylethanolamine at the cell surface. We found that increasing intracellular Ca(2+) levels with ionomycin or thapsigargin induces rapid transbilayer movement of NBD-labelled phospholipids in the parasite plasma membrane that is bidirectional, independent of cellular ATP and not specific to the polar lipid head group. The findings suggest the presence of a Ca(2+)-dependent lipid scramblase activity in Leishmania parasites. Our studies further show that lipid scrambling is not activated by rapid exposure of promastigotes to higher physiological temperature that increases intracellular Ca(2+) levels. (C) 2011 Elsevier B.V. All rights reserved.

Ca2+ regulates the Drosophila Stoned-A and Stoned-B proteins interaction with the C2B domain of Synaptotagmin-1.

The dicistronic Drosophila stoned gene is involved in exocytosis and/or endocytosis of synaptic vesicles. Mutations in either stonedA or stonedB cause a severe disruption of neurotransmission in fruit flies. Previous studies have shown that the coiled-coil domain of the Stoned-A and the µ-homology domain of the Stoned-B protein can interact with the C2B domain of Synaptotagmin-1. However, very little is known about the mechanism of interaction between the Stoned proteins and the C2B domain of Synaptotagmin-1. Here we report that these interactions are increased in the presence of Ca(2+). The Ca(2+)-dependent interaction between the µ-homology domain of Stoned-B and C2B domain of Synaptotagmin-1 is affected by phospholipids. The C-terminal region of the C2B domain, including the tryptophan-containing motif, and the Ca(2+) binding loop region that modulate the Ca(2+)-dependent oligomerization, regulates the binding of the Stoned-A and Stoned-B proteins to the C2B domain. Stoned-B, but not Stoned-A, interacts with the Ca(2+)-binding loop region of C2B domain. The results indicate that Ca(2+)-induced self-association of the C2B domain regulates the binding of both Stoned-A and Stoned-B proteins to Synaptotagmin-1. The Stoned proteins may regulate sustainable neurotransmission in vivo by binding to Ca(2+)-bound Synaptotagmin-1 associated synaptic vesicles.

Catalytic Enantioselective Halocyclizations beyond Lactones: Emerging Routes to Enantioenriched Nitrogenous Heterocycles

Electrophilic halogen-induced reactions of unactivated olefins are an important class of transformations, whose catalytic enantioselective variants have surfaced during the past few years as effective means of olefin heterodifunctionalization. This article covers important developments in the area of enantioselective halocyclizations, specifically in the context of the synthesis of nitrogenous heterocycles.

Analytic expressions for alpha particle preformation in heavy nuclei

Experimental alpha decay energies and half-lives are investigated systematically to extract alpha particle preformation in heavy nuclei. Formulas for the preformation factors are proposed that can be used to guide microscopic studies on preformation factors and perform accurate calculations of the alpha decay half-lives. There is little evidence for the existence of an island of long stability of superheavy nuclei.

Systematic study of the pi(-)/pi(+) ratio in heavy-ion collisions with the same neutron/proton ratio but different masses

A systematic study of the pi(-)/pi(+) ratio in heavy-ion collisions with the same neutron/proton ratio but different masses can help single out effects of the nuclear mean field on pion production. Based on simulations using the IBUU04 transport model, it is found that the pi(-)/pi(+) ratio in head-on collisions of Ca-48 + Ca-48, Sn-124 + Sn-124, and Au-197 + Au-197 at beam energies from 0.25 to 0.6 GeV/nucleon increases with increasing the system size or decreasing the beam energies. A comprehensive analysis of the dynamical isospin fractionation and the pi(-)/pi(+) ratio as well as their time evolution and spatial distributions demonstrates clearly that the pi(-)/pi(+) ratio is an effective probe of the high-density behavior of the nuclear symmetry energy.

The influence of nuclear orientation in fusion dynamics

Fusion barriers have been calculated for different orientations of the axial symmetry axis of deformed projectile-and target-nucleus. Using the concept of dinuclear system, considering the strong competition between fusion and quasifission processes, by solving the master equation numerically to calculate the fusion probability of superheavy nuclei, we have estimated the dependence of the fusion probabilities for Ge-76 + Pb-208 and Ca-48 + Pu-244 on the orientation angles of the symmetry axis of projectile-and target-nucleus, which shows that belly-belly is the most favorable orientation for synthesizing superheavy nuclei.

Probing balance energy using momentum- and isospin-dependent potential

Using the momentum- and isospin-dependent Boltmann-Uehling-Uhlenbeck (BUU) model, we investigate the transverse flow and balance energy in two isotopic colliding systems Ca-48+Fe-58 and Cr-48+Ni-58 by adopting different symmetry potentials. By comparing the results between the two colliding systems, we find that the difference between the balance energies of two isotopic systems can be considered as a sensitive probe to the density dependence of symmetry energy.

alpha decay half-lives of new superheavy nuclei within a generalized liquid drop model

The alpha decay half-lives of the recently produced isotopes of the 112, 114, 116 and 118 nuclei and decay products have been calculated in the quasi-molecular shape path using the experimental Q(alpha) value and a Generalized Liquid Drop Model including the proximity effects between nucleons in the neck or the gap between the nascent fragments. Reasonable estimates are obtained for the observed alpha decay half-lives. The results are compared with calculations using the Density-Dependent M3Y effective interaction and the Viola-Seaborg-Sobiczewski formulae. Generalized Liquid Drop Model predictions are provided for the alpha decay half-lives of other superheavy nuclei using the Finite Range Droplet Model Q(alpha) and compared with the values derived from the VSS formulae.

Effects of elastic and inelastic NN scattering cross sections on pi(-)/pi(+) ratios in heavy-ion collisions at intermediate energies

Based on the isospin-dependent Boltzmann-Uehling-Uhlenbeck transport model and the scaling model according to nucleon effective mass, effects of elastic and inelastic NN scattering cross sections on pi(-)/pi(+) in the neutron-rich reaction of Ca-48 + Ca-48 at a beam energy of 400 MeV/nucleon are studied. It is found that cross-section effects of both NN elastic and inelastic scatterings affect Delta(1232), pi(-) and pi(+) production, as well as the value of pi(-)/pi(+).

Medium effects on pi(-)/pi(+) in heavy-ion collisions at intermediate energies

Based on the isospin-dependent transport model IBUU and on the scaling model according to nucleon effective mass, effects of elastic and inelastic NN scattering cross-sections on pi(-)/pi(+) in the neutron-rich reaction Ca-48 + Ca-48 at a beam energy of 400MeV/nucleon are studied. It is found that cross-section effects of both NN elastic and inelastic scatterings affect Delta(1232), pi(-) and pi(+) productions as well as the value of pi(-)/pi(+).

30MeV/u~(40)Ar引起反应中的碎片发射机制

本论文中重点研究了30MeV/u 40Ar+58Ni，64Ni和115In反应中中等质量碎片（IMF）的发射机制。实验中，测量了实验室系5°～140°角度范围内出射碎片的能谱和角分布。对前角区出射的IMF（3≤Z≤13）实现了同位素鉴别，对中后角区出射的碎片在低探测阈（<2MeV/u ）的前提下实现了直到Z～30的元素鉴别。 用运动源模型对不同角度下出射的碎片能谱进行了分析和讨论，并结合角分布特征定性地研究了碎片的三个发射源。通过对各源的贡献随角度以及出射碎片电荷数Z的演化，观察到：类弹源主要发射的是那些前角区出射的、接近束流速度的高能碎片；中等速度源的发射是中角度区出射碎片和前角区低能碎片的主要来源；后角区出射的碎片则主要来自于类熔合源的发射。并观察到相对于类熔合源非平衡源更容易发射较轻的碎片。 通过对前角区出射IMF（3≤Z≤13）的能谱和同位素分布的分析，确定了那些基本保持束流速度的碎片主要来自于弹核碎裂过程。用各种模型对实验同位素分布进行了拟合，发现Sümmerer等人给出的经验公式和abrasion-ablation模型均能比较满意地拟合实验同位素分布的宽度和峰位。同时也观察到abrasion-ablation模型计算对奇Z元素的同位素分布能给出较好的拟合，但对偶Z元素的同位素分布，计算结果与实验值相比出现向丰中子方向的系统性偏移（～lamu）。另外，还着重研究了这些产物的靶核相关性问题。通过系统性分析以及同位旋相关的量子分子动力学（IQMD）模型计算，得出了弹核碎裂产物的靶核相关性是源于靶核表面中子与质子分布的不同和平均场及核子核子相互作用的同位旋效应相关。并且，通过计算还指出了靶核中子皮的厚度对于用弹核碎裂方法产生丰中子同位素的重要性。 通过用统计模型拟合后角区出射碎片的电荷分布，指出了这些碎片主要来自于非完全熔合过程中形成的复合系统的统计发射。 实验中观察到30MeV/u 40Ar轰击Ni和In靶在中角区出射的碎片的电荷分布有不同的特征。相对来说，前者更服从power-law，后者则倾向于服从指数规律。结合核态方程和QMD模型计算分析得出，在30MeV/u 的40Ar引起的反应中，对于弾靶质量接近对称的碰撞对所形成的系统，在一定的碰撞条件下可能已进入spinodal区，而非对称碰撞对的碰撞中压缩能还难以使得系统在膨胀时进入力学不稳定区。从而对观察到的实验现象进行了说明，并认为30MeV/u 40Ar轰击与其质量接近的靶核的反应中出射的碎片中已有相当数量的动力学发射成分的贡献。 利用实验中在前角区出射的接近束流速度的碎片的同位素产额提取了类弹源的温度参数。观察到直接由实验同位素产额比得到的表观核温度与所选择的同位素组合有较强烈的依赖关系，而与靶核和实验室探测角基本无关。利用M.B.Tsang等人给出的修正方法，提取了经边馈效应修正后的发射源温度。得到该温度值与反应靶、探测角以及用于提出温度的同位素组合没有明显的依赖关系，均为～4MeV。并用abrasion-ablation模型计算进行了讨论，得到在假定能级密度参数的倒数k=10MeV时，该温度值与abrasion-ablation模型计算是一致的。

RADIATION STABILITY OF PTFE IRRADIATED UNDER VARIOUS CONDITIONS

As a typical example of a polymer degraded by radiation, the radiation stability of PTFE was observed to depend upon irradiation conditions. Increases in irradiation temperature and crystallinity were found to increase its radiation stability whereas increase in the concentration of oxygen in the system over a certain range was observed to have little effect on radiation-induced reactions of PTFE as measured by changes in number-average molecular weight, melting temperature and crystallinity.

A STUDY OF ION KINETIC ENERGY SPECTROMETRY OF FERROCENE DOUBLY CHARGED IONS IN GAS PHASE

The unimolecular charge separation reactions of the doubly charged ions FeC10H102+, FeC10H theta 2+, FeC10H82+ produced in the ion source by electron impact from ferrocene have been studied using Mass analyzed Ion Kinetic Energy Spectrometry (MIKES) technique. From the values of the kinetic energy releases (T), the intercharge distances (R) of the exploding doubly charged ions in their transition structures have been estimated and some structural informations about the transition states can be obtained. The collision induced reactions of the FeC10H102+ ion with Ar have been studied using MIKES, we postulate a new type of continuing reaction which may be "collisional charge separation induced dissociation".

Partial characterization of the hemolytic activity of the nematocyst venom from the jellyfish Cyanea nozakii Kishinouye

Using a recently developed technique to extract jellyfish venom from nematocysts, the present study investigated the hemolytic activity of Cyanea nozakii Kishinouye nematocyst venom on chicken erythrocytes. Venom extract caused a significant concentration-dependent hemolytic effect. The extract could retain its activity at -80 degrees C but was unstable when kept at 4 degrees C and -20 degrees C for 2 days. The hemolytic activity was inhibited by heating within the range of 37-100 degrees C. The extract was active over a pH range of 5.0-8.63 and the pH optima for the extract was 7.8. Incubation of the venom with sphingomyelin specially inhibited hemolytic activity by up to 70%. Cu2+ and Mn2+ greatly reduced the hemolytic activity while Mg2+, Sr2+ and Ba2+ produced a relatively low inhibiting effect on the hemolytic activity. Treatment with Ca2+ induced a concentration-dependent increase in the hemolytic activity. In the presence of 5 mM EDTA, all the hemolytic activity was lost, however, the venom containing 1.5 mM EDTA was stable in the long-term storage. PLA(2) activity was also found in the nematocyst venom of C. nozakii. These characteristics provide us a fundamental knowledge in the C. nozakii nematocyst venom which would benefit future research. (C) 2010 Published by Elsevier Ltd.