Analysis of nitrogen tetroxide samples Final report

Chemical analysis of nitrogen tetroxide trace impuritie

Dispersive Gap Mode of Phonons in Anisotropic Superconductors

We estimate the effect of the superconducting gap anisotropy in the dispersive gap mode of phonons, which is observed by the neutron scattering on borocarbide superconductors. We numerically analyze the phonon spectrum considering the electron-phonon coupling, and examine contributions coming from the gap suppression and the sign change of the pairing function on the Fermi surface. When the sign of the pairing function is changed by the nesting translation, the gap mode does not appear. We also discuss the suppression of the phonon softening of the Kohn anomaly due to the onset of superconductivity. We demonstrate that observation of the gap dispersive mode is useful for sorting out the underlying superconducting pairing function.Comment: 7 pages, 12 figures, to be published in J. Phys. Soc. Jp

Calcitriol and Calcipotriol Modulate Transport Activity of ABC Transporters and Exhibit Selective Cytotoxicity in MRP1-overexpressing Cells

Efflux transporters P-glycoprotein (P-gp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) can affect the efficacy and toxicity of a wide variety of drugs and are implicated in multidrug resistance (MDR). Eight test compounds, recently identified from an intramolecular FRET-based high throughput screening, were characterized for their interaction with MRP1. We report that the active metabolite of vitamin D3, calcitriol, and its analog calcipotriol are selectively cytotoxic to MRP1-overexpressing cells, besides inhibiting transport function of P-gp, MRP1, and BCRP. Calcitriol and calcipotriol consistently displayed a potent inhibitory activity on MRP1-mediated doxorubicin and calcein efflux in MRP1-overexpressing H69AR and HEK293/MRP1 cells. Vesicular transport studies confirmed a strong inhibitory effect of calcitriol and calcipotriol on MRP1-mediated uptake of tritiumlabeled estradiol glucuronide and leukotriene C4. In cytotoxicity assays, MRP1-overexpressing cells exhibited hypersensitivity toward calcitriol and calcipotriol. Such collateral sensitivity, however, was not observed in HEK293/P-gp and HEK293/BCRP cells, although the vitamin D3 analogs inhibited calcein efflux in P-gp-overexpressing cells, and mitoxantrone efflux in BCRP-overexpressing cells. The selective cytotoxicity of calcitriol and calpotriol toward MRP1 over-expressing cells can be eliminated with MRP1 inhibitor MK571. Our data indicate a potential role of calcitriol and its analogs in targeting malignancies in which MRP1 expression is prominent and contributes to MDR

Development of Novel Intramolecular FRET-Based ABC Transporter Biosensors to Identify New Substrates and Modulators

Multidrug resistance protein 1 (MRP1) can efflux a wide variety of molecules including toxic chemicals, drugs, and their derivatives out of cells. Substrates of MRP1 include anti-cancer agents, antibiotics, anti-virals, anti-human immunodeficiency virus (HIV), and many other drugs. To identify novel substrates and modulators of MRP1 by exploiting intramolecular fluorescence resonance energy transfer (FRET), we genetically engineered six different two-color MRP1 proteins by changing green fluorescent protein (GFP) insertion sites, while keeping the red fluorescent protein (RFP) at the C-terminal of MRP1. Four of six recombinant proteins showed normal expression, localization, and transport activity. We quantified intramolecular FRET using ensemble fluorescence spectroscopy in response to binding of known substrate or ATP alone, substrate/ATP, and trapping of the transporter in closed conformation by vanadate. Recombinant MRP1 proteins GR-881, GR-888, and GR-905 exhibited reproducible and higher FRET changes under all tested conditions and are very promising for use as MRP1 biosensors. Furthermore, we used GR-881 to screen 40 novel anti-cancer drugs and identified 10 hits that potentially directly interact with MRP1 and could be substrates or modulators. Profiling of drug libraries for interaction with MRP1 can provide very useful information to improve the efficacy and reduce the toxicity of various therapies

High-content Screening of Clinically Tested Anticancer Drugs Identifies Novel Inhibitors of Human MRP1 (ABCC1)

Multidrug resistance protein 1 (MRP1/ABCC1), an integral transmembrane efflux transporter, belongs to the ATP-binding cassette (ABC) protein superfamily. MRP1 governs the absorption and disposition of a wide variety of endogenous and xenobiotic substrates including various drugs across organs and physiological barriers. Additionally, its overexpression has been implicated in multidrug resistance in chemotherapy of multiple cancers. Here, we describe the development of a high content imaging-based screening assay for MRP1 activity. This live cell-based automated microscopy assay is very robust and allows simultaneous detection of cell permeable, non-toxic and potent inhibitors. The validity of the assay was demonstrated by profiling a library of 386 anti-cancer compounds, which are under clinical trials, for interactions with MRP1. The assay identified 12 potent inhibitors including two known MRP1 inhibitors, cyclosporineA and rapamycin. On the other hand, MRP1-inhibitory activity of tipifarnib, AZD1208, deforolimus, everolimus, temsirolimus, HS-173, YM201636, ESI-09, TAK-733, and CX-6258 has not been previously reported. Inhibition of MRP1 activity was further validated using flow cytometry and confocal microscopy for the respective detection of calcein and doxorubicin in MRP1-overexpressing cells. Among the identified compounds, tipifarnib, AZD1208, rapamycin, deforolimus, everolimus, TAK-733, and temsirolimus resensitized MRP1-overexpressing H69AR cells towards vincristine, a cytotoxic chemotherapeutic agent, by 2–6-fold. Using purified HEK293 membrane vesicles overexpressing MRP1, MRP2, MRP3, and MRP4, we also demonstrated that the identified compounds exert differential and selective response on the uptake of estradiol glucuronide, an endogenous MRP substrate. In summary, we demonstrated the effectiveness of the high content imaging-based high-throughput assay for profiling compound interaction with MRP1

Incommensurate Charge and Spin Fluctuations in d-wave Superconductors

We show analytic results for the irreducible charge and spin susceptibilities, $\chi_0 (\omega, {\bf Q})$, where ${\bf Q}$ is the momentum transfer between the nodes in d-wave superconductors. Using the BCS theory and a circular Fermi surface, we find that the singular behavior of the irreducible charge susceptibility leads to the dynamic incommensurate charge collective modes. The peaks in the charge structure factor occur at a set of wave vectors which form an ellipse around ${\bf Q}_{\pi}=(\pi,\pi)$ and ${\bf Q}_0=(0,0)$ in momentum space with momentum dependent spectral weight. It is also found that, due to the non-singular irreducible spin susceptibility, an extremely strong interaction via random phase approximation is required to support the magnetic peaks near ${\bf Q}_{\pi}$. Under certain conditions, the peaks in the magnetic structure factor occur near ${\bf Q}=(\pi,\pi (1 \pm \delta))$ and $(\pi (1 \pm \delta),\pi)$.Comment: 5 pages, 3 figure

Strong correlation effects in the doped Hubbard model in infinite dimensions

The density of states and the optical conductivity of the doped Hubbard model on a Bethe lattice with infinite connectivities have been studied using an analytic variant of the Lanczos continued fraction method. The spectral weight of the gap states and the position of the chemical potential upon hole or electron doping have been studied. We argue that the strong correlation effects such as gap states and midinfrared band shown in two dimensions also appear in infinite dimensions.Comment: 9 pages, revtex, 3 figures upon reques

Endovascular repair or open repair for ruptured abdominal aortic aneurysm: a Cochrane systematic review

OBJECTIVES: Emergency endovascular aneurysm repair (eEVAR) may improve outcomes for patients with ruptured abdominal aortic aneurysm (RAAA). The study aim was to compare the outcomes for eEVAR with conventional open surgical repair for the treatment of RAAA. SETTING: A systematic review of relevant publications was performed. Randomised controlled trials (RCTs) comparing eEVAR with open surgical repair for RAAA were included. PARTICIPANTS: 3 RCTs were included, with a total of 761 patients with RAAA. INTERVENTIONS: Meta-analysis was performed with fixed-effects models with ORs and 95% CIs for dichotomous data and mean differences with 95% CIs for continuous data. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was short-term mortality. Secondary outcome measures included aneurysm-specific and general complication rates, quality of life and economic analysis. RESULTS: Overall risk of bias was low. There was no difference between the 2 interventions on 30-day (or in-hospital) mortality, OR 0.91 (95% CI 0.67 to 1.22; p=0.52). 30-day complications included myocardial infarction, stroke, composite cardiac complications, renal complications, severe bowel ischaemia, spinal cord ischaemia, reoperation, amputation and respiratory failure. Reporting was incomplete, and no robust conclusion was drawn. For complication outcomes that did include at least 2 studies in the meta-analysis, there was no clear evidence to support a difference between eEVAR and open repair. Longer term outcomes and cost per patient were evaluated in only a single study, thus precluding definite conclusions. CONCLUSIONS: Outcomes between eEVAR and open repair, specifically 30-day mortality, are similar. However, further high-quality trials are required, as the paucity of data currently limits the conclusions