How close is the bench to the bedside? Metabolic profiling in cancer research

Metabolic profiling using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) is integral to the rapidly expanding field of metabolomics, which is making progress in toxicology, plant science and various diseases, including cancer. In the area of oncology and metabolic phenotyping, researchers have probed the known changes in malignant cellular pathways using new experimental techniques to gain more insights, and others are exploiting these same cellular pathways for therapeutic drug targets and for novel cancer biomarkers, with the ultimate goal of translation to the clinic. Here, we discuss the challenges and opportunities in metabolic phenotyping for discovering novel cancer biomarkers, and we assess the clinical applicability of MS and NMR

Determination of Abundances of Fifty-Two Elements in Natural Waters by ICP-MS with Freeze-Drying Pre-concentration

To precisely determine the abundances of fifty-two elements found within natural water samples, with mass fractions down to fg g(-1) level, we have developed a method which combines freeze-drying pre-concentration (FDC) and isotope dilution internal standardisation (ID-IS). By sublimation of H2O, the sample solution was reduced to 0.3 mol l(-1) to avoid hydrolysis. Matrix-affected signal suppression was not significant for the solutions with NaCl concentrations lower than 0.2 and 0.1 cg g(-1) for quadrupole ICP-MS and sector field ICP-MS, respectively. The recovery yields of elements after FDC were 97-105%. The detection limits for the sample solutions prepared by FDC were <= 10 pg g(-1), except for Na, K and Ca. Blanks prepared using FDC were at pg-levels, except for eleven elements (Na, Mg, Al, P, Ca, Mn, Fe, Co, Ni, Cu and Zn). The abundances of fifty-two elements in bottled drinking water were determined from five different geological sources with mass fractions ranging from the fg g(-1) to mu g g(-1) level with high accuracy

Efficient in vivo knock-down of estrogen receptor alpha: application of recombinant adenovirus vectors for delivery of short hairpin RNA

BACKGROUND: Adenovirus (Ad) mediated gene transfer is a well-established tool to transiently express constructs in livers of mice in vivo. In the present study, we determined the specificity and efficiency of Ad vectors expressing short hairpin (sh) RNA constructs to knock-down the estrogen receptor α (ERα). RESULTS: Two different shRNA constructs derived from the murine ERα coding sequence were designed (shERα). In vitro, transfection of three mouse cell lines with pSUPER-shERα constructs resulted in up to 80% reduction of endogenous ERα activity. A single mismatch in the target sequence eliminated the reduction of ERα activity, demonstrating the specificity of shERα. The subsequently generated Ad.shERα vectors were equally effective in vitro. In vivo, intravenous administration of Ad.shERα resulted in 70% reduced hepatic mouse ERα mRNA levels. Co-injection of Ad.shERα with an Ad vector containing a luciferase (luc) gene driven by an estrogen responsive element (ERE) containing promoter resulted in a significant (90% on day five) down-regulation of hepatic luciferase activity, as determined by non-invasive optical imaging. Down-regulation was sustained up to day seven post-injection. CONCLUSION: Ad mediated transfer of shERα expression constructs results in efficient and specific knockdown of endogenous ERα transcription both in vitro and in vivo

Effect of different drying methods on the protein and product quality of hairtail fish meat gel

Three different methods, namely hot air drying (HA), microwave vacuum drying (MV), and vacuum freeze drying (FD), were employed to investigate the effect of drying method on the quality of hairtail fish meat gel. Compared with HA and MV, FD samples showed a better quality in terms of moisture content, water absorption index, and water solubility index, and had the highest overall acceptance in sensory evaluation. FD preserved the protein from degradation and formed an ordered porous microstructure. The nitrogen fraction assay revealed that protein was degraded into 40–100 kDa fragments during drying in HA, which was almost not affected by MV and FD. Overall, FD was the most suitable method for drying of meat gel made from hairtail, followed by MV and HA

The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats

<p>Abstract</p> <p>Background</p> <p>Activation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats.</p> <p>Methods</p> <p>DSS rats were fed low salt (LS, 0.3% NaCl) or high salt (HS, 8% NaCl) diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min), or GLP-1 (25 pmol/kg/min) for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day) or AC3174 plus captopril.</p> <p>Results</p> <p>HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP) was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p < 0.05). AC3174 plus captopril attenuated the deleterious effects of high salt on posterior wall thickness, LV mass, and the ratio of LV mass to body weight (P ≤ 0.05). In contrast, GLP-1 had no effect on these cardiovascular parameters. All treatments reduced LV wall stress. GLP-1, AC3174, captopril, or AC3174 plus captopril normalized fasting insulin and HOMA-IR (P ≤ 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P ≤ 0.05). Renal morphology in HS rats was associated with extensive sclerosis. Monotherapy with AC3174, captopril, or GLP-1 attenuated renal damage. However, AC3174 plus captopril produced the most effective improvement.</p> <p>Conclusions</p> <p>Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.</p

Far-infrared absorption in parallel quantum wires with weak tunneling

We study collective and single-particle intersubband excitations in a system of quantum wires coupled via weak tunneling. For an isolated wire with parabolic confinement, the Kohn's theorem guarantees that the absorption spectrum represents a single sharp peak centered at the frequency given by the bare confining potential. We show that the effect of weak tunneling between two parabolic quantum wires is twofold: (i) additional peaks corresponding to single-particle excitations appear in the absorption spectrum, and (ii) the main absorption peak acquires a depolarization shift. We also show that the interplay between tunneling and weak perpendicular magnetic field drastically enhances the dispersion of single-particle excitations. The latter leads to a strong damping of the intersubband plasmon for magnetic fields exceeding a critical value.Comment: 18 pages + 6 postcript figure

Two novel transcriptional regulators are essential for infection-related morphogenesis and pathogenicity of the rice blast fungus Magnaporthe oryzae.

This is the final version of the article. Available from the publisher via the DOI in this record.The cyclic AMP-dependent protein kinase A signaling pathway plays a major role in regulating plant infection by the rice blast fungus Magnaporthe oryzae. Here, we report the identification of two novel genes, MoSOM1 and MoCDTF1, which were discovered in an insertional mutagenesis screen for non-pathogenic mutants of M. oryzae. MoSOM1 or MoCDTF1 are both necessary for development of spores and appressoria by M. oryzae and play roles in cell wall differentiation, regulating melanin pigmentation and cell surface hydrophobicity during spore formation. MoSom1 strongly interacts with MoStu1 (Mstu1), an APSES transcription factor protein, and with MoCdtf1, while also interacting more weakly with the catalytic subunit of protein kinase A (CpkA) in yeast two hybrid assays. Furthermore, the expression levels of MoSOM1 and MoCDTF1 were significantly reduced in both Δmac1 and ΔcpkA mutants, consistent with regulation by the cAMP/PKA signaling pathway. MoSom1-GFP and MoCdtf1-GFP fusion proteins localized to the nucleus of fungal cells. Site-directed mutagenesis confirmed that nuclear localization signal sequences in MoSom1 and MoCdtf1 are essential for their sub-cellular localization and biological functions. Transcriptional profiling revealed major changes in gene expression associated with loss of MoSOM1 during infection-related development. We conclude that MoSom1 and MoCdtf1 functions downstream of the cAMP/PKA signaling pathway and are novel transcriptional regulators associated with cellular differentiation during plant infection by the rice blast fungus.Funding: This work was supported by National Key Basic Research and Development Program of China (2012CB114002), by Program for Changjiang Scholars and Innovative Research Team in University (IRT0943), by the Natural Science Foundation of China (Grant Nos. 30970129 and 31071648) and the Doctoral Fund of Ministry of Education of China (20100101110097) to ZW

Theory of Luminescent Emission in Nanocrystal ZnS:Mn with an Extra Electron

We consider the effect of an extra electron injected into a doped quantum dot $ZnS:Mn^{2+}$. The Coulomb interaction and the exchange interaction between the extra electron and the states of the Mn ion will mix the wavefunctions, split the impurity energy levels, break the previous selection rules and change the transition probabilities. Using this model of an extra electron in the doped quantum dot, we calculated the energy and the wavefunctions, the luminescence probability and the transition lifetime and compare with the experiments. Our calculation shows that two orders of magnitudes of lifetime shortening can occur in the transition $^4T_1-^6A_1$ when an extra electron is present.Comment: 15 pages, 2 Figs No change in Fig

Low-temperature structural model of hcp solid C70_{70}

We report intermolecular potential-energy calculations for solid C_${70}$ and determine the optimum static orientations of the molecules at low temperature; we find them to be consistent with the monoclinic structural model proposed by us in an earlier report [Solid State Commun. {\bf 105), 247 (1998)]. This model indicates that the C_5 axis of the molecule is tilted by an angle $\approx$18^o from the monoclinic b axis in contrast with the molecular orientation proposed by Verheijen {\it et al.} [J. Chem. Phys. {\bf 166}, 287 (1992)] where the C_5 axis is parallel to the monoclinic b axis. In this calculation we have incorporated the effective bond charge Coulomb potential together with the Lennard-Jones potential between the molecule at the origin of the monoclinic unit cell and its six nearest neighbours, three above and three below. The minimum energy configuration for the molecular orientations turns out to be at $\theta$=18^o, $\phi$=8^o, and $\psi$=5^o, where $\theta$, $\phi$, and $\psi$ define the molecular orientations.Comment: ReVTeX (4 pages) + 2 PostScript figure

Developing Antidote Controlled Antiplatelet Therapies By Targeting The Vwf ‐ Gp Ib‐Ix‐V Interaction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106054/1/jth02400.pd