Interval Analysis of Worst-case Stationary Moments for Stochastic Chemical Reactions with Uncertain Parameters

The dynamics of cellular chemical reactions are variable due to stochastic noise from intrinsic and extrinsic sources. The intrinsic noise is the intracellular fluctuations of molecular copy numbers caused by the probabilistic encounter of molecules and is modeled by the chemical master equation. The extrinsic noise, on the other hand, represents the intercellular variation of the kinetic parameters due to the variation of global factors affecting gene expression. The objective of this paper is to propose a theoretical framework to analyze the combined effect of the intrinsic and the extrinsic noise modeled by the chemical master equation with uncertain parameters. More specifically, we formulate a semidefinite program to compute the intervals of the stationary solution of uncertain moment equations whose parameters are given only partially in the form of the statistics of their distributions. The semidefinite program is derived without approximating the governing equation in contrast with many existing approaches. Thus, we can obtain guaranteed intervals of the worst possible values of the moments for all parameter distributions satisfying the given statistics, which are prohibitively hard to estimate from sample-path simulations since sampling from all possible uncertain distributions is difficult. We demonstrate the proposed optimization approach using two examples of stochastic chemical reactions and show that the solution of the optimization problem gives practically useful upper and lower bounds of the statistics of the stationary copy number distributions

Theoretical study of intermolecular proton transfer using diabatic potential

13301甲第4557号博士（理学）金沢大学博士論文本文Ful

Theoretical study of intermolecular proton transfer using diabatic potential

13301甲第4557号博士（理学）金沢大学博士論文要旨Abstrac

A comparative theoretical study of the hydride transfer mechanisms during LiAlH4 and LiBH4 reductions

This work examined the hydride transfer processes during the reduction of formaldehyde by LiAlH4 or LiBH4, including investigations of the geometries, solvent effects and charge transfer processes along the reaction coordinate, using density functional theory (DFT). The energy and geometry results demonstrate that the transition state (TS) structure for the LiAlH4-formaldehyde complex is reactant-like, while the structure generated by LiBH4 has a product-like geometry, consistent with the Hammond postulate. From a charge density analysis, we also found that both complexes undergo the same essential hydride transfer mechanism, which consists of: (1) single electron transfer to the carbonyl carbon, (2) formation of a bridge bond (X-H-C; X=Al or B) and (3) hydrogen transfer driven by electron transfer. Subsequently, in a fourth step, a single electron flows through the X-H-C bond during transfer of the hydrogen, such that hydrogen atom or proton-coupled electron transfer occurs. In both systems, the presence of tetrahydrofuran as a solvent affects the structure and energy values during the reaction, but not the charge transfer characteristics. We propose that the rate-determining steps during hydride transfer when employing LiAlH4 and LiBH4 are one electron transfer to the carbonyl carbon and B-H bond dissociation, respectively. © 2015 Elsevier B.V.Embargo Period 24 month

Simulation of molecular Auger spectra using a two-electron Dyson propagator

In order to simulate Auger electron spectra (AES), we propose the use of the two-electron Dyson propagator with the shifted denominator approximation (SD2). The double ionization potentials (DIPs) of molecules calculated using the SD2 method have shown good agreement with experimental data. This method can be used to calculate each DIP separately, and reducing the matrix dimensionality into that of only a two-hole configurations. We carried out AES simulations of water (H2O), ethylene (C2H4), and formaldehyde (H2CO) molecules and compared with the observed spectra. Furthermore Auger line shapes of glycine and hydrated glycine molecules were simulated, it found out that the peaks of nitrogen K-LL Auger were broadened due to hydration. From these results, we conclude that the SD2 method is very useful for the calculation of DIPs to investigate the properties of a double ionized molecule. © 2016 Elsevier B.V. All rights reserved.Embargo Period 24 month

Monitoring method for transgene expression in target tissue by blood sampling

In this study, we have developed a novel method to monitor transgene expression in tissues by blood sampling. We administered plasmid DNA (pDNA) encoding non-secretory form of firefly luciferase as a reporter gene and pDNA encoding secretable Gaussia princeps luciferase as a monitor gene simultaneously into mice. Good positive correlations were found between log-transgene expression of the reporter gene and the monitor gene in the treated muscle, between the monitor gene in the treated muscle and plasma, and consequently between the reporter gene in the treated muscle and the monitor gene in plasma after naked pDNA transfer into the muscle of mice. Such positive correlations were also found with gastric serosal surface instillation of naked pDNA, intravenous injection of lipoplex, and hydrodynamics-based injection of naked pDNA. We developed monitoring method of transgene expression in tissues by blood sampling, which was named ‘Therapeutic transgene monitoring (TTM)’, after ‘Therapeutic drug monitoring (TDM)’

Brain Dp140 alters glutamatergic transmission and social behaviour in the mdx52 mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a muscle disorder caused by DMD mutations and is characterized by neurobehavioural comorbidities due to dystrophin deficiency in the brain. The lack of Dp140, a dystrophin short isoform, is clinically associated with intellectual disability and autism spectrum disorders (ASDs), but its postnatal functional role is not well understood. To investigate synaptic function in the presence or absence of brain Dp140, we utilized two DMD mouse models, mdx23 and mdx52 mice, in which Dp140 is preserved or lacking, respectively. ASD-like behaviours were observed in pups and 8-week-old mdx52 mice lacking Dp140. Paired-pulse ratio of excitatory postsynaptic currents, glutamatergic vesicle number in basolateral amygdala neurons, and glutamatergic transmission in medial prefrontal cortex-basolateral amygdala projections were significantly reduced in mdx52 mice compared to those in wild-type and mdx23 mice. ASD-like behaviour and electrophysiological findings in mdx52 mice were ameliorated by restoration of Dp140 following intra-cerebroventricular injection of antisense oligonucleotide drug-induced exon 53 skipping or intra-basolateral amygdala administration of Dp140 mRNA-based drug. Our results implicate Dp140 in ASD-like behaviour via altered glutamatergic transmission in the basolateral amygdala of mdx52 mice

Towards HCP-Style macaque connectomes: 24-Channel 3T multi-array coil, MRI sequences and preprocessing

© 2020 The Author(s) Macaque monkeys are an important animal model where invasive investigations can lead to a better understanding of the cortical organization of primates including humans. However, the tools and methods for noninvasive image acquisition (e.g. MRI RF coils and pulse sequence protocols) and image data preprocessing have lagged behind those developed for humans. To resolve the structural and functional characteristics of the smaller macaque brain, high spatial, temporal, and angular resolutions combined with high signal-to-noise ratio are required to ensure good image quality. To address these challenges, we developed a macaque 24-channel receive coil for 3-T MRI with parallel imaging capabilities. This coil enables adaptation of the Human Connectome Project (HCP) image acquisition protocols to the in-vivo macaque brain. In addition, we adapted HCP preprocessing methods to the macaque brain, including spatial minimal preprocessing of structural, functional MRI (fMRI), and diffusion MRI (dMRI). The coil provides the necessary high signal-to-noise ratio and high efficiency in data acquisition, allowing four- and five-fold accelerations for dMRI and fMRI. Automated FreeSurfer segmentation of cortex, reconstruction of cortical surface, removal of artefacts and nuisance signals in fMRI, and distortion correction of dMRI all performed well, and the overall quality of basic neurobiological measures was comparable with those for the HCP. Analyses of functional connectivity in fMRI revealed high sensitivity as compared with those from publicly shared datasets. Tractography-based connectivity estimates correlated with tracer connectivity similarly to that achieved using ex-vivo dMRI. The resulting HCP-style in vivo macaque MRI data show considerable promise for analyzing cortical architecture and functional and structural connectivity using advanced methods that have previously only been available in studies of the human brain