USER'S GUIDE - GENERAL WEED MANAGEMENT MODEL VERSION 1.0 - DECEMBER 1994

Crop Production/Industries,

Effects of fluorine substitution on substrate conversion by cytochromes P450 17A1 and 21A2

Cytochromes P450 17A1 (CYP7A1) and 21A2 (CYP21A2) catalyze key reactions in the production of steroid hormones, including mineralocorticoids, glucocorticoids, and androgens. With the ultimate goal of designing probes that are selectively metabolized to each of these steroid types, fluorinated derivatives of the endogenous substrates, pregnenolone and progesterone, were prepared to study the effects on CYP17A1 and CYP21A2 activity. In the functional assays, the hydroxylase reactions catalysed by each of these enzymes were blocked when fluorine was introduced at the site of metabolism (positions 17 and 21 of the steroid core, respectively). CYP17A1, furthermore, performed the 17,20-lyase reaction on substrates with a fluorine installed at the 21-position. Importantly, none of the substitutions examined herein prevented compound entry into the active sites of either CYP17A1 or CYP21A2 as demonstrated by spectral binding assays. Taken together, the results suggest that fluorine might be used to redirect the metabolic pathways of pregnenolone and progesterone to specific types of steroids

Benzylmorpholine analogs as selective inhibitors of lung cytochrome P450 2A13 for the chemoprevention of lung cancer in tobacco users

Purpose: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. Methods: Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is a major challenge in compound design. Results: A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. Conclusions: Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure

Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2

Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects

Constraining the period of the ringed secondary companion to the young star J1407 with photographic plates

Context. The 16 Myr old star 1SWASP J140747.93-394542.6 (V1400 Cen) underwent a series of complex eclipses in May 2007, interpreted as the transit of a giant Hill sphere filling debris ring system around a secondary companion, J1407b. No other eclipses have since been detected, although other measurements have constrained but not uniquely determined the orbital period of J1407b. Finding another eclipse towards J1407 will help determine the orbital period of the system, the geometry of the proposed ring system and enable planning of further observations to characterize the material within these putative rings. Aims. We carry out a search for other eclipses in photometric data of J1407 with the aim of constraining the orbital period of J1407b. Methods. We present photometry from archival photographic plates from the Harvard DASCH survey, and Bamberg and Sonneberg Observatories, in order to place additional constraints on the orbital period of J1407b by searching for other dimming and eclipse events. Using a visual inspection of all 387 plates and a period-folding algorithm we performed a search for other eclipses in these data sets. Results. We find no other deep eclipses in the data spanning from 1890 to 1990, nor in recent time-series photometry from 2012-2018. Conclusions. We rule out a large fraction of putative orbital periods for J1407b from 5 to 20 years. These limits are still marginally consistent with a large Hill sphere filling ring system surrounding a brown dwarf companion in a bound elliptical orbit about J1407. Issues with the stability of any rings combined with the lack of detection of another eclipse, suggests that J1407b may not be bound to J1407.Comment: 8 pages, 3 tables, 4 figures, accepted for publication in A&A. LaTeX files of the paper, scripts for the figures, and a minimal working FPA can be found under https://github.com/robinmentel/Constraining-Period

Evolution of circular, non-equatorial orbits of Kerr black holes due to gravitational-wave emission: II. Inspiral trajectories and gravitational waveforms

The inspiral of a ``small'' ($\mu \sim 1-100 M_\odot$) compact body into a ``large'' ($M \sim 10^{5-7} M_\odot$) black hole is a key source of gravitational radiation for the space-based gravitational-wave observatory LISA. The waves from such inspirals will probe the extreme strong-field nature of the Kerr metric. In this paper, I investigate the properties of a restricted family of such inspirals (the inspiral of circular, inclined orbits) with an eye toward understanding observable properties of the gravitational waves that they generate. Using results previously presented to calculate the effects of radiation reaction, I assemble the inspiral trajectories (assuming that radiation reacts adiabatically, so that over short timescales the trajectory is approximately geodesic) and calculate the wave generated as the compact body spirals in. I do this analysis for several black hole spins, sampling a range that should be indicative of what spins we will encounter in nature. The spin has a very strong impact on the waveform. In particular, when the hole rotates very rapidly, tidal coupling between the inspiraling body and the event horizon has a very strong influence on the inspiral time scale, which in turn has a big impact on the gravitational wave phasing. The gravitational waves themselves are very usefully described as ``multi-voice chirps'': the wave is a sum of ``voices'', each corresponding to a different harmonic of the fundamental orbital frequencies. Each voice has a rather simple phase evolution. Searching for extreme mass ratio inspirals voice-by-voice may be more effective than searching for the summed waveform all at once.Comment: 15 pages, 11 figures, accepted for publication in PRD. This version incorporates referee's comments, and is much less verbos

Heirloom rice in Ifugao: an ‘anti-commodity’ in the process of commodification

We analyse the marketing of ‘heirloom rices’ produced in the Cordillera mountains of northern Luzon, the Philippines, as the commodification of a historical ‘anti-commodity’. We contend that, historically, rice was produced for social, cultural and spiritual purposes but not primarily for sale or trade. The Ifugaos were able to sustain terraced wet-rice cultivation within a system of ‘escape agriculture’ because they were protected from Spanish interference by the friction of terrain and distance. ‘Heirloom rice’ is a boundary concept that enables social entrepreneurs to commodify traditional landraces. We analyse the implications for local rice production and conservation efforts.Templeton Foundatio

Exact two-particle eigenstates in partially reduced QED

We consider a reformulation of QED in which covariant Green functions are used to solve for the electromagnetic field in terms of the fermion fields. It is shown that exact few-fermion eigenstates of the resulting Hamiltonian can be obtained in the canonical equal-time formalism for the case where there are no free photons. These eigenstates lead to two- and three-body Dirac-like equations with electromagnetic interactions. Perturbative and some numerical solutions of the two-body equations are presented for positronium and muonium-like systems, for various strengths of the coupling.Comment: 33 pages, LaTex 2.09, 4 figures in EPS forma

Multiple (inverse) binomial sums of arbitrary weight and depth and the all-order epsilon-expansion of generalized hypergeometric functions with one half-integer value of parameter

We continue the study of the construction of analytical coefficients of the epsilon-expansion of hypergeometric functions and their connection with Feynman diagrams. In this paper, we show the following results: Theorem A: The multiple (inverse) binomial sums of arbitrary weight and depth (see Eq. (1.1)) are expressible in terms of Remiddi-Vermaseren functions. Theorem B: The epsilon expansion of a hypergeometric function with one half-integer value of parameter (see Eq. (1.2)) is expressible in terms of the harmonic polylogarithms of Remiddi and Vermaseren with coefficients that are ratios of polynomials. Some extra materials are available via the www at this http://theor.jinr.ru/~kalmykov/hypergeom/hyper.htmlComment: 24 pages, latex with amsmath and JHEP3.cls; v2: some typos corrected and a few references added; v3: few references added