We investigated four different problems using coarse grained computational models : self-assembly of single stranded (ss) DNA virus, ejection dynamics of double stranded(ds) DNA from phages, translocation of ssDNA through MspA protein pore, and segmental dynamics of a polymer translocating through a synthetic nanopore. In the first part of the project, we investigated the self-assembly of a virus with and without its genome. A coarse-grained model was proposed for the viral subunit proteins and its genome (ssDNA). Langevin dynamics simulation, and replica exchange method were used to determine the kinetics and energetics of the self-assembly process, respectively. The self-assembly follows a nucleation-growth kind of mechanism. The ssDNA plays a crucial role in the self-assembly by acting as a template and enhancing the local concentration of the subunits. The presence of the genome does not changes the mechanism of the self-assembly but it reduces the nucleation time and enhances the growth rate by almost an order of magnitude. The second part of the project involves the investigation of the dynamics of the ejection of dsDNA from phages. A coarse-grained model was used for the phage and dsDNA. Langevin dynamics simulation was used to investigate the kinetics of the ejection. The ejection is a stochastic process and a slow intermediate rate kinetics was observed for most ejection trajectories. We discovered that the jamming of the DNA at the pore mouth at high packing fraction and for a disordered system is the reason for the intermediate slow kinetics. The third part of the project involves translocation of ssDNA through MspA protein pore. MspA protein pore has the potential for genome sequencing because of its ability to clearly distinguish the four different nucleotides based on their blockade current, but it is a challenge to use this pore for any practical application because of the very fast traslocation time. We resolved the state of DNA translocation reported in the recent experimental work . We also investigated two methods for slowing down the translocation process: pore mutation and use of alternating voltage. Langevin dynamics simulation and Poisson Nernst Planck solver were used for the investigation. We demonstrated that mutation of the protein pore or applying alternating voltage is not a perfect solution for increasing translocation time deterministically. Both strategies resulted in enhanced average translocation time as well as the width of the translocation time distribution. The increase in the width of the translocation time distribution is undesired. In the last part of the project, we investigated the applicability of the polyelectrolyte theory in the computer simulation of polyelectrolyte translocation through nanopores. We determined that the Debye Huckel approximation is acceptable for most translocation simulations as long as the coarse grained polymer bead size is comparable or larger than the Debye length. We also determined that the equilibrium translocation theory is applicable to the polyelectrolyte translocation through a nanopore under biasing condition. The unbiased translocation behavior of a polyelectrolyte chain is qualitatively different from the Rouse model predictions, except for the case where the polyelectrolyte is very small compared to the nanopore. .

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is poorly understood and therapeutic strategies are lacking. This study aimed to identify plasma proteins with pathophysiological relevance in HFpEF and with respect to spironolactone-induced effects. We assessed 92 biomarkers in plasma samples from 386 HFpEF patients—belonging to the Aldo-DHF trial—before (baseline, BL) and after one-year treatment (follow up, FU) with spironolactone (verum) or a placebo. At BL, various biomarkers showed significant associations with the two Aldo-DHF primary end point parameters: 33 with E/e’ and 20 with peak VO2. Ten proteins including adrenomedullin, FGF23 and inflammatory peptides (e.g., TNFRSF11A, TRAILR2) were significantly associated with both parameters, suggesting a role in the clinical HFpEF presentation. For 13 proteins, expression changes from BL to FU were significantly different between verum and placebo. Among them were renin, growth hormone, adrenomedullin and inflammatory proteins (e.g., TNFRSF11A, IL18 and IL4RA), indicating distinct spironolactone-mediated effects. BL levels of five proteins, e.g., inflammatory markers such as CCL17, IL4RA and IL1ra, showed significantly different effects on the instantaneous risk for hospitalization between verum and placebo. This study identified plasma proteins with different implications in HFpEF and following spironolactone treatment. Future studies need to define their precise mechanistic involvement.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) accounts for half of all clinical heart failure presentations, but unfortunately lacks effective therapies. Therefore, it has become more urgent to elucidate the pathophysiology underlying this disease, both by using patient data and the development of more accurate animal models. With clinical evidence suggesting that skeletal muscle abnormality is a significant factor in the development of exercise intolerance, this thesis investigates whether the salty drinking water, unilateral nephrectomy, and aldosterone (SAUNA) HFpEF mouse model also demonstrates similar skeletal muscle abnormality as seen in patients. METHODS: Eight-weeks old C57BL/6J mice were subjected to a left nephrectomy and given a mini-osmotic pump to deliver a continuous infusion of either saline (Sham) or aldosterone (HFpEF). The mice were then maintained on a standard rodent chow and a 1% sodium chloride solution. After 4 weeks, the soleus and gastrocnemius muscles were harvested. Histological analyses were performed to examine fiber composition, cross-sectional area of fiber, capillary density, and fibrosis. Quantitative PCR (qPCR) and western blot analyses were performed to examine the expression changes in mitochondrial oxidative phosphorylation, vasculature, fibrosis and inflammation. RESULTS: HFpEF mice showed significant increase in systolic and diastolic blood pressure, increased heart/tibia length ratio, increased wet/dry lung ratio, decreased bodyweight as well as decreased weight of soleus and gastrocnemius muscle relative to tibia length. In oxidative soleus muscle, histological analyses showed a reduction in the abundance of type 1 and type 2A oxidative fiber, reduced cross-sectional area of type 2A fiber, decreased capillary density and increased fibrosis. Molecular analyses showed alterations that are consistent with histological data as well as increased gene expression of inflammatory mediators. In glycolytic gastrocnemius muscle, histological analysis indicated cross-sectional area was reduced for type 2B fibers and increased in type 1 fibers, and decreased capillary density. However, no changes in fiber abundance or in fibrosis was observed. Molecular data was consistent with these findings and revealed an increased gene expression of inflammatory mediators CONCLUSION: Skeletal muscle in SAUNA HFpEF mice displayed significant abnormalities relative to their sham counterparts. These results thus support that SAUNA HFpEF mouse model is suitable and relevant to study skeletal muscle abnormalities and could contribute to the development of novel therapies for HFpEF. / 2025-06-21T00:00:00Z

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13585号 / 論医博第2305号 / 新制||医||1070(附属図書館) / (主査)教授 石見 拓, 教授 古川 壽亮, 教授 近藤 尚己 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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京都大学 / 新制・課程博士 / 博士(理学) / 甲第24414号 / 理博第4913号 / 新制||理||1702(附属図書館) / 京都大学大学院理学研究科物理学・宇宙物理学専攻 / (主査)准教授 浅井 歩, 教授 一本 潔, 教授 横山 央明 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DFAM

The autonomic flexibility model has proven to be a useful theoretical tool relating reductions in physiological variability found to accompany anxiety and concomitant reductions in behavioral (e.g., cognitive and emotional) flexibility. The present study aimed to extend the autonomic flexibility model through the inclusion of individual differences in the sensitivity of the independent motivational systems presumed to underlie anxiety and impulsivity, namely the behavioral inhibition and activation systems (BIS/BAS; Gray, 1994). Contrary to the predicted inverse relationship between BIS sensitivity and measures of physiological variability, findings suggest BAS sensitivity is associated with increased trait-like vagally mediated heart rate variability across diverse tasks as well as greater flexibility in responding within tasks. Numerous BIS*BAS interactions emerged as significant predictors of trait reactivity. Results are discussed in terms of the interface between (1) mesolimbic dopaminergic projections to the nucleus accumbens and (2) the network of central nervous system structures believed to play a large role in controlling peripheral physiology. / Ph. D.