Chemoenzymatic Synthesis of Cryptophycin Anticancer Agents by an Ester Bond-Forming Non-ribosomal Peptide Synthetase Module

Cryptophycins (Crp) are a group of cyanobacterial depsipeptides with activity against drug-resistant tumors. Although they have been shown to be promising, further efforts are required to return these highly potent compounds to the clinic through a new generation of analogues with improved medicinal properties. Herein, we report a chemosynthetic route relying on themultifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Crp analogues. CrpD-M2 is a unique nonribosomal peptide synthetase (NRPS) module comprised of condensation-adenylation-ketoreduction-thiolation (C-A-KR-T) domains. We interrogated A-domain 2-keto and 2-hydroxy acid activation and loading, and KR domain activity in the presence of NADPH and NADH. The resulting 2-hydroxy acid was elongated with three synthetic Crp chain elongation intermediate analogues through ester bond formation catalyzed by CrpD-M2 C domain. Finally, the enzyme-bound seco-Crp products were macrolactonized by the Crp thioesterase. Analysis of these sequential steps was enabled through LC-FTICR-MS of enzyme-bound intermediates and products. This novel chemoenzymatic synthesis of Crp involves four sequential catalytic steps leading to the incorporation of a 2-hydroxy acid moiety in the final chain elongation intermediate. The presented work constitutes the first example where a NRPS-embedded KR domain is employed for assembly of a fully elaborated natural product, and serves as a proof-of-principle for chemoenzymatic synthesis of new Crp analogues

Twelve experiments in restorative justice: the Jerry Lee program of randomized trials of restorative justice conferences

Objectives: We conducted and measured outcomes from the Jerry Lee Program of 12 randomized trials over two decades in Australia and the United Kingdom (UK), testing an identical method of restorative justice taught by the same trainers to hundreds of police officers and others who delivered it to 2231 offenders and 1179 victims in 1995–2004. The article provides a review of the scientific progress and policy effects of the program, as described in 75 publications and papers arising from it, including previously unpublished results of our ongoing analyses. Methods: After random assignment in four Australian tests diverting criminal or juvenile cases from prosecution to restorative justice conferences (RJCs), and eight UK tests of supplementing criminal or juvenile proceedings with RJCs, we followed intention-to-treat group differences between offenders for up to 18 years, and for victims up to 10 years. Results: We distil and modify prior research reports into 18 updated evidence-based conclusions about the effects of RJCs on both victims and offenders. Initial reductions in repeat offending among offenders assigned to RJCs (compared to controls) were found in 10 of our 12 tests. Nine of the ten successes were for crimes with personal victims who participated in the RJCs, with clear benefits in both short- and long-term measures, including less prevalence of post-traumatic stress symptoms. Moderator effects across and within experiments showed that RJCs work best for the most frequent and serious offenders for repeat offending outcomes, with other clear moderator effects for poly-drug use and offense seriousness. Conclusions: RJ conferences organized and led (most often) by specially-trained police produced substantial short-term, and some long-term, benefits for both crime victims and their offenders, across a range of offense types and stages of the criminal justice processes on two continents, but with important moderator effects. These conclusions are made possible by testing a new kind of justice on a programmatic basis that would allow prospective meta-analysis, rather than doing one experiment at a time. This finding provides evidence that funding agencies could get far more evidence for the same cost from programs of identical, but multiple, RCTs of the identical innovative methods, rather than funding one RCT at a time

Strain-induced insulator state in La_0.7Sr_0.3CoO_3

We report on the observation of a strain-induced insulator state in ferromagnetic La_0.7Sr_0.3CoO_3 films. Tensile strain above 1% is found to enhance the resistivity by several orders of magnitude. Reversible strain of 0.15% applied using a piezoelectric substrate triggers huge resistance modulations, including a change by a factor of 10 in the paramagnetic regime at 300 K. However, below the ferromagnetic ordering temperature, the magnetization data indicate weak dependence on strain for the spin state of the Co ions. We interpret the changes observed in the transport properties in terms of a strain-induced splitting of the Co e_g levels and reduced double exchange, combined with a percolation-type conduction in an electronic cluster state

Reversible strain effect on the magnetization of LaCoO3 films

The magnetization of ferromagnetic LaCoO3 films grown epitaxially on piezoelectric substrates has been found to systematically decrease with the reduction of tensile strain. The magnetization change induced by the reversible strain variation reveals an increase of the Co magnetic moment with tensile strain. The biaxial strain dependence of the Curie temperature is estimated to be below 4K/% in the as-grown tensile strain state of our films. This is in agreement with results from statically strained films on various substrates

CD-ROM publication of the Mars digital cartographic data base

The recently completed Mars mosaicked digital image model (MDIM) and the soon-to-be-completed Mars digital terrain model (DTM) are being transcribed to optical disks to simplify distribution to planetary investigators. These models, completed in FY 1991, provide a cartographic base to which all existing Mars data can be registered. The digital image map of Mars is a cartographic extension of a set of compact disk read-only memory (CD-ROM) volumes containing individual Viking Orbiter images now being released. The data in these volumes are pristine in the sense that they were processed only to the extent required to view them as images. They contain the artifacts and the radiometric, geometric, and photometric characteristics of the raw data transmitted by the spacecraft. This new set of volumes, on the other hand, contains cartographic compilations made by processing the raw images to reduce radiometric and geometric distortions and to form geodetically controlled MDIM's. It also contains digitized versions of an airbrushed map of Mars as well as a listing of all feature names approved by the International Astronomical Union. In addition, special geodetic and photogrammetric processing has been performed to derive rasters of topographic data, or DTM's. The latter have a format similar to that of MDIM, except that elevation values are used in the array instead of image brightness values. The set consists of seven volumes: (1) Vastitas Borealis Region of Mars; (2) Xanthe Terra of Mars; (3) Amazonis Planitia Region of Mars; (4) Elysium Planitia Region of Mars; (5) Arabia Terra of Mars; (6) Planum Australe Region of Mars; and (7) a digital topographic map of Mars

Non-Markovian spin relaxation in two-dimensional electron gas

We analyze by Monte-Carlo simulations and analytically spin dynamics of two-dimensional electron gas (2DEG) interacting with short-range scatterers in nonquantizing magnetic fields. It is shown that the spin dynamics is non-Markovian with the exponential spin relaxation followed by the oscillating tail due to the electrons residing on the closed trajectories. The tail relaxes on a long time scale due to an additional smooth random potential and inelastic processes. The developed analytical theory and Monte-Carlo simulations are in the quantitative agreement with each other.Comment: 6 pages, 3 figure

Hormander class of pseudo-differential operators on compact Lie groups and global hypoellipticity

In this paper we give several global characterisations of the Hormander class of pseudo-differential operators on compact Lie groups. The result is applied to give criteria for the ellipticity and the global hypoellipticity of pseudo-differential operators in terms of their matrix-valued full symbols. Several examples of the first and second order globally hypoelliptic differential operators are given. Where the global hypoelliptiticy fails, one can construct explicit examples based on the analysis of the global symbols.Comment: 20 page

Non-exponential spin relaxation in magnetic field in quantum wells with random spin-orbit coupling

We investigate the spin dynamics of electrons in quantum wells where the Rashba type of spin-orbit coupling is present in the form of random nanosize domains. We study the effect of magnetic field on the spin relaxation in these systems and show that the spatial randomness of spin-orbit coupling limits the minimum relaxation rate and leads to a Gaussian time-decay of spin polarization due to memory effects. In this case the relaxation becomes faster with increase of the magnetic field in contrast to the well known magnetic field suppression of spin relaxation.Comment: published version, minor change