In Vivo Evaluation of White Matter Abnormalities in Children with Duchenne Muscular Dystrophy Using DTI.

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy is an X-linked disorder characterized by progressive muscle weakness and prominent nonmotor manifestations, such as a low intelligence quotient and neuropsychiatric disturbance. We investigated WM integrity in patients with Duchenne muscular dystrophy using DTI. MATERIALS AND METHODS: Fractional anisotropy and mean, axial, and radial diffusivity (DTI measures) were used to assess WM microstructural integrity along with neuropsychological evaluation in patients with Duchenne muscular dystrophy (n = 60) and controls (n = 40). Exon deletions in the DMD gene were confirmed using multiplex ligation-dependent probe amplification. Patients were classified into proximal (DMD Dp140+) and distal (DMD Dp140-) subgroups based on the location of the exon deletion and expression of short dystrophin Dp140 isoform. WM integrity was examined using whole-brain Tract-Based Spatial Statistics and atlas-based analysis of DTI data. The Pearson correlation was performed to investigate the possible relationship between neuropsychological scores and DTI metrics. RESULTS: The mean ages of Duchenne muscular dystrophy and control participants were 8.0 ± 1.2 years and 8.2 ± 1.4 years, respectively. The mean age at disease onset was 4.1 ± 1.8 years, and mean illness duration was 40.8 ± 25.2 months. Significant differences in neuropsychological scores were observed between the proximal and distal gene-deletion subgroups, with more severe impairment in the distal-deletion subgroup (P < .05). Localized fractional anisotropy changes were seen in the corpus callosum, parietal WM, and fornices in the patient subgroup with Dp140+, while widespread changes were noted in the Dp140- subgroup. The Dp140+ subgroup showed increased axial diffusivity in multiple WM regions relative to the Dp140- subgroup. No significant correlation was observed between clinical and neuropsychological scores and diffusion metrics. CONCLUSIONS: Widespread WM differences are evident in patients with Duchenne muscular dystrophy relative to healthy controls. Distal mutations in particular are associated with extensive WM abnormalities and poor neuropsychological profiles.

Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk.

Essentials Microbe-dependent production of trimethylamine N-oxide (TMAO) contributes to thrombosis risk. The impact of host flavin monooxygenase 3 (FMO3) modulation on platelet function is unknown. Genetic manipulation of FMO3 in mice alters systemic TMAO levels and thrombosis potential. Genetic manipulation of FMO3 is associated with alteration of gut microbial community structure. SUMMARY: Background Gut microbes play a critical role in the production of trimethylamine N-oxide (TMAO), an atherogenic metabolite that impacts platelet responsiveness and thrombosis potential. Involving both microbe and host enzymatic machinery, TMAO generation utilizes a metaorganismal pathway, beginning with ingestion of trimethylamine (TMA)-containing dietary nutrients such as choline, phosphatidylcholine and carnitine, which are abundant in a Western diet. Gut microbial TMA lyases use these nutrients as substrates to produce TMA, which upon delivery to the liver via the portal circulation, is converted into TMAO by host hepatic flavin monooxygenases (FMOs). Gut microbial production of TMA is rate limiting in the metaorganismal TMAO pathway because hepatic FMO activity is typically in excess. Objectives FMO3 is the major FMO responsible for host generation of TMAO; however, a role for FMO3 in altering platelet responsiveness and thrombosis potential in vivo has not yet been explored. Methods The impact of FMO3 suppression (antisense oligonucleotide-targeting) and overexpression (as transgene) on plasma TMAO levels, platelet responsiveness and thrombosis potential was examined using a murine FeCl3 -induced carotid artery injury model. Cecal microbial composition was examined using 16S analyses. Results Modulation of FMO3 directly impacts systemic TMAO levels, platelet responsiveness and rate of thrombus formation in vivo. Microbial composition analyses reveal taxa whose proportions are associated with both plasma TMAO levels and in vivo thrombosis potential. Conclusions The present studies demonstrate that host hepatic FMO3, the terminal step in the metaorganismal TMAO pathway, participates in diet-dependent and gut microbiota-dependent changes in both platelet responsiveness and thrombosis potential in vivo.

Simulating the unimolecular decomposition pathways of cyclotrimethylnitramine (RDX) : Decomposition pathways of RDX.

Based on the three known proposed pathways for the uni-molecular decomposition of RDX, we have formulated the rate equations. A kinetic Monte Carlo code has been developed and used to simulate the uni-molecular decomposition of RDX based on these equations. The KMC simulations allow one to explore each of the decomposition pathways individually and also the three competing pathways at a specified temperature and pressure. The pressure dependence is incorporated using Lindemann's formalism. The code is validated by reproducing the species evolution along each pathway. Amongst the three proposed pathways, the most likely path of RDX decomposition and the time evolution of various molecular species at different ambient temperatures and pressures are obtained. An analytical model has been developed to reproduce the decomposition pathways, which matches the simulation results.

Molecular dynamics analysis of the transient temperature increase at void locations in shocked materials: RDX and Cu.

Molecular dynamics (MD) simulations of high velocity impact (1-6 km/s) of RDX crystal with a nanometer-sized void, has been carried out to understand the mechanism of increase in temperature at void locations under shock loading. Similar simulations are then carried out on single-crystal copper for better interpretation of the results. A reactive potential that can simulate chemical reactions (ReaxFF) has been used for RDX, whereas an EAM potential has been used for Cu. Increased temperature at the void locations are observed under shock loading. The atomic motion, temperature, average potential energy per atom (PE), and average kinetic energy per atom (KE) in and around the voids are closely monitored in order to understand the reason for temperature increase. We compare our results with existing proposed mechanisms and show that some of the proposed mechanisms are not necessary for increased temperature at a void location. It is shown that the directed particle velocity is efficiently is converted into randomized velocity due to the presence of voids thereby increasing the local temperature transiently. In this initial stage (few picoseconds) of the shock, chemical reactions of energetic materials do not play a part in the temperature rise.

Voxel based parallel post processor for void nucleation and growth analysis of atomistic simulations of material fracture.

Molecular dynamics (MD) simulations are used in the study of void nucleation and growth in crystals that are subjected to tensile deformation. These simulations are run for typically several hundred thousand time steps depending on the problem. We output the atom positions at a required frequency for post processing to determine the void nucleation, growth and coalescence due to tensile deformation. The simulation volume is broken up into voxels of size equal to the unit cell size of crystal. In this paper, we present the algorithm to identify the empty unit cells (voids), their connections (void size) and dynamic changes (growth and coalescence of voids) for MD simulations of large atomic systems (multi-million atoms). We discuss the parallel algorithms that were implemented and discuss their relative applicability in terms of their speedup and scalability. We also present the results on scalability of our algorithm when it is incorporated into MD software LAMMPS.