Investigating lithium ion conductivity in amorphous solids containing [V10O28]6− clusters by computer simulation

Computer simulation method was applied to investigate the migration of lithium ion in three amorphous solid systems containing polyoxovanadate (POV) clusters [V₁₀O₂₈]^6 ? . The cluster was adopted from a recently synthesized crystalline poly[octa-μ-aqua-octaaqua-μ-decavanadato-hexalithium] (POAODH). The simulated POV systems correspond to amorphous solid half-dehydrated solid and completely dehydrated solid doped with LiCl salt. The simulation results show large diffusion constants of lithium ions in all systems in spite of highly negatively charged [V₁₀O₂₈]^6 ?  clusters presented in the system. The estimated ionic conductivity due to the migration of lithium ions reaches a magnitude of 10^? 4 S/m. The conductivity increases as the water content in the system decreases. The analysis of moving trajectories shows the lithium ion moves around the oxygen sites of POV clusters and hops between them. The estimated displacement of lithium ion is about 4～5 Å, which is much larger than the corresponding displacement of lithium ion in a polymer matrix. Rapidly rotating clusters shown by orientation correlation function analysis, in conjunction with the large separation between clusters in the system, provides favorable conditions for the large amplitude migration of lithium ions.     

Circadian and seasonal variation of endogenous ubiquinone plasma level

Coenzyme Q10 (CoQ10) or ubiquinone, a redox component of the mitochondrial electron transport chains, is a powerful antioxidant and membrane stabilizer that may prevent cellular damage during myocardial ischemia and reperfusion therapy. Coenzyme Q10 has been used primarily as an adjuvant therapy for some cardiomyopathies. However, one of the main problems in CoQ10 administration is the high variability of endogenous plasma and tissue levels, which seems to be dependent on several factors. This work explores temporal 24h and seasonal variation as well as gender and racial differences in endogenous plasma ubiquinone concentration. Coenzyme Q10 measurements (quantified by HPLC-UV) of 16 healthy volunteers were done during the daytime hours of activity beginning at 09:00h one day and ending at 09:00h the next day (13 different determinations) in two distinct months, April and October, of the year. A statistically significant circadian rhythm in plasma ubiquinone concentration that includes only the fundamental 24h component was demonstrated both in the April and October data. Furthermore, the time-point means of the ubiquinone concentration in the October study were invariably higher than those obtained in the April study. No statistically significant differences were found in CoQ10 concentration between male and female subjects, both in April and in October. In addition, racial differences were demonstrated; lower plasma ubiquinone levels were found in Caucasian compared to African subjects. However, the latter small group of subjects failed to demonstrate a circadian rhythm, neither in the April nor in the October analysis.     

Low Fetal Weight is Directly Caused by Sequestration of Parasites and Indirectly by IL-17 and IL-10 Imbalance in the Placenta of Pregnant Mice with Malaria

The sequestration of infected erythrocytes in the placenta can activate the syncytiotrophoblast to release cytokines that affect the micro-environment and influence the delivery of nutrients and oxygen to fetus. The high level of IL-10 has been reported in the intervillous space and could prevent the pathological effects. There is still no data of Th17 involvement in the pathogenesis of placental malaria. This study was conducted to reveal the influence of placental IL-17 and IL-10 levels on fetal weights in malaria placenta. Seventeen pregnant BALB/C mice were divided into control (8 pregnant mice) and treatment group (9 pregnant mice infected by Plasmodium berghei). Placental specimens stained with hematoxylin and eosin were examined to determine the level of cytoadherence by counting the infected erythrocytes in the intervillous space of placenta. Levels of IL-17 and IL-10 in the placenta were measured using ELISA. All fetuses were weighed by analytical balance. Statistical analysis using Structural Equation Modeling showed that cytoadherence caused an increased level of placental IL-17 and a decreased level of placental IL-10. Cytoadherence also caused low fetal weight. The increased level of placental IL-17 caused low fetal weight, and interestingly low fetal weight was caused by a decrease of placental IL-10. It can be concluded that low fetal weight in placental malaria is directly caused by sequestration of the parasites and indirectly by the local imbalance of IL-17 and IL-10 levels.     

Capillary electrophoresis of methotrexate polyglutamates and its application in evaluation of γ-glutamyl hydrolase activity

A rapid and sensitive procedure for the separation of methotrexate (MTX) polyglutamates² using capillary electrophoresis (CE) is described as it applies to the in vitro assay of the enzyme γ-glutamyl hydrolase (GGH, EC 3.4.22.12). Distinct separation of MTX and polyglutamylated forms (up to glu₄) is achieved within 10 min using a 75 μm I.D. capillary (50 cm, +25 kV), and enables quantitation of both reactant and enzyme products. As activity can be reliably determined using less than 5×10⁵ eukaryotic cells, this new technique can be used to measure GGH in patient tumor samples and investigate the relationship between GGH levels and clinical MTX resistance.     

Comparative EPR study on high-spin ferric porphine complexes and cytochrome P-450 having rhombic character

Comparative EPR studies were made on two high-spin Fe(III) porphine model systems and mammalian liver microsomal cytochromes P-450, all of which exhibit approximately the same degrees of rhombicity in their EPR spectra. Comparison of g values and linewidths as a function of temperature, and of the microwave power saturation demonstrated that EPR characteristics of P-450 are more similar to the Fe(III) porphines having the thiolate axial ligand than in the other model systems, the mixed crystals of Fe(III) porphine with the corresponding free base porphine, in which no thiolate ligand is involved.There is, however, a discrepancy between P-450 and the model thiolates with respect to the size of the zero-field parameter D. These observations indicate that P-450 heme has essential structural features in common with thiolates but the Fe-S bond of P-450 may be modified from its normal orientation in model thiolates, probably as a result of the constraints imposed by the protein stucture.     

Identification of side arm-modified DOTA scaffolds as multi-site binding ligands for cancer cells over normal cells

The metal-chelated 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-tetraamide (DOTA) scaffold has been widely used as a contrast agent for diagnostic purposes in positron emission tomography (PET) and magnetic resonance imaging (MRI), but not as a biomarker targetable ligand. While the oxygen atoms at the stem of the four arms of the DOTA scaffold are needed for metal chelation, we previously introduced various physiochemical properties to extend these arms in a chemical library fashion to enhance the imaging contrast mechanism. We developed two such on-bead libraries, with 80 and 76 DOTA derivatives, where one arm was used to attach the DOTA scaffold onto resin beads and the other three arms were chemically modified. We now hypothesized that the chemical moieties used to modify these three arms can also recognize biomarkers on a cell surface. Therefore in this current study, we used such 76 derivatives of DOTA library to screen against HeLa cervical cancer cells. We found that two of the four ‘hits’ identified displayed higher binding towards HeLa cells than the unmodified parent DOTA. Furthermore, one of those ‘hits’ displayed better binding towards cervical and prostate cancer cells than lung and breast cancer cells and normal HBEC-3KT and RWPE1 cells. This indicates that this derivative can recognize a biomarker specific for certain types of cancer cells. If the compound has intrinsic activity, this can be used as a theranostic agent for real time therapy monitoring applications in the future. We believe that our DOTA derivative-based library approach can be applied to other types of cell and protein screens on various disease types in the future.     

Pertussis Toxin in the A10 Region Increases Dopamine Synthesis and Metabolism

Inhibitory regulation of dopamine neurons is mediated by dopamine autoreceptor and gamma-aminobutyric acidB receptor opening of potassium channels. Increased potassium conductance by either receptor is G protein dependent. To evaluate the role of G proteins in vivo, pertussis toxin (PTX) was microinjected into the A10 dopamine region and changes in dopamine metabolism and synthesis measured. PTX produced an elevation in dopamine metabolism and synthesis in the A10 region and nucleus accumbens for up to 4 days after injection. By day 7 the levels of the dopamine precursor and metabolites had returned to normal. A less consistent increase was also measured in the A9 dopamine region and the prefrontal cortex. Although dopamine synthesis and metabolism had returned to normal by day 7, the in vitro ADP-ribosylation of G proteins in the A10 region by PTX remained depressed by approximately 50% from day 1 to day 14 after administration, returning to normal by day 30. The data suggest that in vivo ribosylation of G proteins may lead to a short-term attenuation of the tonic inhibitory control of dopamine neurons, which can be compensated for by PTX-insensitive mechanisms.     

Identification of novel therapeutic targets for neuropathic pain based on gene expression patterns

Neuropathic pain (NP) caused by nerve injury or dysfunction is one of the most challenging neurological diseases. In-depth study of disease signatures contributes to the development of novel target treatment for NP. In this study, we analyzed expression profiles of qualified NP datasets (GSE24982 and GSE63442) deposited at Gene Expression Omnibus database by systematic bioinformatics approaches. We analyzed the differentially expressed genes of high and low pain compared with normal control group, and between spinal nerve ligation (SNL) injury model and sham-operation group. A total of 1,243 upregulated and 1,533 downregulated genes were identified in GSE24982, 380 upregulated and 355 downregulated genes were identified in GSE63442. By comparing low-pain samples with the corresponding sham-operation group, we identified 457 upregulated and 409 downregulated genes. Overlapping genes were screened out and signaling pathway and expression regulation model analyses were performed. SCN10A and SST were identified as biomarkers for NP. In conclusion, our study showed the expression pattern of gene about NP. These identified biomarkers could serve as potential therapeutic targets for treating NP.