PEPTIDE DEFORMYLASE: A MODELING STUDY OF THE ACTIVE SITES OF PLANTS AND BACTERIA AND THE DESIGN, SYNTHESIS, AND BIOLOGICAL ACTIVITY ANALYSIS OF PEPTIDE-BASED INHIBITORS

All nascent polypeptides synthesized in bacteria, mitochondria, or chloroplastsstart with a N-formylmethionine. Peptide deformylase (PDF) is a mononuclear metal ionprotein that is responsible for removing the N-formyl group of nascent proteins found inbacteria and chloroplasts in order for them to become mature proteins. It is possible, asseen from the literature with actinonin, to chelate the enzyme\u27s metal ion and inhibit thefunction of protein production essentially resulting in death of the bacteria, or plant. Thisstudy examines the active site of Arabidopsis thaliana (At) types of PDF (AtDEF1 andAtDEF2, respectively) as well as bacterial DEF2 using sequence alignments andcomputational modeling. This work also investigates the biological efficacy of designingand synthesizing inhibitors that mimic actinonin or the D1 substrate that will halt, orseverely retard, the activity of the PDF enzyme in vitro and in vivo. Through thisresearch, we were able to determine specific residues that were conserved amongst theplant DEF2 sequences that were present less than 20% of the time in plant DEF1 andbacteria DEF2. This data allowed us to hypothesize plant DEF2\u27s substrate specificity aswell as a possible design that is selective towards plants and not bacteria. Also, based onpreliminary results, the novel thiol-actinonin chimera that was synthesized showedinhibition activity of AtDEF2 during in vitro enzyme assays

Cerebral atrophy in mild cognitive impairment and Alzheimer disease: rates and acceleration.

OBJECTIVE: To quantify the regional and global cerebral atrophy rates and assess acceleration rates in healthy controls, subjects with mild cognitive impairment (MCI), and subjects with mild Alzheimer disease (AD). METHODS: Using 0-, 6-, 12-, 18-, 24-, and 36-month MRI scans of controls and subjects with MCI and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we calculated volume change of whole brain, hippocampus, and ventricles between all pairs of scans using the boundary shift integral. RESULTS: We found no evidence of acceleration in whole-brain atrophy rates in any group. There was evidence that hippocampal atrophy rates in MCI subjects accelerate by 0.22%/year2 on average (p = 0.037). There was evidence of acceleration in rates of ventricular enlargement in subjects with MCI (p = 0.001) and AD (p < 0.001), with rates estimated to increase by 0.27 mL/year2 (95% confidence interval 0.12, 0.43) and 0.88 mL/year2 (95% confidence interval 0.47, 1.29), respectively. A post hoc analysis suggested that the acceleration of hippocampal loss in MCI subjects was mainly driven by the MCI subjects that were observed to progress to clinical AD within 3 years of baseline, with this group showing hippocampal atrophy rate acceleration of 0.50%/year2 (p = 0.003). CONCLUSIONS: The small acceleration rates suggest a long period of transition to the pathologic losses seen in clinical AD. The acceleration in hippocampal atrophy rates in MCI subjects in the ADNI seems to be driven by those MCI subjects who concurrently progressed to a clinical diagnosis of AD

Measurement of the ground-state distributions in bistable mechanically interlocked molecules using slow scan rate cyclic voltammetry

In donor–acceptor mechanically interlocked molecules that exhibit bistability, the relative populations of the translational isomers—present, for example, in a bistable [2]rotaxane, as well as in a couple of bistable [2]catenanes of the donor–acceptor vintage—can be elucidated by slow scan rate cyclic voltammetry. The practice of transitioning from a fast scan rate regime to a slow one permits the measurement of an intermediate redox couple that is a function of the equilibrium that exists between the two translational isomers in the case of all three mechanically interlocked molecules investigated. These intermediate redox potentials can be used to calculate the ground-state distribution constants, K. Whereas, (i) in the case of the bistable [2]rotaxane, composed of a dumbbell component containing π-electron-rich tetrathiafulvalene and dioxynaphthalene recognition sites for the ring component (namely, a tetracationic cyclophane, containing two π-electron-deficient bipyridinium units), a value for K of 10 ± 2 is calculated, (ii) in the case of the two bistable [2]catenanes—one containing a crown ether with tetrathiafulvalene and dioxynaphthalene recognition sites for the tetracationic cyclophane, and the other, tetrathiafulvalene and butadiyne recognition sites—the values for K are orders (one and three, respectively) of magnitude greater. This observation, which has also been probed by theoretical calculations, supports the hypothesis that the extra stability of one translational isomer over the other is because of the influence of the enforced side-on donor–acceptor interactions brought about by both π-electron-rich recognition sites being part of a macrocyclic polyether

Measurement of Spin-orbit Misalignment and Nodal Precession for the Planet around Pre-main-sequence Star PTFO 8-8695 from Gravity Darkening

PTFO 8-8695b represents the first transiting exoplanet candidate orbiting a pre-main-sequence star (van Eyken et al. 2012, ApJ, 755, 42). We find that the unusual lightcurve shapes of PTFO 8-8695 can be explained by transits of a planet across an oblate, gravity-darkened stellar disk. We develop a theoretical framework for understanding precession of a planetary orbit's ascending node for the case when the stellar rotational angular momentum and the planetary orbital angular momentum are comparable in magnitude. We then implement those ideas to simultaneously and self-consistently fit two separate lightcurves observed in 2009 December and 2010 December. Our two self-consistent fits yield Mp = 3.0 M_Jup and Mp = 3.6 M_Jup for assumed stellar masses of M* = 0.34 M_☉ and M* = 0.44 M_☉ respectively. The two fits have precession periods of 293 days and 581 days. These mass determinations (consistent with previous upper limits) along with the strength of the gravity-darkened precessing model together validate PTFO 8-8695b as just the second hot Jupiter known to orbit an M-dwarf. Our fits show a high degree of spin-orbit misalignment in the PTFO 8-8695 system: 69° ± 2° or 73°.1 ± 0°.5, in the two cases. The large misalignment is consistent with the hypothesis that planets become hot Jupiters with random orbital plane alignments early in a system's lifetime. We predict that as a result of the highly misaligned, precessing system, the transits should disappear for months at a time over the course of the system's precession period. The precessing, gravity-darkened model also predicts other observable effects: changing orbit inclination that could be detected by radial velocity observations, changing stellar inclination that would manifest as varying vsin i, changing projected spin-orbit alignment that could be seen by the Rossiter–McLaughlin effect, changing transit shapes over the course of the precession, and differing lightcurves as a function of wavelength. Our measured planet radii of 1.64 R_Jup and 1.68 R_Jup in each case are consistent with a young, hydrogen-dominated planet that results from a "hot-start" formation mechanism

Multicomponent kinematics in a massive filamentary IRDC

To probe the initial conditions for high-mass star and cluster formation, we investigate the properties of dense filaments within the infrared dark cloud G035.39-00.33 (IRDC G035.39) in a combined Very Large Array (VLA) and the Green Bank Telescope (GBT) mosaic tracing the NH3 (1,1) and (2,2) emission down to 0.08 pc scales. Using agglomerative hierarchical clustering on multiple line-of-sight velocity component fitting results, we identify seven extended velocity-coherent components in our data, likely representing spatially coherent physical structures, some exhibiting complex gas motions. The velocity gradient magnitude distribution peaks at its mode of 0.35 km/s/pc and has a long tail extending into higher values of 1.5 - 2 km/s/pc, and is generally consistent with those found toward the same cloud in other molecular tracers and with the values found towards nearby low-mass dense cloud cores at the same scales. Contrary to observational and theoretical expectations, we find the non-thermal ammonia line widths to be systematically narrower (by about 20%) than those of N2H+ (1-0) line transition observed with similar resolution. If the observed ordered velocity gradients represent the core envelope solid-body rotation, we estimate the specific angular momentum to be about 2 x 10^21 cm^2/s, similar to the low-mass star-forming cores. Together with the previous finding of subsonic motions in G035.39, our results demonstrate high levels of similarity between kinematics of a high-mass star-forming IRDC and the low-mass star formation regime.Comment: 22 pages, 14 figures, accepted to Ap

Halide: a language and compiler for optimizing parallelism, locality, and recomputation in image processing pipelines

Image processing pipelines combine the challenges of stencil computations and stream programs. They are composed of large graphs of different stencil stages, as well as complex reductions, and stages with global or data-dependent access patterns. Because of their complex structure, the performance difference between a naive implementation of a pipeline and an optimized one is often an order of magnitude. Efficient implementations require optimization of both parallelism and locality, but due to the nature of stencils, there is a fundamental tension between parallelism, locality, and introducing redundant recomputation of shared values. We present a systematic model of the tradeoff space fundamental to stencil pipelines, a schedule representation which describes concrete points in this space for each stage in an image processing pipeline, and an optimizing compiler for the Halide image processing language that synthesizes high performance implementations from a Halide algorithm and a schedule. Combining this compiler with stochastic search over the space of schedules enables terse, composable programs to achieve state-of-the-art performance on a wide range of real image processing pipelines, and across different hardware architectures, including multicores with SIMD, and heterogeneous CPU+GPU execution. From simple Halide programs written in a few hours, we demonstrate performance up to 5x faster than hand-tuned C, intrinsics, and CUDA implementations optimized by experts over weeks or months, for image processing applications beyond the reach of past automatic compilers.United States. Dept. of Energy (Award DE-SC0005288)National Science Foundation (U.S.) (Grant 0964004)Intel CorporationCognex CorporationAdobe System

Visual ratings of atrophy in MCI: prediction of conversion and relationship with CSF biomarkers.

Medial temporal lobe atrophy (MTA) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) pathology may aid the early detection of AD in mild cognitive impairment (MCI). However, the relationship between structural and pathological markers is not well understood. Furthermore, while posterior atrophy (PA) is well recognized in AD, its value in predicting conversion from late-onset amnestic MCI to AD is unclear. In this study we used visual ratings of MTA and PA to assess their value in predicting conversion to AD in 394 MCI patients. The relationship of atrophy patterns with CSF Aβ1-42, tau, and p-tau(181) was further investigated in 114 controls, 192 MCI, and 99 AD patients. There was a strong association of MTA ratings with conversion to AD (p < 0.001), with a weaker association for PA ratings (p = 0.047). Specific associations between visual ratings and CSF biomarkers were found; MTA was associated with lower levels of Aβ1-42 in MCI, while PA was associated with elevated levels of tau in MCI and AD, which may reflect widespread neuronal loss including posterior regions. These findings suggest both that posterior atrophy may predict conversion to AD in late-onset MCI, and that there may be differential relationships between CSF biomarkers and regional atrophy patterns