Radiation effects on microcrystalline cellulose in 1-butyl-3-methylimidazolium chloride ionic liquid

The radiation processing of cellulose in ionic liquids (ILs) demands a comprehensive knowledge of radiation effects on cellulose in ILs. Herein, gamma radiation-induced degradation kinetics of microcrystalline cellulose (MCC) in 1-butyl-3-methylimidazolium chloride ([Bmim]Cl) was studied by viscometry. The intrinsic viscosity of MCC in [Bmim]Cl decreased slightly with increasing dose; while chemical structure and crystalline state of cellulose has no obvious change up to 300kGy. The radiation degradation rate constant (k) of MCC in [Bmim]Cl was 2.60×10(-7)/kGy, lower than that of solid cellulose, but higher than that in N-methylmorpholine-N-oxide (NMMO) solvent. Furthermore, k value decreased to 1.12×10(-7)/kGy in dimethyl sulfoxide (DMSO)/[Bmim]Cl system due to the free radicals scavenging of DMSO. The radicals generated during irradiation play main role in the radiation degradation of MCC in [Bmim]Cl. This work provides a new way to control the average molecular weight of cellulose by radiation-induced degradation of cellulose in ILs.     

Perturbation of zebrafish swimbladder development by enhancing Wnt signaling in Wif1 morphants

Wnt signaling plays critical roles in development of both tetrapod lung and fish swimbladder, which are the two evolutionary homologous organs. Our previous data reveal that down-regulation of Wnt signaling leads to defective swimbladder development. However, the effects of up-regulation of Wnt signaling on swimbladder development remain unclear. By knockdown of the Wnt protein inhibitory gene wif1, we demonstrated that up-regulation of Wnt signaling also resulted in perturbed development of the swimbladder. Specifically, the growth of epithelium and mesenchyme was greatly inhibited, the smooth muscle differentiation was abolished, and the organization of mesothelium was disturbed. Furthermore, our data reveal that it is the reduced cell proliferation, but not enhanced apoptosis, that contributes to the disturbance of swimbladder development in wif1 morphants. Blocking Wnt signaling by the Wnt antagonist IWR-1 did not affect wif1 expression in the swimbladder, but complete suppression of Hedgehog signaling in smo-/- mutants abolished wif expression, consistent with our earlier report of a negative feedback regulation of Wnt signaling in the swimbladder by the Hedgehog signaling. Our works established the importance of proper level of Wnt signaling for normal development of swimbladder in zebrafish.     

Effects of strontium on photosynthetic characteristics of oilseed rape seedlings

The threat of environmental strontium pollution led to an increased interest to elucidating the mechanisms of this metal toxicity in the organism. To investigate strontium effects on vital photosynthesis characteristics, three-leaf stage oilseed rape seedlings (Brassica napus L., cv. Mianyou No.15), raised in the hydroponic culture, were provided with a nutrient solution containing 0, 10, 20, and 40 mM SrCl₂. Strontium uptake and distribution in oilseed rape plants and its effect on various aspects of photosynthesis were investigated after 0, 7, 14, and 21 days of strontium treatment. Oilseed rape seedlings demonstrated a strong ability of strontium accumulation. Strontium absorbed by roots was primarily transferred to leaves and accumulated there. The leaf photosynthetic oxygen evolution rate, chlorophyll content, and Rubisco (EC 4.1.3.9) and phosphoenolpyruvate carboxylase (PEPCase; EC 4.1.1.31) activities declined progressively with increasing concentration of applied strontium and also with increasing the duration of exposure time. These results indicate that strontium accumulated in leaves damaged various processes of photosynthesis, such as energy absorption, energy transfer, and photosynthetic carbon assimilation.     

Chromosome Segregation Analysis in Human Embryos Obtained from Couples Involving Male Carriers of Reciprocal or Robertsonian Translocation

The objective of this study was to investigate the frequency and type of chromosome segregation patterns in cleavage stage embryos obtained from male carriers of Robertsonian (ROB) and reciprocal (REC) translocations undergoing preimplantation genetic diagnosis (PGD) at our reproductive center. We used FISH to analyze chromosome segregation in 308 day 3 cleavage stage embryos obtained from 26 patients. The percentage of embryos consistent with normal or balanced segregation (55.1% vs. 27.1%) and clinical pregnancy (62.5% vs. 19.2%) rates were higher in ROB than the REC translocation carriers. Involvement of non-acrocentric chromosome(s) or terminal breakpoint(s) in reciprocal translocations was associated with an increase in the percent of embryos consistent with adjacent 1 but with a decrease in 3∶1 segregation. Similar results were obtained in the analysis of nontransferred embryos donated for research. 3∶1 segregation was the most frequent segregation type in both day 3 (31%) and spare (35%) embryos obtained from carriers of t(11;22)(q23;q11), the only non-random REC with the same breakpoint reported in a large number of unrelated families mainly identified by the birth of a child with derivative chromosome 22. These results suggest that chromosome segregation patterns in day 3 and nontransferred embryos obtained from male translocation carriers vary with the type of translocation and involvement of acrocentric chromosome(s) or terminal breakpoint(s). These results should be helpful in estimating reproductive success in translocation carriers undergoing PGD.     

KCN1, a Novel Synthetic Sulfonamide Anticancer Agent: In Vitro and In Vivo Anti-Pancreatic Cancer Activities and Preclinical Pharmacology

The purpose of the present study was to determine the in vitro and in vivo anti-cancer activity and pharmacological properties of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1. In the present study, we investigated the in vitro activity of KCN1 on cell proliferation and cell cycle distribution of pancreatic cancer cells, using the MTT and BrdUrd assays, and flow cytometry. The in vivo anti-cancer effects of KCN1 were evaluated in two distinct xenograft models of pancreatic cancer. We also developed an HPLC method for the quantitation of the compound, and examined its stability in mouse plasma, plasma protein binding, and degradation by mouse S9 microsomal enzymes. Furthermore, we examined the pharmacokinetics of KCN1 following intravenous or intraperitoneal injection in mice. Results showed that, in a dose-dependent manner, KCN1 inhibited cell growth and induced cell cycle arrest in human pancreatic cancer cells in vitro, and showed in vivo anticancer efficacy in mice bearing Panc-1 or Mia Paca-2 tumor xenografts. The HPLC method provided linear detection of KCN1 in all of the matrices in the range from 0.1 to 100 µM, and had a lower limit of detection of 0.085 µM in mouse plasma. KCN1 was very stable in mouse plasma, extensively plasma bound, and metabolized by S9 microsomal enzymes. The pharmacokinetic studies indicated that KCN1 could be detected in all of the tissues examined, most for at least 24 h. In conclusion, our preclinical data indicate that KCN1 is a potential therapeutic agent for pancreatic cancer, providing a basis for its future development.     

Human Fidgetin is a microtubule severing the enzyme and minus-end depolymerase that regulates mitosis

Fidgetin is a member of the AAA protein superfamily with important roles in mammalian development. Here we show that human Fidgetin is a potent microtubule severing and depolymerizing the enzyme used to regulate mitotic spindle architecture, dynamics and anaphase A. In vitro, recombinant human Fidgetin severs taxol-stabilized microtubules along their length and promotes depolymerization, primarily from their minus-ends. In cells, human Fidgetin targets to centrosomes, and its depletion with siRNA significantly reduces the velocity of poleward tubulin flux and anaphase A chromatid-to-pole motion. In addition, the loss of Fidgetin induces a microtubule-dependent enlargement of mitotic centrosomes and an increase in the number and length of astral microtubules. Based on these data, we propose that human Fidgetin actively suppresses microtubule growth from and attachment to centrosomes.     

Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC(50) values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.