Charge Delocalization in Self-Assembled Mixed-Valence Aromatic Cation Radicals

The spontaneous assembly of aromatic cation radicals (D+•) with their neutral counterpart (D) affords dimer cation radicals (D2+•). The intermolecular dimeric cation radicals are readily characterized by the appearance of an intervalence charge-resonance transition in the NIR region of their electronic spectra and by ESR spectroscopy. The X-ray crystal structure analysis and DFT calculations of a representative dimer cation radical (i.e., the octamethylbiphenylene dimer cation radical) have established that a hole (or single positive charge) is completely delocalized over both aromatic moieties. The energetics and the geometrical considerations for the formation of dimer cation radicals is deliberated with the aid of a series of cyclophane-like bichromophoric donors with drastically varied interplanar angles between the cofacially arranged aryl moieties. X-ray crystallography of a number of mixed-valence cation radicals derived from monochromophoric benzenoid donors established that they generally assemble in 1D stacks in the solid state. However, the use of polychromophoric intervalence cation radicals, where a single charge is effectively delocalized among all of the chromophores, can lead to higher-order assemblies with potential applications in long-range charge transport. As a proof of concept, we show that a single charge in the cation radical of a triptycene derivative is evenly distributed on all three benzenoid rings and this triptycene cation radical forms a 2D electronically coupled assembly, as established by X-ray crystallography

Exon expression arrays as a tool to identify new cancer genes

Background: Identification of genes that are causally implicated in oncogenesis is a major goal in cancer research. An estimated 10-20% of cancer-related gene mutations result in skipping of one or more exons in the encoded transcripts. Here we report on a strategy to screen in a global fashion for such exon-skipping events using PAttern based Correlation (PAC). The PAC algorithm has been used previously to identify differentially expressed splice variants between two predefined subgroups. As genetic changes in cancer are sample specific, we tested the ability of PAC to identify aberrantly expressed exons in single samples. Principal Findings: As a proof-of-principle, we tested the PAC strategy on human cancer samples of which the complete coding sequence of eight cancer genes had been screened for mutations. PAC detected all seven exon-skipping mutants among 12 cancer cell lines. PAC also identified exon-skipping mutants in clinical cancer specimens although detection was compromised due to heterogeneous (wild-type) transcript expression. PAC reduced the number candidate genes/exons for subsequent mutational analysis by two to three orders of magnitude and had a substantial true positive rate. Importantly, of 112 randomly selected outlier exons, sequence analysis identified two novel exon skipping events, two novel base changes and 21 previously reported base changes (SNPs). Conclusions: The ability of PAC to enrich for mutated transcripts and to identify known and novel genetic changes confirms its suitability as a strategy to identify candidate cancer genes

New physiological activities of myosuppressin, sulfakinin and NVP-like peptide in Zophobas atratus beetle

Three neuropeptides Zopat-MS-2 (pEDVDHVFLRFa), Zopat-SK-1 (pETSDDYGHLRFa) and Zopat-NVPL-4trunc. (GRWGGFA), recently isolated from the neuroendocrine system of the Zophobas atratus beetle, were tested for their myotropic and hyperglycaemic activities in this species. These peptides exerted differentiated dose-dependent and tissue specific physiological effects. Zopat-MS-2 inhibited contractions of the isolated heart, ejaculatory duct, oviduct and hindgut of adult beetles and induced bimodal effects in the heart contractile activity of pupae in vivo. It also increased the haemolymph free sugar level in larvae of this species, apart from myotropic activity. Zopat-SK-1 showed myostimulatory action on the isolated hindgut of the adult beetles, but it decreased contractions of the heart, ejaculatory duct and oviduct. Injections of this peptide at a dose of 2 μg also caused delayed cardioinhibitory effects on the heartbeat of the pupae. Together with the ability to increase free sugar level in the haemolymph of larvae these were new physiological activities of sulfakinins in insects. Zopat-NVPL-4trunc. inhibited the muscle contractions of the two organs: hindgut and ejaculatory duct but it was inactive on the oviduct and the heart of the adult beetles. This peptide also increased free sugar level concentration in the haemolymph of Z. atratus larvae. These physiological actions are the first biological activities discovered for this group of the insect peptides. The present work showed pleiotropic activity of three neuropeptides and indicates that the visceral muscle contractions and the haemolymph sugar homeostasis in Z. atratus are regulated by complex mechanisms

The p21-Dependent Radiosensitization of Human Breast Cancer Cells by MLN4924, an Investigational Inhibitor of NEDD8 Activating Enzyme

Radiotherapy is a treatment choice for local control of breast cancer. However, intrinsic radioresistance of cancer cells limits therapeutic efficacy. We have recently validated that SCF (SKP1, Cullins, and F-box protein) E3 ubiquitin ligase is an attractive radiosensitizing target. Here we tested our hypothesis that MLN4924, a newly discovered investigational small molecule inhibitor of NAE (NEDD8 Activating Enzyme) that inactivates SCF E3 ligase, could act as a novel radiosensitizing agent in breast cancer cells. Indeed, we found that MLN4924 effectively inhibited cullin neddylation, and sensitized breast cancer cells to radiation with a sensitivity enhancement ratio (SER) of 1.75 for SK-BR-3 cells and 1.32 for MCF7 cells, respectively. Mechanistically, MLN4924 significantly enhanced radiation-induced G2/M arrest in SK-BR-3 cells, but not in MCF7 cells at early time point, and enhanced radiation-induced apoptosis in both lines at later time point. However, blockage of apoptosis by Z-VAD failed to abrogate MLN4924 radiosensitization, suggesting that apoptosis was not causally related. We further showed that MLN4924 failed to enhance radiation-induced DNA damage response, but did cause minor delay in DNA damage repair. Among a number of tested SCF E3 substrates known to regulate growth arrest, apoptosis and DNA damage response, p21 was the only one showing an enhanced accumulation in MLN4924-radiation combination group, as compared to the single treatment groups. Importantly, p21 knockdown via siRNA partialy inhibited MLN4924-induced G2/M arrest and radiosensitization, indicating a causal role played by p21. Our study suggested that MLN4924 could be further developed as a novel class of radiosensitizer for the treatment of breast cancer

Field and chirality effects on electrochemical charge transfer rates: Spin dependent electrochemistry

This work examines whether electrochemical redox reactions are sensitive to the electron spin orientation by examining the effects of magnetic field and molecular chirality on the charge transfer process. The working electrode is either a ferromagnetic nickel film or a nickel film that is coated with an ultrathin (5\u201330 nm) gold overlayer. The electrode is coated with a self-assembled monolayer that immobilizes a redox couple containing chiral molecular units, either the redox active dye toluidine blue O with a chiral cysteine linking unit or cytochrome c. By varying the direction of magnetization of the nickel, toward or away from the adsorbed layer, we demonstrate that the electrochemical current depends on the orientation of the electrons\u2019 spin. In the case of cytochrome c, the spin selectivity of the reduction is extremely high, namely, the reduction occurs mainly with electrons having their spin-aligned antiparallel to their velocity

Can Charisma Be Taught? Tests of Two Interventions

We tested whether we could teach individuals to behave more charismatically, andwhether changes in charisma affected leader outcomes. In Study 1, a mixed-design fieldexperiment, we randomly assigned 34 middle-level managers to a control or anexperimental group. Three months later, we reassessed the managers using theircoworker ratings (Time 1 raters = 343; Time 2 raters = 321). In Study 2, a within-subjectslaboratory experiment, we videotaped 41 MBA participants giving a speech. We thentaught them how to behave more charismatically, and they redelivered the speech6 weeks later. Independent assessors (n = 135) rated the speeches. Results from thestudies indicated that the training had significant effects on ratings of leader charisma(mean D = .62) and that charisma had significant effects on ratings of leaderprototypicality and emergence...............................................................................................................................

The impact of surgically induced ischaemia on protein levels in patients undergoing rectal cancer surgery

The goal of targeted therapy has driven a search for markers of prognosis and response to adjuvant therapy. The surgical resection of a solid tumour induces tissue ischaemia and acidosis, both potent mediators of gene expression. This study investigated the impact of colorectal cancer (CRC) surgery on prognostic and predictive marker levels. Tumour expression of thymidylate synthase, thymidine phosphorylase, cyclin A, vascular endothelial growth factor (VEGF), carbonic anhydrase-9, hypoxia inducible factor-1α, and glucose transporter-1 (GLUT-1) proteins was determined before and after rectal cancer surgery. Spectral imaging of tissue sections stained by immunohistochemistry provided quantitative data. Surgery altered thymidylate synthase protein expression (P=0.02), and this correlated with the change in the proliferation marker cyclin A. The expression of hypoxia inducible factor-1α, VEGF, and GLUT-1 proteins was also different following surgery. Colorectal cancer surgery significantly impacts on intratumoral gene expression, suggesting archival specimens may not accurately reflect in situ marker levels. Although rectal cancer was the studied model, the results may be applicable to any solid tumour undergoing extirpation in which molecular markers have been proposed to guide patient therapy

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Background: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. Methods: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. Results: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, Ptrend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, Ptrend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, Ptrend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, Ptrend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. Conclusion: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. O M Sinilnikova1,2, A C Antoniou3, J Simard4, S Healey5, M Léoné1, D Sinnett6,7, A B Spurdle5, J Beesley5, X Chen5, kConFab8, M H Greene9, J T Loud9, F Lejbkowicz10, G Rennert10, S Dishon10, I L Andrulis11,12, OCGN11, S M Domchek13, K L Nathanson13, S Manoukian14, P Radice15,16, I Konstantopoulou17, I Blanco18, A L Laborde19, M Durán20, A Osorio21, J Benitez21, U Hamann22, F B L Hogervorst23, T A M van Os24, H J P Gille25, HEBON23, S Peock3, M Cook3, C Luccarini26, D G Evans27, F Lalloo27, R Eeles28, G Pichert29, R Davidson30, T Cole31, J Cook32, J Paterson33, C Brewer34, EMBRACE3, D J Hughes35, I Coupier36,37, S Giraud1, F Coulet38, C Colas38, F Soubrier38, E Rouleau39, I Bièche39, R Lidereau39, L Demange40, C Nogues40, H T Lynch41, GEMO1,2,42, R K Schmutzler43, B Versmold43, C Engel44, A Meindl45, N Arnold46, C Sutter47, H Deissler48, D Schaefer49, U G Froster50, GC-HBOC43,44,45,46,47,48,49,50, K Aittomäki51, H Nevanlinna52, L McGuffog3, D F Easton3, G Chenevix-Trench5 and D Stoppa-Lyonnet42 on behalf of the Consortium of Investigators of Modifiers of BRCA1/