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Nowadays, electric vehicles (EVs) are becoming one of the most popular traffic modes in urban mobility system. As a new mode, it has its unique characteristics but also have many features in common with conventional transportation tools. One main advantage of the EV is that it uses the clean energy as the power of driving, which can significantly improve the sustainability of the current mobility system. Therefore, this new traffic mode has been widely and strongly supported by all sectors of society. Many governments around the world even plan to totally forbid the sale of conventional fuel vehicles to promote people’s acceptance towards the EV. However, a critical obstacle to continued progress in this technology is the range anxiety and the inconvenience of the current charging schemes, which to a great extent, limit the flexibility of drivers’ trip scheduling. In the case of this anxiety, the concept of Battery Swapping Station (BSS) becomes popular at present. This infrastructure is expected to provide battery swapping services to the EV like a fuel station, which can greatly eliminate the range anxiety and enhance the flexibility of trip scheduling for EV drivers. This thesis aims to make the construction planning for this future infrastructure. To be specific, it is to find the optimal spatial distribution of BSSs in the urban traffic network. For solving this type of problem, there have already been many studies that developed optimization models with objectives such as minimizing the overall construction and operation costs of the system or maximizing the overall operational profits. There are also a few studies take the routing problem into consideration as well. However, another important stakeholder in this problem is completely missed in existing research, that is the urban resident. Urban residents now are becoming more and more concerned about the living environments in the city, so they should not be neglected when trying to solve the locating pr, Civil Engineering

At present, many studies have begun to focus on evaluating urban accessibility and livability, which can be a series of great guidance for future urban planning considering residents’ personal perceptions of various living aspects. It can be observed from the existing literature that urban accessibility has a mature evaluation system, considering travel distance, trip purpose, travel time, individual’s perceived utility, and other constraints. However, the existing studies review urban livability from many very different directions, and no consolidated concept is proposed or concluded. This makes the evaluation of urban livability hardly provide a comprehensive understanding of the concept of urban livability. In this case, this additional research aims to propose a general framework describing the urban livability concept and its connotation. Besides, several indicators shall be selected from this framework to be quantified and calculated so that there could be a specific quantitative method for evaluating urban livability based on this framework., Civil Engineering | Transport and Planning

Summary Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) is caused by loss-of-function mutations in SEIPIN, a protein implicated in both adipogenesis and lipid droplet expansion but whose molecular function remains obscure. Here, we identify physical and functional interactions between SEIPIN and microsomal isoforms of glycerol-3-phosphate acyltransferase (GPAT) in multiple organisms. Compared to controls, GPAT activity was elevated in SEIPIN-deficient cells and tissues and GPAT kinetic values were altered. Increased GPAT activity appears to underpin the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss. Overexpression of Gpat3 blocked adipogenesis, and Gpat3 knockdown in SEIPIN-deficient preadipocytes partially restored differentiation. GPAT overexpression in yeast, preadipocytes, and fly salivary glands also formed supersized lipid droplets. Finally, pharmacological inhibition of GPAT in Seipin−/− mouse preadipocytes partially restored adipogenesis. These data identify SEIPIN as an evolutionarily conserved regulator of microsomal GPAT and suggest that GPAT inhibitors might be useful for the treatment of human BSCL2 patients.

Null mutations of the Niemann-Pick type C1 (NPC1) gene cause NPC disease, a lysosomal storage disorder characterized by cholesterol accumulation in late endosomes (LE) and lysosomes (Ly).Nascent ormutated NPC1 is degraded through the ubiquitin-proteasome pathway, but how NPC1 degradation is regulated remains currently unknown. In the present study, we demonstrated a link between NPC1 degradation and the Akt (protein kinase B)/mTOR [mammalian (or mechanistic) target of rapamycin] signalling pathway in cervical cancer cell lines. We provided evidence that activated Akt/mTOR pathway increased NPC1 degradation by ∼50% in C33A cells when compared with SiHa or HeLa cells. NPC1 degradation in C33A cells was reversed when Akt/mTOR activation was blocked by specific inhibitors or when mTORC1 (mTOR complex 1) was disrupted by regulatory associated protein of mTOR (Raptor) knockdown. Importantly, inhibition of the Akt/mTOR pathway led to decreased NPC1 ubiquitination in C33A cells, pointing to a role of Akt/mTOR in the proteasomal degradation of NPC1. Moreover, we found that NPC1 depletion in several cancer cell lines inhibited cell proliferation and migration. Our results uncover Akt as a key regulator of NPC1 degradation and link NPC1 to cancer cell proliferation and migration.

The regulatory pool of cholesterol is located in the endoplasmic reticulum (ER) and is key to how mammalian cells sense and respond to changes in cellular cholesterol levels. The extent of cholesterol esterification by the ER-resident protein, acyl-coenzyme A:cholesterol acyl-transferase (ACAT), has become the standard method for monitoring cholesterol transport to the ER and is assumed to reflect the regulatory pool of ER cholesterol. The oxysterol, 25-hydroxycholesterol (25HC), is thought to trigger intracellular cholesterol transport to the ER. Chapter 3 of this thesis addressed whether or not cholesterol esterification necessarily reflects cholesterol movement to the cholesterol homeostatic machinery in the ER as determined by SREBP processing. Three agents that inhibited the ability of 25HC to induce cholesterol esterification (progesterone, nigericin, and monensin) did not have a corresponding effect on 25HC suppression of SREBP processing. Moreover, ACAT inhibition did not alter the sensitivity of SREBP processing to 25HC. These findings indicate that cholesterol esterification by the ER-resident protein ACAT is dissociable from cholesterol transport to the cholesterol homeostatic machinery in the ER.In order to readily analyse and quantify the processing of SREBP-2, the master regulator of cholesterol homeostasis, the second part of this study (Chapter 4) established a stable cell-line (13A/PS) that expresses the fusion protein PLAP-BP2 (secreted form of placental alkaline phosphatase joined to the luminal loop of SREBP-2 on the NH2- terminal side of Site-1). Processing of PLAP-BP2 mimics the cleavage of SREBP. The PLAP-BP2 cleavage assay was shown to be a valuable method for analysing and quantifying SREBP-2 processing. Compared to transiently transfected cells, the stable 13A/PS cells were more responsive to changes of sterol status in regards to PLAP secretion. Considering the reliability and consistency of the experiments, the 13A/PS cell-line is therefo