Cyclic pyrrole-imidazole polyamides targeted to the androgen response element

Hairpin pyrrole−imidazole (Py-Im) polyamides are a class of cell-permeable DNA-binding small molecules that can disrupt transcription factor−DNA binding and regulate endogenous gene expression. The covalent linkage of antiparallel Py-Im ring pairs with an γ-amino acid turn unit affords the classical hairpin Py-Im polyamide structure. Closing the hairpin with a second turn unit yields a cyclic polyamide, a lesser-studied architecture mainly attributable to synthetic inaccessibility. We have applied our methodology for solution-phase polyamide synthesis to cyclic polyamides with an improved high-yield cyclization step. Cyclic 8-ring Py-Im polyamides 1−3 target the DNA sequence 5′-WGWWCW-3′, which corresponds to the androgen response element (ARE) bound by the androgen receptor transcription factor to modulate gene expression. We find that cyclic Py-Im polyamides 1−3 bind DNA with exceptionally high affinities and regulate the expression of AR target genes in cell culture studies, from which we infer that the cycle is cell permeable

Lag Length Selection for Unit Root Tests in the Presence of Nonstationary Volatility

A number of recent papers have focused on the problem of testing for a unit root in the case where the driving shocks may be unconditionally heteroskedastic. These papers have, however, taken the lag length in the unit root test regression to be a deterministic function of the sample size, rather than data-determined, the latter being standard empirical practice. We investigate the finite sample impact of unconditional heteroskedasticity on conventional data-dependent lag selection methods in augmented Dickey–Fuller type regressions and propose new lag selection criteria which allow for unconditional heteroskedasticity. Standard lag selection methods are shown to have a tendency to over-fit the lag order under heteroskedasticity, resulting in significant power losses in the (wild bootstrap implementation of the) augmented Dickey–Fuller tests under the alternative. The proposed new lag selection criteria are shown to avoid this problem yet deliver unit root tests with almost identical finite sample properties as the corresponding tests based on conventional lag selection when the shocks are homoskedastic

Policy recommendations from the 13th ICABR conference on the emerging bioeconomy

The International Consortium on Agricultural Biotechnology Research held its 13th annual conference in Ravello, Italy in June 2009. The theme of the conference was the bioeconomy,and this topic was addressed through research presentations from academia, government, and industry. Numerous presentations from developing countries highlighted the benefits of agricultural biotechnology in these nations. The broad range of presentations provided a wealth of insights, resulting in three policy recommendations regarding future funding, international regulation, and technology transfer.global food crisis, biofuels, food safety, innovation

Single-dose pharmacokinetic and toxicity analysis of pyrrole–imidazole polyamides in mice

Purpose: Pyrrole–imidazole (Py-Im) polyamides are programmable, sequence-specific DNA minor groove–binding ligands. Previous work in cell culture has shown that various polyamides can be used to modulate the transcriptional programs of oncogenic transcription factors. In this study, two hairpin polyamides with demonstrated activity against androgen receptor signaling in cell culture were administered to mice to characterize their pharmacokinetic properties. Methods: Py-Im polyamides were administered intravenously by tail vein injection. Plasma, urine, and fecal samples were collected over a 24-h period. Liver, kidney, and lung samples were collected postmortem. Concentrations of the administered polyamide in the plasma, excretion, and tissue samples were measured using LC/MS/MS. The biodistribution data were analyzed by both non-compartmental and compartmental pharmacokinetic models. Animal toxicity experiments were also performed by monitoring weight loss after a single subcutaneous (SC) injection of either polyamide. Results: The biodistribution profiles of both compounds exhibited rapid localization to the liver, kidneys, and lungs upon injection. Plasma distribution of the two compounds showed distinct differences in the rate of clearance, the volume of distribution, and the AUCs. These two compounds also have markedly different toxicities after SC injection in mice. Conclusions: The variations in pharmacokinetics and toxicity in vivo stem from a minor chemical modification that is also correlated with differing potency in cell culture. The results obtained in this study could provide a structural basis for further improvement of polyamide activity both in cell culture and in animal models

Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide

Pyrrole-imidazole (Py-Im) polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE)-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress

ASASSN-15pz: Revealing Significant Photometric Diversity among 2009dc-like, Peculiar SNe Ia

We report comprehensive multi-wavelength observations of a peculiar Type Ia-like supernova ("SN Ia-pec") ASASSN-15pz. ASASSN-15pz is a spectroscopic "twin" of SN 2009dc, a so-called "Super-Chandrasekhar-mass" SN, throughout its evolution, but it has a peak luminosity M_B,peak = -19.69 +/- 0.12 mag that is \approx 0.6 mag dimmer and comparable to the SN 1991T sub-class of SNe Ia at the luminous end of the normal width-luminosity relation. The synthesized Ni56 mass of M_Ni56 = 1.13 +/- 0.14 M_sun is also substantially less than that found for several 2009dc-like SNe. Previous well-studied 2009dc-like SNe have generally suffered from large and uncertain amounts of host-galaxy extinction, which is negligible for ASASSN-15pz. Based on the color of ASASSN-15pz, we estimate a host extinction for SN 2009dc of E(B-V)_host=0.12 mag and confirm its high luminosity (M_B, peak[2009dc] \approx -20.3 mag). The 2009dc-like SN population, which represents ~1% of SNe Ia, exhibits a range of peak luminosities, and do not fit onto the tight width-luminosity relation. Their optical light curves also show significant diversity of late-time (>~ 50 days) decline rates. The nebular-phase spectra provide powerful diagnostics to identify the 2009dc-like events as a distinct class of SNe Ia. We suggest referring to these sources using the phenomenology-based "2009dc-like SN Ia-pec" instead of "Super-Chandrasekhar SN Ia," which is based on an uncertain theoretical interpretation.Comment: 21 pages, 16 figures, accepted for publication in Ap

The Intrinsic Quantum Excitations of Low Temperature Glasses

Several puzzling regularities concerning the low temperature excitations of glasses are quantitatively explained by quantizing domain wall motions of the random first order glass transition theory. The density of excitations agrees with experiment and scales with the size of a dynamically coherent region at $T_g$, being about 200 molecules. The phonon coupling depends on the Lindemann ratio for vitrification yielding the observed universal relation $l/\lambda \simeq 150$ between phonon wavelength $\lambda$ and mean free path $l$. Multilevel behavior is predicted to occur in the temperature range of the thermal conductivity plateau.Comment: 4 pages, submitted to PR