Acetaminophen overdose is the leading cause of acute liver failure, with one available treatment, NAC. Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. Promoting intrinsic liver regeneration could address this unmet need by temporally activating key hepatocyte regenerative pathways in order to accelerate recovery from acute APAP-induced liver injury. In aim 1, we established an efficient, safe, non-integrative method to transiently express HGF and EGF in hepatocytes via nucleoside-modified mRNA-LNP delivery in mice. We confirmed specific hepatotropism of mRNA-LNP via intravenous injection of firefly luciferase encoding mRNA-LNP, with protein expression lasting about 3 days. In the liver, virtually all hepatocytes were transfected along with a subpopulation of endothelial and Kupffer cells. In homeostasis, HGF mRNA-LNP efficiently induced hepatocyte proliferation. In a chronic liver injury mouse model recapitulating nonalcoholic fatty liver disease, injections of both HGF and EGF mRNA-LNP sharply reversed steatosis and accelerated restoration of liver function. Likewise, HGF and EGF mRNA-LNP accelerated liver regeneration after APAP-induced acute liver injury with rapid return to baseline of levels of serum liver injury markers such as ALT. This study introduced mRNA-LNP as a potentially translatable safe therapeutic intervention to harness liver regeneration via controlled expression of endogenous mitogens in vivo. In aim 2, we characterized the sexually differential injury induced between males and females following APAP overdose. Consistent with the literature, our data showed higher resistance of female mice to APAP, shown by reduced liver necrosis, cell death, and detection of serum injury markers compared to males. Moreover, our single-cell RNA sequencing analyses revealed that female hepatocytes and endothelial cells express significantly higher levels of GH receptor and GH pathway activation than male cells, while males have upregulated inflammatory and cell death pathway activation. Therefore, in aim 3, we took advantage of the greater resistance of female mice and greater activation of the GH pathway to evaluate a novel treatment for APAP-induced acute liver injury utilizing growth hormone. Sex hormones and their receptors have been implicated in driving sexual dimorphism in many liver processes. Specifically, pituitary GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. In harnessing this female-specific advantage, we demonstrated that injection of recombinant human GH protein in APAP-injured mice accelerates liver recovery, promotes survival, and is superior to standard-of-care NAC. Delivery of slow-released human GH mRNA-LNP also rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice. In conclusion, this study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients. / 2025-11-02T00:00:00Z

An analysis is presented on the use of a proof-mass actuator as a regenerative force actuator for the mitigation of earthquake disturbances in civil structures. A proof-mass actuator is a machine which accelerates a mass along a linear path. Such actuators can facilitate two-way power flow. In regenerative force actuation, a bi- directional power-electronic drive is used to facilitate power flow both to and from the proof-mass actuator power supply. With proper control system design, this makes it possible to suppress a disturbance on a structure using mostly energy extracted from the disturbance itself, rather than from an external power source. In this study, three main objectives are accomplished. First, a new performance measure, called the "required energy capacity," is proposed as an assessment of the minimum size of the electric power supply necessary to facilitate the power flow required of the closed-loop system for a given disturbance. The relationship between the required energy capacity and the linear control system design, which is based on positive position feedback concepts, is developed. The dependency of the required energy capacity on hybrid realizations of the control law are discussed, and hybrid designs are found which minimize this quantity for specific disturbance characteristics. As the second objective, system identification and robust estimation methods are used to develop a stochastic approach to the performance assessment of structural control systems, which evaluates the average worst-case performance for all earthquakes "similar" to an actual data record. This technique is used to evaluate the required energy capacity for a control system design. In the third objective, a way is found to design a battery capacity which takes into account the velocity rating of the proof-mass actuator. Upon sizing this battery, two nonlinear controllers are proposed which automatically regulate the power flow in the closed-loop system to accommodate a power supply with a finite energy capacity, regardless of the disturbance size. Both controllers are based on a linear control system design. One includes a nonlinearity which limits power flow out of the battery supply. The other includes a nonlinearity which limits the magnitude of the proof-mass velocity. The latter of these is shown to yield superior performance. / Master of Science

No / The science and engineering of biomaterials have improved the human life expectancy. Tissue engineering is one of the nascent strategies with an aim to fulfill this target. Tissue engineering scaffolds are one of the most significant aspects of the recent tissue repair strategies; hence, it is imperative to design biomimetic substrates with suitable features. Conductive substrates can ameliorate the cellular activity through enhancement of cellular signaling. Biocompatible polymers with conductivity can mimic the cells’ niche in an appropriate manner. Bioconductive polymers based on aniline oligomers can potentially actualize this purpose because of their unique and tailoring properties. The aniline oligomers can be positioned within the molecular structure of other polymers, thus painter acting with the side groups of the main polymer or acting as a comonomer in their backbone. The conductivity of oligoaniline-based conductive biomaterials can be tailored to mimic the electrical and mechanical properties of targeted tissues/organs. These bioconductive substrates can be designed with high mechanical strength for hard tissues such as the bone and with high elasticity to be used for the cardiac tissue or can be synthesized in the form of injectable hydrogels, particles, and nanofibers for noninvasive implantation; these structures can be used for applications such as drug/gene delivery and extracellular biomimetic structures. It is expected that with progress in the fields of biomaterials and tissue engineering, more innovative constructs will be proposed in the near future. This review discusses the recent advancements in the use of oligoaniline-based conductive biomaterials for tissue engineering and regenerative medicine applications.

Background: The regenerative function of stem cells from the apical papilla (SCAPs) is affected by the presence of bacteria from infected root canals. Living microorganisms influence SCAP function but the effect of inactive bacteria and its components on SCAPs needs further investigation. Aim: To investigate the effect of residual bacterial products on the proliferation of SCAP under anaerobic conditions. Methods: Five opportunistic bacterial strains from infected dental root canals namely Fusobacterium nucleatum, Enterococcus faecalis, Actinomyces gerensceria, Slackia exigua, and Peptostreptococcaceae yuri, and two probiotic strains Lactobacillus gasseri, Lactobacillus reuteri were used in this study. SCAPs collected from three healthy young patients were exposed to UV-inactivated bacteria or bacterial DNA. Real-Time Cell Analyzer (RTCA) was used to determine real-time proliferation of SCAPs after 80 hours exposure of inactivated bacteria or their DNA. Results: UV killed Fusobacterium nucleatum and Enterococcus Faecalis DNA affects proliferation of stem cells from dental apical papilla as monitored in real-time. Inactivated probiotic species do not affect SCAPs in terms of proliferation. Conclusion:  Inactivated bacteria can affect SCAP function by modulating their proliferation. Further investigations studying SCAP modulation and differentiation are warranted to understand and improve regenerative endodontic procedures.

京都大学 / 新制・論文博士 / 博士(医科学) / 乙第13518号 / 論医科博第10号 / 新制||医科||10(附属図書館) / (主査)教授 金子 新, 教授 松田 秀一, 教授 山中 伸弥 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24289号 / 医博第4905号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小濱 和貴, 教授 妹尾 浩, 教授 長船 健二 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In HEV and EV, higher fuel economy is achieved by operating the ICE and electric motor in the most efficient region and by using regenerative braking. Such a braking system converts, transfers, stores and reuses kinetic energy which would otherwise be dissipated as heat through friction brakes to the environment. This research investigates the control of braking for a mixed-mode braking system in a these vehicles based on the proportion of braking energy that can be stored. Achieving mixed-mode braking requires the ‘blending’ of the two systems (regenerative and friction), and in brake blending, the electric motor/generator (M/G) and the hydraulic actuation pressure are controlled together to meet the driver’s braking demand. The research presented here has established a new robust dynamic modelling procedure for the design of combined regenerative and hydraulic braking systems. Direct torque control and pressure control were selected as the control criteria in both brakes. Two simulation models have been developed in Matlab/Simulink to generate analysis the performance of the control strategy in the blended braking system. Integration of the regenerative braking system with ABS has also been completed, based on two conditions, with and without the deactivation of the regenerative braking. Verification of the models is presented, based on experimental work on two EVs manufactured by TATA Motors; the ACE light commercial vehicle and the VISTA small passenger car. It is concluded that braking demand and vehicle speed determine the operating point of the motor/generator and hence the regenerative braking ratio.

Daylight is an essential element for both the built and natural environment. A careful design that acknowledges daylight performance can improve energy efficiency and environment protection, thus making construction more sustainable. However, allocating time to deeply evaluate all the aspects in a project might be challenging. In this framework, the aim is to analyze, through a specific designed case study, the different available options when it comes to manage daylight as a building material. Climate adaptation as a base for an architectural project is essential to achieve a regenerative evolution of the built environment. It should be holistically considered from the very outset, to conclude in a livable, sustainable and quality-designed space.  The aim of the present research is to thoroughly analyze daylight in order to use it as an input at the very early stage of an architectural project. Analyzing two different latitudes, Uruguay and Sweden, provided with a wide range of information, evidencing that assessing daylight is as complex as crucial.  Hence, the combination of academic methods with professional practice is key to design the built environment. By using an experimental cabin as case study, and with the support of the program Climate Studio, daylight is analyzed in these two different locations.

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