Background: The differential effects of using topical oils for the prevention or treatment of baby dry skin on skin barrier function may contribute to the development of childhood atopic eczema. Prevalence of atopic eczema has increased from 5% of children aged 2 to 15 years in the 1940s, to approaching 30% more recently. This increase cannot be attributed to genetic changes. It is likely that increases stem from environmental factors, including the increased use of some inappropriately formulated commercial and natural baby skincare products. Midwives, health visitors and other maternity service health professionals, in the UK, routinely recommend the use of olive oil and sunflower oil for baby dry skin or massage, but the effect of these oils on newborn baby skin has not been studied. Aim: The aim of this research was to assess the feasibility and acceptability of testing the hypothesis that the regular application of sunflower oil, when compared to no oil or olive oil, had an effect on skin barrier function of newborn term babies. Study Design: A pilot, assessor-blinded, single centre, three-arm, randomised controlled trial, with nested qualitative component, underpinned by post-positivism. Methods: Quantitative methods were used to establish proof of concept that the use of topical oils had some effect on newborn baby skin barrier function, and to assess the feasibility of trial processes and parameters. Qualitative methods were used to explore the acceptability to parents of having a newborn baby participating in a randomised controlled trial, and trial design and procedures. The study was conducted in St. Mary’s hospital, a large teaching hospital in North West England. Data were collected between September 2013 and August 2014.The randomised controlled trial included 115 babies who were randomised to three groups: sunflower oil, olive oil and no oil, using a computer-generated varied size block randomisation with concealed allocation. Parents of babies randomised to the oil groups were blinded to which oil they were allocated. Data were collected using standardised case report forms for demographic and clinical observation data, weekly telephone questionnaires and a follow-up questionnaire, informed by previous baby skincare trials. The qualitative study encompassed semi-structured interviews, conducted within six months of birth. The sample was a subset of the trial participants, purposively sampled to incorporate a mix of treatment groups and positive and negative experiences derived from the follow-up questionnaire. Data also included two open-text questions from the follow-up questionnaire. Quantitative data were managed using IBM SPSS Statistics versions 20 and 22 and analysed descriptively. Qualitative data were managed in NVivo 10 and analysed using Framework Analysis. Results: The pilot study found that a definitive randomised controlled trial is not the optimal next step. A longitudinal observational study and further mechanistic work is recommended. Recruitment was challenging and loss to follow-up was higher than anticipated. Protocol adherence was reasonable and the study was acceptable to parents. Some statistically significant results were obtained, which must be interpreted with caution as the study was not powered to detect such a difference. These results showed that both oils may impede the development of the skin barrier function from birth; clinical importance of the results is not known. Conclusion: A longitudinal observational study is required, which maps the diagnosis of atopic eczema with environmental factors such as the use of baby skincare products from birth. Mechanistic work is also required to consider the optimal skincare formulation. As any intervention should do more good than harm, it would be wrong to support the recommendation of topical olive oil or sunflower oil for newborn baby dry skin or massage, based on the study data.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21804号 / 農博第2317号 / 新制||農||1065(附属図書館) / 学位論文||H31||N5176(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 菅原 達也, 教授 佐藤 健司, 教授 松井 徹 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

RATIONALE - Metabolic enzymes, like pyruvate kinase M2 (PKM2), play an essential role in altering endothelial cell (EC) phenotypes and behavior. Extensive research has elucidated the function of PKM2, a rate-limiting glycolytic enzyme, in the context of cancer cells and in activated immune cells, but its role in EC biology is only newly emerging. Recent findings show PKM2 acts as a key regulator of angiogenesis. Where exogenous circulating PKM2 induces EC cell proliferation leading to increased tumor angiogenesis and growth. Also, PKM2 deficient ECs exhibit decreased proliferation and migration. The relevance of PKM2 in modulating vascular barrier function is yet to be defined. OBJECTIVE -This study attempts to elucidate the role of PKM2 in regulating vascular barrier function. METHODS AND RESULTS - In vivo, EC specific deletion of PKM2 promotes increased vascular permeability in pulmonary capillary vessels and increased VEGF-induced acute vessel permeability in mouse dermal vessels. Similarly, in vitro, PKM2 deficient ECs exhibit decreased electrical resistance, disrupted VE-cadherin junctions and gap formations (illustrated via florescent VE-cadherin staining and phosphorylation of VE- cadherin protein at tyrosine residue Y658). Mechanistically, the deletion of PKM2 in ECs leads to increased angiopoietin-2 (Ang-2) expression, a well-known modulator of vascular permeability. Also, deletion of Ang-2 was sufficient to attenuate vascular leakage in PKM2 deficient endothelium, indicating that vascular leaky phenotype observed in PKM2 deficient endothelium is mediated by increased Ang-2 expression. CONCLUSIONS - PKM2, by modulating Ang-2 expression, plays a vital role in maintaining vascular barrier function. / 2019-07-11T00:00:00Z

No / Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy profile of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening. / EPSRC

京都大学 / 新制・課程博士 / 博士(農学) / 甲第23940号 / 農博第2489号 / 新制||農||1090(附属図書館) / 学位論文||R4||N5375(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 菅原 達也, 教授 佐藤 健司, 教授 松井 徹 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

The Cx43 CT mimetic peptide, αCT1, originally designed to bind to ZO1 and thereby inhibit Cx43/ZO1 interaction, was used as a tool to probe the role of Cx43/ZO1 association in regulation of epithelial/endothelial barrier function. Using both in vitro and ex vivo methods of barrier function measurement, including Electric Cell-Substrate Impedance Sensing(ECIS), a TRITC-dextran transwell permeability assay, and a FITC-dextran cardiovascular leakage protocol involving Langendorff-perfused mouse hearts, αCT1 was found to protect the endothelium from thrombin-induced breakdown in cell-cell contacts. Barrier protection was accompanied by significant remodeling of the F-actin cytoskeleton, characterized by a redistribution of F-actin away from the cytoplasmic and nuclear regions of the cell, towards the endothelial cell periphery, in association with alterations in cellular orientation distribution. In line with observations of increased cortical F-actin, αCT1 upregulated cell-cell border localization of endothelial VE-cadherin, the Tight Junction protein Zonula Occludens 1 (ZO1) , and the Gap Junction Protein (GJ) Connexin43 (Cx43). A ZO1-binding-incompetent variant of αCT1, αCT1-I, indicated that these effects on barrier function and barrier-associated proteins, were likely associated with Cx43 CT sequences retaining ability to interact with ZO1. These results implicate the Cx43 CT and its interaction with ZO1, in the regulation of endothelial barrier function, while revealing the therapeutic potential of αCT1 in the treatment of vascular edema. / Doctor of Philosophy / Endothelial cells make up blood vessels within the heart and regulate the exchange of fluids between the circulation and heart tissue. In many forms of heart disease, the cardiac endothelium is disrupted, resulting in a damaging leakage and buildup of fluids within the heart. This work explores how a small peptide, derived from a naturally occurring molecule, may help to prevent fluid-associated damage to the heart by stabilizing the blood endothelium.

Moisturizers are used in various types of dry skin disorders, but also by people with healthy skin. It is not unusual that use of moisturizers is continued for weeks, months, or even years. A number of moisturizers have been shown to improve the skin barrier function, while others to deteriorate it, but the reason for observed effects remains unknown. Further understanding of the mechanism by which long-term treatment with moisturizers influences the skin barrier would have clinical implications, as barrier-deteriorating creams may enhance penetration of allergens or irritants and predispose to dry skin and eczema, while barrier-improving ones could reduce many problems. The present research combined non-invasive techniques with analyses of skin biopsies, allowing studies of the epidermis at molecular and cellular level. Test moisturizers were examined on healthy human volunteers for their effect on the skin barrier, with regard to such factors as pH, lipid type, and presence of a humectant, as well as complexity of the product. After a 7-week treatment with the moisturizers, changes in transepidermal water loss, skin capacitance, and susceptibility to an irritant indicated a modified skin barrier function. Moreover, the mRNA expression of several genes involved in the assembly, differentiation and desquamation of the stratum corneum, as well as lipid metabolism, was altered in the skin treated with one of the moisturizers, while the other moisturizer induced fewer changes. In conclusion, long-term use of moisturizers may strengthen the barrier function of the skin, but also deteriorate it and induce skin dryness. Moisturizers have also a significant impact on the skin biochemistry, detectable at molecular level. Since the type of influence is determined by the composition of a moisturizer, more careful selection of ingredients could help to design moisturizers generating a desired clinical effect, and to avoid ingredients with a negative impact on the skin.

Atopic dermatitis (AD), ichthyosis vulgaris (IV), and X-linked recessive ichthyosis (XLRI) are characterized by dry skin and impaired skin barrier. AD and IV are related to loss-of-function mutations in FLG (encoding filaggrin), whereas XLRI is caused by deletions or inactivating mutations in the steroid sulphatase gene (STS). Patients regularly use moisturizing creams, but little is known about the creams’ effects on the skin barrier. The present work combines objective scorings, non-invasive techniques, and molecular analyses of skin biopsies to characterize the skin in 57 patients with AD, IV, or XLRI, and in 14 healthy controls. Patients were classified according to their FLG and STS mutation status: AD with FLG+/+ (n = 14), AD with FLG+/– (n = 14), AD/IV with FLG–/– (n = 15), and XLRI with STS– (n = 14), as well as one man with a novel point mutation. Assessments were conducted at baseline and after four weeks of treatment with three different moisturizers applied to volar forearm skin. At baseline, dryness scoring and non-invasive assessments verified impaired skin barrier function in all patients. In patients with AD/IV, microarray analysis identified 300–3000 up- or downregulated mRNA transcripts involved in signalling pathways important for inflammation and barrier repair. The skin phenotype and number of altered transcripts were correlated with the FLG mutation status, with FLG–/– patients displaying the highest transepidermal water loss (TEWL) and the most altered transcript levels. In contrast, despite an equally dysfunctional skin barrier, only limited changes in mRNA transcripts occurred in XLRI patients. Treatment with moisturizers improved skin dryness similarly in all groups, but TEWL behaved differently: it decreased slightly in the AD/IV group and increased in the XLRI group, especially after urea treatment. Only minute effects on skin pH and mRNA expression were observed. In conclusion, FLG mutations elicit pro-inflammatory mechanisms probably aimed at restoring barrier competence. This does not occur in patients with XLRI, presumably because STS deficiency automatically increases the barrier thickness. Moisturizing treatment improves skin dryness in patients with AD, IV, or XLRI, but does not seem to normalize the altered epidermal gene expression profile in AD/IV patients.

Autonomous systems are slowly moving into the mainstream with things like self driving cars and autonomous robots in storage facilities already in use today. The aim of this project is to simulate a virtual bakery with a baker-robot (agent)that is able to complete recipes within strict deadlines.Signal temporal logic (STL) is used to define instructions that can be understood by the agent. In order to carry out these instructions, a control barrier function (CBF) is used.CBFs are time and state dependent, are used to describe the desired behavior of the agent, and are designer made. If the CBF corresponding to the task is non-negative from beginning to end during the task, the task has been completed successfully.A virtual robot was used in this project and was tasked with moving to and staying in different areas, which represents picking up and dropping off ingredients, all whilst staying within the boundaries of the bakery. The focus of this work is on completing the large amount (10+) of sequential tasks required to completea recipe. The CBF remained positive during the task, and the task was completed successfully. / Autonoma system börjar ta mer och mer plats i vardagen med saker som självkörande bilar och autonoma robotar i lagerlokaler som redan används idag. Syftet med det här projektet är att simulera ett virtuellt bageri med en bagarrobot (agent) som kan laga recept under strikta tidskrav. Signal temporal logic (STL) används för att definiera instruktioner som kan förstås av agenten. För att genomföra dessa instruktioner korrekt används en control barrier function (CBF). CBF:er är tidsoch tillståndsberoende, används för att beskriva agentens önskade beteende, och är skapade av en designer. Om CBF:en är positiv från början till slut under uppgiftens gång så har uppgiften genomförts som önskat. En virtuell robot användes i det här projektet och fick i uppdrag att flytta till och stanna inom olika områden, vilket representerar att plocka upp och lämna ingredienser, allt medan den vistas inom bageriets gränser. Fokus för detta arbete ligger på att slutföra den stora mängd (10+) av sekventiella uppgifter sim krävs för att laga ett recept. CBF:en var positiv under hela uppgiften, och uppgiften genomfördes framgångsrikt. / Kandidatexjobb i elektroteknik 2022, KTH, Stockholm

The security of multi-robot systems is critical in various applications such as patrol, transportation, and search and rescue operations, where they face threats from adversaries attempting to gain control of the robots. These compromised robots are significant threats as they allow attackers to steer robots towards forbidden areas without being detected, potentially causing harm or compromising the mission. To address this problem, we propose a resilient planning, task assignment, and control framework. The proposed framework builds a multi-robot plan where robots are designed to get close enough to other robots according to a co-observation schedule, in order to mutually check for abnormal behaviors. For the first part of the thesis, we propose an optimal trajectory solver based on the alternating direction method of multipliers (ADMM) to generate multi-agent trajectories that satisfy spatio-temporal requirements introduced by the co-observation schedules. As part of the formulation, we provide a new reachability constraint to guarantee that, despite adversarial movement by the attacker, a compromised robot cannot reach forbidden areas between co-observations without being detected. In the second part of the thesis, to further enhance the system's performance, reliability, and robustness, we propose to deploy multiple robots on each route to form sub-teams. A new cross-trajectory co-observation scheme between sub-teams is introduced that preserves the optimal unsecured trajectories. The new planner ensures that at least one robot in each sub-team sticks to the planned trajectories, while sub-teams can constantly exchange robots during the task introducing additional co-observations that can secure originally unsecured routes. We show that the planning of cross-trajectory co-observations can be transformed into a network flow problem and solved using traditional linear program technique. In the final part of the thesis, we show that the introduction of sub-teams also improves the multi-robot system's robustness to unplanned situations, allowing servicing unplanned online events without breaking the security requirements. This is achieved by a distributed task assignment algorithm based on consensus ADMM which can handle tasks with different priorities. The assignment result and security requirements are formulated as spatio-temporal schedules and guaranteed through control barrier function (CBF) based controls.