Common use of Non Commercial Clause in Contracts

Non Commercial. You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. If you believe that this document breaches copyright please contact ▇▇▇▇▇▇▇▇▇▇▇@▇▇▇.▇▇.▇▇ providing details, and we will remove access to the work immediately and investigate your claim. Download date: 04. Oct. 2022 Taking this PhD was a dream which had finally come true. Indeed, it was a challenging experience, that could not have been feasible without continuation help and support. First and foremost, I would like to thank ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇ ▇ Hughes, my first supervisor whose understanding and patience from inception of this project was truly appreciated. His guidance, ideas and suggestions supported me throughout this life-changing journey. It was a pleasure to study under his supervision. I would also like to thank ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇, my second supervisor for his great help and advice. His critical scientific insight gave me beneficial experiences during this study. Special thanks to Professor ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇ my postgraduate co-ordinator for all his support. I am indebted to many of friends and colleagues who generously spent time and shared their experiences with me in my laboratory work. In particular, my sincere gratitude goes to ▇▇. ▇▇▇▇▇ ▇▇▇▇▇▇▇ who assisted me in my first year of study with his tremendous knowledge and ideas. Also, many thanks to ▇▇. ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇ Firena Garna for their heartful help and support. I would also like to thank ▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ and all other laboratory staff for their advice. Special thanks to my PhD friend ▇▇▇▇▇ who was always by my side and supported me spiritually. I would also like to thank my beloved parents for their support and encouragement in throughout my life which allowed me to pursue my dreams. I would heartedly like to offer this work to my father’s spirit who passed away recently, who was always encouraging me and was the greatest inspiration in my life. My special appreciation goes to my husband ▇▇▇▇▇ who was always supportive and making this long journey without his unconditional love was unattainable. Most of all I would like to thank my beloved daughter ▇▇▇ who is always my motivation and source of energy. My thanks also go to my brothers for always being by my side and for encouraging me. Mesenchymal stem cells (MSCs) are adult stem cells which are characterised by self- renewal and differentiation capacity into three mesenchymal lineages: osteoblast, chondrocyte and adipocytes. MicroRNAs (miRNAs) are a class of non-coding short RNAs (20-22 nucleotides) which target messenger RNAs to supress protein synthesis and regulate cell function. There is increasing evidence that miRNAs can play key roles in the regulation of multiple biological processes include stem cell regulation. Therefore, the aim of this study was to investigate the potential role of miRNAs in the regulation of MSC fate decisions. Firstly, 4 different MSC cell lines were tested for their differentiation capacity following induction with osteogenic, adipogenic, or chondrogenic media. From these results one cell line was selected for use in further studies. The expression of 9 candidate miRNAs which had previously been shown to be associated with regulation of other stem cells were tested during osteogenic or adipogenic induction. To identify novel miRNAs associated with MSC regulation, clonally derived MSCs with osteogenic, adipogenic or bipotent differentiation patterns were tested using ▇▇▇▇▇ array. From the results of the array 2 family members of the ▇▇▇▇▇-302 (a and b) were selected for further investigation. MiR-302a and b expression was validated by qRT-PCR in the clonally derived cell lines and in primary MSC cultures. To determine the role of the miR-302 family during MSC differentiation, their functional activity was tested by knock-down and over expression, via transfection of a ▇▇▇▇▇-302 family inhibitor or individual miR-302a and miR-302b mimics into MSCs and the cells were treated with osteogenic, adipogenic or growth medium as control for 14 days. Then lineage specific gene expression was measured by qRT-PCR. Expression patterns of the 9 candidate genes showed no reproducible significant effects during osteoblastic or adipocytic differentiation. ▇▇▇▇▇-302a and b were both down regulated during differentiation of MSCs into both osteogenic and adipogenic lineages. Knock-down of ▇▇▇▇▇-302 family in MSCs caused a significant upregulation of between 2-5 times of RUNX2 expression and between 3-10 times of ALP expression during osteogenic differentiation of MSCs. Overexpression of miR-302b did not have any significant reproducible effects on osteogenic differentiation of MSCs. In contrast, over expression of miR-302a resulted in increased RUNX2 expression by 1.5-2 fold on day 2 and ALP expression by almost 50 fold after day 4. Inhibition or over expression of miR-302 family had no early effects on adipogenesis of MSCs, but at day 14 FAB4 was upregulated nearly 40% in inhibited cells and between 20-30% in miR-302a overexpressed cells. In contrast overexpression of miR-302b downregulated FAB4 by a range of between 10-80% at day 14. ALP enzyme activity rose at day 7 after inhibition of miR-302 and decreased at day 10 and 14 after miR-302a over expression significantly. The results suggest that ▇▇▇▇▇-302 acts to maintain MSC phenotype by specific repression of osteogenic differentiation. The results also suggest that this may be specifically due to the action of miR-302a. In contrast the miR-302 family had little or no effects on adipogenic differentiation of MSCs, with the exception of a transient upregulation of FAB4 at a late stage of differentiation due to miR-302 inhibition.

Non Commercial. You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. If you believe that this document breaches copyright please contact ▇▇▇▇▇▇▇▇▇▇▇@▇▇▇.▇▇.▇▇ providing details, and we will remove access to the work immediately and investigate your claim. Download date: 0408. Oct. 2022 Taking 2023 I hereby declare that except where specific reference is made to the work of others, the contents of this disserta- tion are original and have not been submitted in whole or in part for consideration for any other degree or qualification in this, or any other university. This dissertation is my own work and contains nothing which is the outcome of work done in collaboration with others, except as specified in the text. In the name of Allah, the Gracious, the Merciful. With the sheer grace of God, I have made it here. I am eternally grateful that I have been given such great opportunities in this life, Alhamdulillah. “Make the most of your life, and get to the top”, I have always been encouraged. During my Master’s and my PhD, I have had the utmost privilege of working with Professor ▇▇▇▇ ▇▇▇▇. His experience, intelligence, scientific insight, supervision, mentoring, and patience have been invaluable. He has always created a positive and inspiring environment that has helped me pursue particularly challenging aspects of research. I am extremely grateful to have had the honor and privilege of working with him. At King’s, I met many other colleagues, BSc, MSc, and PhD was a dream which had finally come truestudents, and academics. IndeedWhether you taught me or I taught you, whether it was just a challenging experiencepleasant conversation while waiting for a lecture or the establishment of a lifetime of friendship, that could not I express my sincere gratitude to you all. I am grateful to have been feasible without continuation help part of the supportive and supportfriendly community at King’s. First and foremost, I am grateful for the funding received by the EPSRC. I would also like to thank extend my sincere gratitude to Professor ▇▇▇▇▇ ▇▇▇▇▇▇ and Associate ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇ ▇ HughesAlís, who served as my first supervisor whose understanding external examiners. Prior to King’s, I was fortunate enough to be taught by many phenomenal teachers. I am eternally grateful to them all for dedicating their lives to ensure that my peers and patience from inception I could have better futures. It is impossible to list them all here; know that you are remembered and will always be valued highly. with him regularly. Without his prayers and inspiration, all of this project was truly appreciated. His guidance, ideas and suggestions supported me throughout this life-changing journey. It was a pleasure to study under his supervisionwould have been impossible. I would also like to thank ▇▇all my family. It is impossible to describe in words how much I appreciate the prayers, love, affection, encouragement, and inspiration they have given me. To all my family, thank you. The quote above is attributed to my beloved parents — ▇▇▇▇▇, my father, and ▇▇▇▇▇, my mother — who are a precious gift for someone like me. They have supported me in every possible way. I do not know how or if I can ever repay them; I will forever cherish them as parents and as friends. They have only ever wanted the best for me, and this work is dedicated to them. My brothers, ▇▇▇▇ and ▇▇▇▇▇▇, have been my second supervisor for his great help best friends from the beginning, and adviceI will forever be thankful to have siblings like them. His critical scientific insight gave me beneficial experiences during this studyThey are all true gems. Special thanks Thank you to Professor all of you. Last but certainly not least, I want to mention a very special person, my fiancée, ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇ my postgraduate co. Thank you very much for your support and encouragement. Machine learning (ML) has facilitated progress in several disciplines as a result of greater resources, data volumes, and algorithmic developments. Particularly in cybersecurity, ML-ordinator based malware detection has proven to be an effective method of classifying software executables as benign or malicious. However, an unintended consequence of the increased usage of machine learning is that the attack surface has been widened through adversarial ML attacks. With such attacks, malicious users can craft input samples with the intention of evading ML models and causing them to output a specific prediction. for example, in an evasion attack, a malicious executable may be carefully constructed so that an ML model misclassifies it as benign, despite its truly malicious nature. Such an attack has important ramifications for the safety of machine learning systems, especially considering the well-established adversarial nature of malware detection. Adversarial attacks are not exclusive to ML-based malware detection; they apply across all his supportdomains. I am indebted Thus, significant effort has been devoted to many developing methods for defending ML models against adversarial attacks. However, as we discuss, these have a number of friends limitations, such as their ineffectiveness, failure to cope with newer types of attacks, and colleagues who generously spent time reduced performance on legitimate queries. furthermore, in ML-based malware detection, defenses against adversarial attacks have received substantially limited attention, despite the threat posed by these attacks. In this dissertation, we aim to establish a fresh understanding of methods to defend against adversarial attacks in ML-based malware detection. We propose two novel defensive methods based on promising ap- proaches, moving target defenses (MTDs) and shared their experiences with me in my laboratory stateful defenses, which are based on other areas of cybersecurity and have never been applied to this domain before. Particularly, we first propose a novel strategic moving target defense against adversarial attacks that overcomes the challenges and limitations of related work. In particular, my sincere gratitude goes to ▇▇. ▇▇▇▇▇ ▇▇▇▇▇▇▇ who assisted me in my first year of study with his tremendous knowledge and ideas. Also, many thanks to ▇▇. ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇ Firena Garna for their heartful help and support. I would also like to thank ▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ and all other laboratory staff for their advice. Special thanks to my PhD friend ▇▇▇▇▇ who was always by my side and supported me spiritually. I would also like to thank my beloved parents for their support and encouragement in throughout my life which allowed me to pursue my dreams. I would heartedly like to offer We show that this work to my father’s spirit who passed away recently, who was always encouraging me and was the greatest inspiration in my life. My special appreciation goes to my husband ▇▇▇▇▇ who was always supportive and making this long journey without his unconditional love was unattainable. Most of all I would like to thank my beloved daughter ▇▇▇ who is always my motivation and source of energy. My thanks also go to my brothers for always being by my side and for encouraging me. Mesenchymal stem cells (MSCs) are adult stem cells which are characterised by self- renewal and differentiation capacity into three mesenchymal lineages: osteoblast, chondrocyte and adipocytes. MicroRNAs (miRNAs) are a class of non-coding short RNAs (20-22 nucleotides) which target messenger RNAs to supress protein synthesis and regulate cell function. There is increasing evidence that miRNAs can play key roles strategic defense outperforms several prior defenses in the regulation first evaluation of multiple biological processes include stem cell regulation. Thereforeits kind, the aim of this study was to investigate the potential role of miRNAs in the regulation of MSC fate decisions. Firstly, 4 different MSC cell lines were tested for their differentiation capacity following induction with osteogenic, adipogenic, or chondrogenic media. From these results one cell line was selected for use in further studies. The expression of 9 candidate miRNAs which had previously been shown to be associated with regulation of other stem cells were tested during osteogenic or adipogenic induction. To identify novel miRNAs associated with MSC regulation, clonally derived MSCs with osteogenic, adipogenic or bipotent differentiation patterns were tested using ▇▇▇▇▇ array. From the results of the array 2 family members of the ▇▇▇▇▇-302 (a and b) were selected for further investigation. MiR-302a and b expression was validated by qRT-PCR in the clonally derived cell lines and in primary MSC cultures. To determine the role of the miR-302 family during MSC differentiation, their functional activity was tested by knock-down and over expression, via transfection of a ▇▇▇▇▇-302 family inhibitor or individual miR-302a and miR-302b mimics into MSCs and the cells were treated with osteogenic, adipogenic or growth medium as control for 14 days. Then lineage specific gene expression was measured by qRT-PCR. Expression patterns of the 9 candidate genes showed no reproducible significant effects during osteoblastic or adipocytic differentiation. ▇▇▇▇▇-302a and b were both down regulated during differentiation of MSCs into both osteogenic and adipogenic lineages. Knock-down of ▇▇▇▇▇-302 family in MSCs caused a significant upregulation of between 2-5 times of RUNX2 expression and between 3-10 times of ALP expression during osteogenic differentiation of MSCs. Overexpression of miR-302b did not have any significant reproducible effects on osteogenic differentiation of MSCs. In contrast, over expression of miR-302a resulted in increased RUNX2 expression by 1.5-2 fold on day 2 and ALP expression by almost 50 fold after day 4. Inhibition or over expression of miR-302 family had no early effects on adipogenesis of MSCs, but at day 14 FAB4 was upregulated nearly 40% in inhibited cells and between 20-30% in miR-302a overexpressed cells. In contrast overexpression of miR-302b downregulated FAB4 by considers a range of between 10threat models. Second, we characterize and evaluate, for the first time, the effectiveness of several MTDs for adversarial ML applied to this domain. In a comprehensive study, we extensively compare their performances with each other and with other types of defenses for adversarial ML. We expose the vulnerability of these MTDs to both existing attack strategies and our proposed novel ones, highlighting the key weaknesses of these approaches. Based on these findings, we present key recommendations for advancing work on MTDs against adversarial ML. Inspired by one of these recommendations, we then propose a novel stateful defense against adversarial attacks on ML-80% at day 14based malware detection. ALP enzyme activity rose at day 7 after inhibition In the first study of miR-302 and decreased at day 10 and 14 after miR-302a over expression significantlyits kind, we showcase our defense’s capabilities under several attack scenarios, demonstrating its ability to reduce attack success in a manner that is superior to a range of prior stateful defenses. The results suggest This dissertation, when taken as a whole, offers a fresh perspective on the various methods that ▇▇▇▇▇-302 acts to maintain MSC phenotype by specific repression of osteogenic differentiation. The results also suggest that this may be specifically due to the action considered promising directions for coping with adversarial attacks on ML-based malware detection. 2.3.3 Attack Detection & Stateful Defenses 28 2.4 focus of miR-302a. In contrast the miR-302 family had little or no effects on adipogenic differentiation of MSCs, with the exception of a transient upregulation of FAB4 at a late stage of differentiation due to miR-302 inhibition.this Dissertation & Related Work 29

Non Commercial. You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. If you believe that this document breaches copyright please contact ▇▇▇▇▇▇▇▇▇▇▇@▇▇▇.▇▇.▇▇ providing details, and we will remove access to the work immediately and investigate your claim. Download date: 0401. Oct. 2022 Taking this PhD was a dream which had finally come true. Indeed, it was a challenging experience, that could not have been feasible without continuation help and support. Jun. 2023 Acknowledgements‌ First and foremostof all, I would like to thank ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇ ▇ Hughesmy supervisor, my first supervisor whose understanding and patience from inception of this project was truly appreciated. His guidance, ideas and suggestions supported me throughout this life-changing journey. It was a pleasure to study under his supervision. I would also like to thank ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇, my second supervisor for his great help constant support and adviceencouragement that motivated me to work hard and complete this tough marathon. His critical scientific insight intellectual guidance helped me to find my way through the complex theoretical concepts and social formations and to put my arguments in an orderly way. In every supervision meeting, he gave me beneficial experiences during the confidence that I was a step closer to the finishing line. It is impossible for me to express my feelings of gratitude towards him with a few words here, but I want to say that I am greatly indebted to him for his help. This thesis would have never been completed without the young people of Turkish and Kurdish descent, who took me into their lives, shared their special moments and secrets with me and cooperated with me throughout the research process. I owe you a very special thank you for your invaluable contributions to this studyresearch and for changing my perspective on social phenomena. Special I want to extend my sincere thanks to Professor my PhD colleagues at King’s College, ▇▇▇▇▇▇▇, ▇▇▇▇▇▇, ▇▇▇▇, ▇▇▇▇▇, ▇▇▇▇▇, ▇▇▇▇▇▇▇, ▇▇▇▇▇▇, ▇▇▇▇▇▇, ▇▇▇▇, ▇▇▇▇▇, ▇▇▇▇▇ and many others, the only people in the world who truly understood the challenges, stress and mental pressure that I have gone through throughout these recent years. The academic discussions with you as well as your advice on how to deal with work-related and personal problems will always be appreciated. The parties, coffee breaks, dinners, lunches and weekend activities we had together will remain unforgettable memories all of my life. My mother and sister, who prayed for me and supported me every step of the way, have been a constant source of encouragement. In particular, my mum’s strong character and will-power to cope with obstacles in life has always been inspirational. During difficult times, your example has reminded of me that anything can be achieved with hard work and optimism. There are not enough words to describe how grateful I am to have you in my life. Finally, I would like express my heartfelt thanks to my husband, ▇▇▇▇▇▇, for being with me on my good and bad days and making me believe that I can overcome all the difficulties in life. I would not have coped with the sleepless nights, stressful periods and mood swings throughout the process without his wise suggestions and positive and constructive attitude towards life. I cannot thank you enough for always being there for me. Abstract‌ Focussing on a group of adolescents of Turkish and Kurdish descent in a North London secondary school, this thesis shows the ways in which ethnicities are experienced and indirectly signalled through everyday language behaviour and popular cultural engagements in superdiverse London. Data was collected on the adolescents’ ordinary social interactions in and around the vicinity of their school for about one year (May 2013 - June 2014), using ethnographic participant observation, informal interviews and retrospective interviews with 13 focal participants. Extensive audio- recording of their naturally occurring speech and interactions were made and substantial fieldnotes were written. The thesis draws on ▇▇▇▇▇▇ ▇▇▇▇’▇ (1988, 1996) theorisation of ‘new ethnicities’. It also draws on flexible perspectives relating to youth language practices – ▇▇▇▇▇▇’▇ my postgraduate co(1992, 2003) ‘local multi-ordinator for all his support. I am indebted to many of friends ethnic vernacular’, Rampton’s (1995a) ‘crossing’ and colleagues who generously spent time Blommaert and shared their experiences with me in my laboratory work. In particular, my sincere gratitude goes to ▇▇. ▇▇▇▇▇ ▇▇▇▇▇▇▇ who assisted me in my first year ’ (2011) ‘linguistic repertoires’. This thesis examines how mundane practices and behaviour are linked to the young people’s ethnic affiliations. The research shows that the ethnic attachments of study young Londoners of Turkish and Kurdish descent cannot be studied within the boundaries of the singular and static concept of ‘Turkish Speaking Community’ or with his tremendous knowledge a narrow formulation of ethnicity within London’s superdiversity. It is argued that one way of developing a deep understanding of how ethnicities are implicitly indicated, explicitly expressed and ideas. Alsolived out, many thanks is to ▇▇. ▇▇▇▇▇▇ ▇▇▇▇▇ pay attention to actual language and ▇▇. ▇▇▇▇ Firena Garna for their heartful help and support. I would also like to thank ▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ and all other laboratory staff for their advice. Special thanks to my PhD friend ▇▇▇▇▇ who was always by my side and supported me spiritually. I would also like to thank my beloved parents for their support and encouragement in throughout my life which allowed me to pursue my dreams. I would heartedly like to offer this work to my father’s spirit who passed away recently, who was always encouraging me and was the greatest inspiration in my life. My special appreciation goes to my husband ▇▇▇▇▇ who was always supportive and making this long journey without his unconditional love was unattainable. Most of all I would like to thank my beloved daughter ▇▇▇ who is always my motivation and source of energy. My thanks also go to my brothers for always being by my side and for encouraging me. Mesenchymal stem cells (MSCs) are adult stem cells which are characterised by self- renewal and differentiation capacity into three mesenchymal lineages: osteoblast, chondrocyte and adipocytes. MicroRNAs (miRNAs) are a class of non-coding short RNAs (20-22 nucleotides) which target messenger RNAs to supress protein synthesis and regulate cell function. There is increasing evidence that miRNAs can play key roles popular cultural practices in the regulation of multiple biological processes include stem cell regulationeveryday. Therefore, the aim of this study was to investigate the potential role of miRNAs in the regulation of MSC fate decisions. Firstly, 4 different MSC cell lines were tested for their differentiation capacity following induction with osteogenic, adipogenic, or chondrogenic media. From these results one cell line was selected for use in further studies. The expression of 9 candidate miRNAs which had previously been shown to be associated with regulation of other stem cells were tested during osteogenic or adipogenic induction. To identify novel miRNAs associated with MSC regulation, clonally derived MSCs with osteogenic, adipogenic or bipotent differentiation patterns were tested using ▇▇▇▇▇ array. From the results A close analysis of the array adolescents’ routine speech patterns reveals their ambivalent, dynamic and multi-faceted identifications with a working- class-inflected Londonness, Kurdishness and Turkishness in contemporary North London. Acknowledgements 2 family members of the ▇▇▇▇▇-302 (a and b) were selected for further investigation. MiR-302a and b expression was validated by qRT-PCR in the clonally derived cell lines and in primary MSC cultures. To determine the role of the miR-302 family during MSC differentiation, their functional activity was tested by knock-down and over expression, via transfection of a ▇▇▇▇▇-302 family inhibitor or individual miR-302a and miR-302b mimics into MSCs and the cells were treated with osteogenic, adipogenic or growth medium as control for 14 days. Then lineage specific gene expression was measured by qRT-PCR. Expression patterns of the 9 candidate genes showed no reproducible significant effects during osteoblastic or adipocytic differentiation. ▇▇▇▇▇-302a and b were both down regulated during differentiation of MSCs into both osteogenic and adipogenic lineages. Knock-down of ▇▇▇▇▇-302 family in MSCs caused a significant upregulation of between 2-5 times of RUNX2 expression and between 3-10 times of ALP expression during osteogenic differentiation of MSCs. Overexpression of miR-302b did not have any significant reproducible effects on osteogenic differentiation of MSCs. In contrast, over expression of miR-302a resulted in increased RUNX2 expression by 1.5-2 fold on day 2 and ALP expression by almost 50 fold after day 4. Inhibition or over expression of miR-302 family had no early effects on adipogenesis of MSCs, but at day 14 FAB4 was upregulated nearly 40% in inhibited cells and between 20-30% in miR-302a overexpressed cells. In contrast overexpression of miR-302b downregulated FAB4 by a range of between 10-80% at day 14. ALP enzyme activity rose at day 7 after inhibition of miR-302 and decreased at day 10 and 14 after miR-302a over expression significantly. The results suggest that ▇▇▇▇▇-302 acts to maintain MSC phenotype by specific repression of osteogenic differentiation. The results also suggest that this may be specifically due to the action of miR-302a. In contrast the miR-302 family had little or no effects on adipogenic differentiation of MSCs, with the exception of a transient upregulation of FAB4 at a late stage of differentiation due to miR-302 inhibition.Abstract 3 CHAPTER 1 - INTRODUCTION: THE TURKISH QUESTION 8

Non Commercial. You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. If you believe that this document breaches copyright please contact ▇▇▇▇▇▇▇▇▇▇▇@▇▇▇.▇▇.▇▇ providing details, and we will remove access to the work immediately and investigate your claim. Download date: 0429. Oct. 2022 Taking this PhD was a dream which had finally come true. Indeed, it was a challenging experience, that could not have been feasible without continuation help and support. First and foremost, I would like to thank Jan. 2024 ▇▇▇▇ ▇▇▇▇▇ PhD – Philosophy King's College London 2022 I hereby declare that except where specific reference is made to the work of others, the contents of this dissertation are original and have not been submitted in whole or in part for consideration for any other degree or qualification in this, or any other university. This dissertation is my own work and contains nothing which is the outcome of work done in collaboration with others, except as specified in the text and Acknowledgements. This dissertation contains fewer than 55 000 words. I wish to sincerely thank my supervisors ▇▇▇▇▇ ▇▇▇▇▇▇▇▇ and ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇ Hughesfor always being available, full of understanding, and helping me throughout my first supervisor whose understanding and patience from inception studies. Without them, none of this project was truly appreciatedwould have been possible. His guidanceI want to extend my gratitude to my thesis examiners, ▇▇▇ ▇▇▇▇▇▇▇, and ▇▇▇▇▇ ▇▇▇▇▇▇, for enthusiastically accepting their role and expressing interest in my work. Specials thanks to ▇▇▇▇ ▇▇▇▇▇▇ for supervising me for a period of time, as well as for his invaluable comments on certain parts of the thesis. I am extremely grateful to ▇▇▇▇▇ ▇▇▇▇▇▇▇▇, ▇▇▇▇▇▇ ▇▇▇▇, and ▇▇▇▇ ▇▇▇▇▇▇▇▇▇ for their assistance with my ideas and suggestions supported me throughout this life-changing journey. It was with the whole process of being a pleasure to study under his supervisionPhD student. I would also like thank everyone at the Department of Philosophy at King’s College London for their help, the conversations and good times we had at the Philosophy Bar and elsewhere. In addition, the UKRI London Arts & Humanities Partnership and the Frankopan Fund have provided me with funding during the course of my studies, which I genuinely appreciate and cherish. I am thankful to thank ▇▇. ▇the special people who have motivated and advised me: ▇▇▇▇▇▇ ▇▇▇▇▇▇, my second supervisor for his great help and advice. His critical scientific insight gave me beneficial experiences during this study. Special thanks to Professor ▇▇▇ ▇▇▇▇▇▇▇▇, ▇▇▇▇ ▇▇▇▇▇▇▇, ▇▇▇ ▇▇▇▇▇▇, ▇▇▇▇▇▇▇ ▇▇▇▇▇, ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇ my postgraduate co-ordinator for all his support. I am indebted to many of friends and colleagues who generously spent time and shared their experiences with me in my laboratory work. In particular, my sincere gratitude goes to ▇▇. ▇▇▇▇▇ ▇▇▇▇▇▇▇ who assisted me in my first year of study with his tremendous knowledge and ideas. Also, many thanks to ▇▇. ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇ Firena Garna for their heartful help and support. I would also like to thank ▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ and all other laboratory staff for their advice. Special thanks to my PhD friend , ▇▇▇▇▇ who was always by ▇▇▇▇▇▇▇▇▇▇, and ▇▇▇-▇▇▇▇ ▇▇▇▇. Most of all, I send my side love and supported me spiritually. I would also like to thank my beloved parents for their support and encouragement in throughout my life which allowed me to pursue my dreams. I would heartedly like to offer this work gratitude to my father’s spirit who passed away recentlyparents, who was always encouraging me and was the greatest inspiration in my life. My special appreciation goes to my husband ▇▇▇▇▇▇▇▇ who was always supportive and making this long journey without his unconditional love was unattainable. Most of all I would like to thank my beloved daughter ▇▇▇ who is always my motivation and source of energy. My thanks also go to my brothers for always being by my side and for encouraging me. Mesenchymal stem cells (MSCs) are adult stem cells which are characterised by self- renewal and differentiation capacity into three mesenchymal lineages: osteoblast, chondrocyte and adipocytes. MicroRNAs (miRNAs) are a class of non-coding short RNAs (20-22 nucleotides) which target messenger RNAs to supress protein synthesis and regulate cell function. There is increasing evidence that miRNAs can play key roles in the regulation of multiple biological processes include stem cell regulation. Therefore, the aim of this study was to investigate the potential role of miRNAs in the regulation of MSC fate decisions. Firstly, 4 different MSC cell lines were tested for their differentiation capacity following induction with osteogenic, adipogenic, or chondrogenic media. From these results one cell line was selected for use in further studies. The expression of 9 candidate miRNAs which had previously been shown to be associated with regulation of other stem cells were tested during osteogenic or adipogenic induction. To identify novel miRNAs associated with MSC regulation, clonally derived MSCs with osteogenic, adipogenic or bipotent differentiation patterns were tested using ▇▇▇▇▇ array. From the results of the array 2 family members of the ▇▇▇▇▇-302 (a and b) were selected for further investigation. MiR-302a and b expression was validated , who are always by qRT-PCR my side, in the clonally derived cell lines and in primary MSC cultures. To determine the role every possible way, as an endless source of the miR-302 family during MSC differentiation, their functional activity was tested by knock-down and over expression, via transfection of a ▇▇▇▇▇-302 family inhibitor or individual miR-302a and miR-302b mimics into MSCs and the cells were treated with osteogenic, adipogenic or growth medium as control for 14 days. Then lineage specific gene expression was measured by qRT-PCR. Expression patterns of the 9 candidate genes showed no reproducible significant effects during osteoblastic or adipocytic differentiation. ▇▇▇▇▇-302a and b were both down regulated during differentiation of MSCs into both osteogenic and adipogenic lineages. Knock-down of ▇▇▇▇▇-302 family in MSCs caused a significant upregulation of between 2-5 times of RUNX2 expression and between 3-10 times of ALP expression during osteogenic differentiation of MSCs. Overexpression of miR-302b did not have any significant reproducible effects on osteogenic differentiation of MSCs. In contrast, over expression of miR-302a resulted in increased RUNX2 expression by 1.5-2 fold on day 2 and ALP expression by almost 50 fold after day 4. Inhibition or over expression of miR-302 family had no early effects on adipogenesis of MSCs, but at day 14 FAB4 was upregulated nearly 40% in inhibited cells and between 20-30% in miR-302a overexpressed cells. In contrast overexpression of miR-302b downregulated FAB4 by a range of between 10-80% at day 14. ALP enzyme activity rose at day 7 after inhibition of miR-302 and decreased at day 10 and 14 after miR-302a over expression significantly. The results suggest that ▇▇▇▇▇-302 acts to maintain MSC phenotype by specific repression of osteogenic differentiation. The results also suggest that this may be specifically due to the action of miR-302a. In contrast the miR-302 family had little or no effects on adipogenic differentiation of MSCs, with the exception of a transient upregulation of FAB4 at a late stage of differentiation due to miR-302 inhibitionsupport.

Non Commercial. You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. If you believe that this document breaches copyright please contact ▇▇▇▇▇▇▇▇▇▇▇@▇▇▇.▇▇.▇▇ providing details, and we will remove access to the work immediately and investigate your claim. Download date: 0414. Oct. 2022 Taking Jun. 2023 I hereby declare that except where specific reference is made to the work of others, the contents of this PhD was a dream thesis are original and have not been submitted in whole or in part for consideration for any other degree or qualification in this, or any other university. This thesis is my own work and contains nothing which had finally come true. Indeedis the outcome of work done in collaboration with others, it was a challenging experience, that could not have been feasible without continuation help except as specified in the text and supportAcknowledgements. First and foremost, I would like thank the Almighty Allah for giving me the strength, health, and blessing to thank complete this unforgettable journey of my life. I owe my deepest gratitude to my supervisor and mentor, ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇ ▇ Hughes, my first supervisor whose understanding and patience from inception of this project was truly appreciated. His guidance, ideas and suggestions supported me throughout this life-changing journey. It was a pleasure to study under his supervision. I would also like to thank ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇, my second supervisor for his great help and advice. His critical scientific insight gave me beneficial experiences during this study. Special thanks to Professor ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇ my postgraduate co-ordinator for all his support. I am indebted to many of friends and colleagues who generously spent time and shared their experiences with me in my laboratory work. In particular, my sincere gratitude goes to ▇▇. ▇▇▇▇▇ ▇▇▇▇▇▇▇ who assisted me in my first year of study with ▇, for his tremendous endless support, patience, motivation, and immense knowledge and ideasexperience during my PhD. I am grateful for believing in me and giving me the freedom to pursue diverse yet coherent research directions, making my PhD a joyous and unforgettable journey. AlsoYour "Six Pillars of Success" talks have always inspired me to be a better version of myself. I want to thank my colleagues and friends at CTR; I wish I could name each and every one of you, truly thankful and privileged to have known and worked with many of you. Special thanks to ▇▇. ▇▇▇▇▇▇ ▇▇▇▇▇ for the insightful comments to improve my work and ▇▇. ▇▇▇▇ Firena Garna for their heartful help and support. I would also like to thank ▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ for his time and valuable discussions towards the beginning of my PhD. I want to thank the people at Wireless@VT, Virginia Tech, USA, especially ▇▇▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇, with whom I was privileged to spend four months at his lab to continue the work on my PhD. Thanks to ▇▇▇ and all other laboratory staff for their advice. Special thanks to my PhD friend ▇▇▇▇▇▇▇▇ who was always by for the help and the valuable discussions we have had together. Last but not least, I am indebted to my side lovely parents and supported me spiritually. I would also like to thank my beloved parents whole family for their the encouragement and support and encouragement in they have shown throughout my life which allowed me PhD; this thesis could have never been finished without them. With the limited bandwidth and capacity available in cellular networks caused by the tremendous increase in connected devices and services, resource allocations such as power and spectrum are crucial. Heterogeneous Networks (HetNets) provide an efficient solution to pursue my dreamsleverage spectrum sharing and power allocation. I would heartedly like The main objective of our research is to offer this work introduce Machine Learning (ML), specifically, Reinforcement Learning (RL), as a game-changer in wireless communication, and to my father’s spirit who passed away recently, who was always encouraging me evaluate the challenges of power allocation for cognitive and was the greatest inspiration in my life. My special appreciation goes to my husband ▇▇▇▇▇ who was always supportive and making this long journey without his unconditional love was unattainable. Most of all I would like to thank my beloved daughter ▇▇▇ who is always my motivation and source of energy. My thanks also go to my brothers for always being by my side and for encouraging me. Mesenchymal stem cells (MSCs) are adult stem cells which are characterised by self- renewal and differentiation capacity into three mesenchymal lineages: osteoblast, chondrocyte and adipocytes. MicroRNAs (miRNAs) are a class of non-coding short RNAs cognitive femtocells. Spectrum sharing offers an efficient solution by allowing secondary User Equipment (20SU) access the resources made available by the Primary Base station (PBS). In our models, we consider downlink analysis of two-22 nucleotidestier HetNet consisting of a single macrocell overlaid by multiple femtocells, several Primary UEs (PU) which target messenger RNAs to supress protein synthesis and regulate cell function. There is increasing evidence that miRNAs can play key roles in the regulation of multiple biological processes include stem cell regulation. Therefore, the aim of this study was to investigate the potential role of miRNAs in the regulation of MSC fate decisions. Firstly, 4 different MSC cell lines were tested for their differentiation capacity following induction with osteogenic, adipogenic, or chondrogenic media. From these results one cell line was selected for use in further studiesindoor SU. The expression primary focus consists of 9 candidate miRNAs which had previously been shown two parts. First, we modeled unique power allocation schemes for two-tier femtocell HetNets and evaluated different RL algorithms. We derived two reward functions that guarantee fair capacity for PU and SU to be associated with regulation meet their Quality of other stem cells were tested during osteogenic or adipogenic inductionService (QoS). To identify Our analysis spans stochastic geometry rate coverage analysis of femtocell networks as a measure of network performance. Second, we introduced a novel miRNAs associated with MSC regulationparadigm that enables Beyond visual line of sight (BVLOS) operations of unmanned aerial vehicles (UAVs) under stringent aviation regulations via Distributional RL algorithms. Moreover, clonally we derived MSCs with osteogenic, adipogenic or bipotent differentiation patterns were tested using ▇▇▇▇▇ arraya non-convex optimization problem to minimize the overall round-trip latency between the UAV and the ground controller. From the The analysis and simulation results presented a comprehensive evaluation of the array 2 family members proposed schemes. Finally, we concluded this thesis with an overall evaluation and summary of the ▇▇▇▇▇-302 (a our research, highlighting its importance, effectiveness, and b) were selected for further investigation. MiR-302a and b expression was validated by qRT-PCR in the clonally derived cell lines and in primary MSC cultures. To determine the role of the miR-302 family during MSC differentiation, their functional activity was tested by knock-down and over expression, via transfection of a ▇▇▇▇▇-302 family inhibitor or individual miR-302a and miR-302b mimics into MSCs and the cells were treated with osteogenic, adipogenic or growth medium as control for 14 days. Then lineage specific gene expression was measured by qRT-PCR. Expression patterns of the 9 candidate genes showed no reproducible significant effects during osteoblastic or adipocytic differentiation. ▇▇▇▇▇-302a and b were both down regulated during differentiation of MSCs into both osteogenic and adipogenic lineages. Knock-down of ▇▇▇▇▇-302 family in MSCs caused a significant upregulation of between 2-5 times of RUNX2 expression and between 3-10 times of ALP expression during osteogenic differentiation of MSCs. Overexpression of miR-302b did not have any significant reproducible effects on osteogenic differentiation of MSCspossible improvement suggestions. In contrastaddition, over expression of miR-302a resulted in increased RUNX2 expression by 1.5-2 fold on day 2 and ALP expression by almost 50 fold after day 4. Inhibition or over expression of miR-302 family had no early effects on adipogenesis of MSCs, but at day 14 FAB4 was upregulated nearly 40% in inhibited cells and between 20-30% in miR-302a overexpressed cells. In contrast overexpression of miR-302b downregulated FAB4 by a range of between 10-80% at day 14. ALP enzyme activity rose at day 7 after inhibition of miR-302 and decreased at day 10 and 14 after miR-302a over expression significantly. The results suggest that ▇▇▇▇▇-302 acts to maintain MSC phenotype by specific repression of osteogenic differentiation. The results also suggest that this may be specifically due to the action of miR-302a. In contrast the miR-302 family had little or no effects on adipogenic differentiation of MSCs, with the exception of a transient upregulation of FAB4 at a late stage of differentiation due to miR-302 inhibitionwe briefly discussed some future research directions.

Non Commercial. You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. If you believe that this document breaches copyright please contact ▇▇▇▇▇▇▇▇▇▇▇@▇▇▇.▇▇.▇▇ providing details, and we will remove access to the work immediately and investigate your claim. Download date: 0414. Oct. 2022 Taking this PhD was a dream which had finally come true. Indeed, it was a challenging experience, that could not have been feasible without continuation help and support. First and foremost, Dec. 2020 I would like to thank first express my deepest thanks and gratitude to my dear supervisors Dr ▇▇▇▇ ▇▇▇▇ and ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇▇. I am very grateful for the opportunity to have been under their supervision throughout the past four years. This thesis would not have been possible without their constant guidance, enlightenment, encouragement and inspiration. I am deeply grateful for the financial support from the Ministry of National Education of Turkey, without which I might not have the opportunity to carry out this research study in this prestigious university. Special thanks should be also given to the participants in this research who opened the doors of their classrooms and allowed me to join in their lives for a time. I also want to express my gratitude to Dr ▇▇▇ ▇▇▇▇▇▇▇▇▇ for his supervision at the start of this PhD and for his invaluable support. Thanks also to Professor ▇▇▇▇▇▇ ▇▇▇▇▇▇, ▇▇ ▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇, and Professor ▇▇▇▇▇ ▇▇▇▇▇ for their advice and encouragement in my academic efforts. My sincere thanks belong also to my fellow PhD students at King’s, in particular ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇, ▇▇▇▇▇▇▇ ▇▇▇▇, ▇▇▇▇▇▇ ▇▇▇▇, ▇▇▇▇▇▇▇ ▇▇▇▇, ▇▇▇▇▇ ▇▇▇▇▇▇, ▇▇▇▇▇ ▇▇▇▇, ▇▇▇▇▇ ▇▇▇▇▇▇, ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇▇, ▇▇▇▇ ▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇ ▇ Hughesand the rest of my colleagues for their kindness, encouragement and friendship throughout my first supervisor whose understanding and patience from inception of this project was truly appreciated. His guidance, ideas and suggestions supported me throughout this life-changing research journey. It was a pleasure to study under his supervision. I would also like wish to thank ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇ for giving me helpful suggestions and encouragement during the writing process. Furthermore, I would like to express my second supervisor infinite gratitude to my family and friends for his great help their constant love, support and advice. His critical scientific insight gave me beneficial experiences during this study. Special thanks to Professor ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇ my postgraduate co-ordinator for all his support. I am indebted to many of friends and colleagues who generously spent time and shared their experiences with faith in me in my laboratory work. In particular, my sincere gratitude goes to ▇▇. ▇▇▇▇▇ ▇▇▇▇▇▇▇ who assisted me in my first year all aspects of study with his tremendous knowledge and ideas. Also, many thanks to ▇▇. ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇ Firena Garna for their heartful help and support. I would also like to thank ▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ and all other laboratory staff for their advicelife. Special thanks to my PhD friend ▇parents and siblings for always sending me their love and encouraging and supporting me at every step I have taken during my long absence abroad. Thank you for all being a part of my life. Finally, my warmest gratitude belongs to my wife ▇▇▇▇ who was always by my side for her love, company, encouragement, and supported me spiritually. I would also like for bringing joy and meaning to thank my beloved parents for their support and encouragement in throughout my life which allowed me to pursue my dreams. I would heartedly like to offer this work to my father’s spirit who passed away recently, who was always encouraging me and was the greatest inspiration in my life. My special appreciation goes to All my husband ▇▇▇▇▇ who was always supportive and making this long journey without his unconditional love was unattainable. Most of all I would like to thank my beloved daughter ▇▇▇ who is always my motivation and source of energy. My thanks also go to my brothers for always being by my side and for encouraging me. Mesenchymal stem cells (MSCs) are adult stem cells which are characterised by self- renewal and differentiation capacity into three mesenchymal lineages: osteoblast, chondrocyte and adipocytes. MicroRNAs (miRNAs) are a class of non-coding short RNAs (20-22 nucleotides) which target messenger RNAs to supress protein synthesis and regulate cell function. There is increasing evidence that miRNAs can play key roles in the regulation of multiple biological processes include stem cell regulation. Therefore, the aim of this study was to investigate the potential role of miRNAs in the regulation of MSC fate decisions. Firstly, 4 different MSC cell lines were tested for their differentiation capacity following induction with osteogenic, adipogenic, or chondrogenic media. From these results one cell line was selected for use in further studies. The expression of 9 candidate miRNAs which had previously been shown to be associated with regulation of other stem cells were tested during osteogenic or adipogenic induction. To identify novel miRNAs associated with MSC regulation, clonally derived MSCs with osteogenic, adipogenic or bipotent differentiation patterns were tested using ▇▇▇▇▇ array. From the results of the array 2 family members of the ▇▇▇▇▇-302 (a and b) were selected for further investigation. MiR-302a and b expression was validated by qRT-PCR in the clonally derived cell lines and in primary MSC cultures. To determine the role of the miR-302 family during MSC differentiation, their functional activity was tested by knock-down and over expression, via transfection of a ▇▇▇▇▇-302 family inhibitor or individual miR-302a and miR-302b mimics into MSCs and the cells were treated with osteogenic, adipogenic or growth medium as control for 14 days. Then lineage specific gene expression was measured by qRT-PCR. Expression patterns of the 9 candidate genes showed no reproducible significant effects during osteoblastic or adipocytic differentiation. ▇▇▇▇▇-302a and b were both down regulated during differentiation of MSCs into both osteogenic and adipogenic lineages. Knock-down of ▇▇▇▇▇-302 family in MSCs caused a significant upregulation of between 2-5 times of RUNX2 expression and between 3-10 times of ALP expression during osteogenic differentiation of MSCs. Overexpression of miR-302b did not have any significant reproducible effects on osteogenic differentiation of MSCs. In contrast, over expression of miR-302a resulted in increased RUNX2 expression by 1.5-2 fold on day 2 and ALP expression by almost 50 fold after day 4. Inhibition or over expression of miR-302 family had no early effects on adipogenesis of MSCs, but at day 14 FAB4 was upregulated nearly 40% in inhibited cells and between 20-30% in miR-302a overexpressed cells. In contrast overexpression of miR-302b downregulated FAB4 by a range of between 10-80% at day 14. ALP enzyme activity rose at day 7 after inhibition of miR-302 and decreased at day 10 and 14 after miR-302a over expression significantly. The results suggest that ▇▇▇▇▇-302 acts to maintain MSC phenotype by specific repression of osteogenic differentiation. The results also suggest that this may be specifically due to the action of miR-302a. In contrast the miR-302 family had little or no effects on adipogenic differentiation of MSCs, with the exception of a transient upregulation of FAB4 at a late stage of differentiation due to miR-302 inhibitionyours.

Non Commercial. You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. If you believe that this document breaches copyright please contact ▇▇▇▇▇▇▇▇▇▇▇@▇▇▇.▇▇.▇▇ providing details, and we will remove access to the work immediately and investigate your claim. Download date: 0424. Oct. 2022 Taking this PhD was Jun. 2024 B e n e d e t t a dream which had finally come true. Indeed, it was M o n z a challenging experience, that could not have been feasible without continuation help and support. First and foremost, n i 1 ACKNOWLEDGEMENTS I would like to thank ▇▇▇▇▇▇▇express my sincerest gratitude to the clinical and research supervisors I had the pleasure to learn from and work with during my clinical training. In particular, I owe a special thanks to ▇▇ ▇▇▇▇▇▇▇ ▇ Hughes, my first supervisor whose understanding and patience from inception of this project was truly appreciated. His guidance, ideas and suggestions supported me throughout this life-changing journey. It was a pleasure to study under his supervision. I would also like to thank ▇▇. ▇▇▇▇▇▇▇ ▇▇▇▇▇▇, my second supervisor for his great help and advice. His critical scientific insight gave me beneficial experiences during this study. Special thanks to Professor ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ and ▇▇▇▇▇▇▇▇▇ my postgraduate co-ordinator for all his support. I am indebted to many of friends and colleagues who generously spent time and shared their experiences with me in my laboratory work. In particular, my sincere gratitude goes to ▇▇. ▇▇▇▇▇ ▇▇▇▇▇▇▇ who assisted me in my first year of study with his tremendous -Cols for their admirable approach, advice and assistance, and immense knowledge and ideascommitment to research of the highest standards. Also, many thanks A very big thank you to ▇▇. ▇▇▇ ▇▇▇▇▇-▇▇▇▇▇, ▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇ ▇, and Dr ▇▇. ▇▇▇▇ Firena Garna ▇▇▇▇▇ for their heartful help constant and supportkind support with research as well as throughout clinical training; I very much valued their ability for creating such a fun, stimulating, professional, and collaborative work environment, making it a real pleasure to work with them. I would also like to thank ▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ and ▇▇. ▇▇, Professor ▇▇▇▇▇ ▇▇▇▇▇▇, ▇▇ and all other laboratory staff for their advice. Special thanks to my PhD friend ▇▇▇▇ ▇▇▇▇▇▇ and my cohort; whilst they are likely unaware of this, they have supported me, stimulated, and shaped my approach, thinking, and personal development in various different ways and forms. My heartfelt thanks to the service users I have worked with during my training, and who was always by taught me so much more than I would have from lectures and textbooks; I am very proud and privileged to do this job and indebted to them for inspiring me and for sharing their stories, fears, and hopes. Finally, I would like to acknowledge my side and supported me spirituallyfamily. I would also like consider myself the luckiest in the world to thank my beloved parents for their support and encouragement in throughout my life which allowed me to pursue my dreams. I would heartedly like to offer this work to my father’s spirit who passed away recently, who was always encouraging me and was the greatest inspiration in my lifehave such an amazing family. My special appreciation goes to my husband parents, ▇▇▇▇▇▇ who was always supportive and making this long journey without his unconditional love was unattainable. Most of all I would like to thank my beloved daughter ▇▇▇ who is always my motivation and source of energy. My thanks also go to my brothers for always being by my side and for encouraging me. Mesenchymal stem cells (MSCs) are adult stem cells which are characterised by self- renewal and differentiation capacity into three mesenchymal lineages: osteoblast, chondrocyte and adipocytes. MicroRNAs (miRNAs) are a class of non-coding short RNAs (20-22 nucleotides) which target messenger RNAs to supress protein synthesis and regulate cell function. There is increasing evidence that miRNAs can play key roles in the regulation of multiple biological processes include stem cell regulation. Therefore, the aim of this study was to investigate the potential role of miRNAs in the regulation of MSC fate decisions. Firstly, 4 different MSC cell lines were tested for their differentiation capacity following induction with osteogenic, adipogenic, or chondrogenic media. From these results one cell line was selected for use in further studies. The expression of 9 candidate miRNAs which had previously been shown to be associated with regulation of other stem cells were tested during osteogenic or adipogenic induction. To identify novel miRNAs associated with MSC regulation, clonally derived MSCs with osteogenic, adipogenic or bipotent differentiation patterns were tested using ▇▇▇▇▇ array. From the results of the array 2 family members of the ▇▇▇▇▇-302 (a , receive my deepest gratitude, for their endless love and b) were selected for further investigationnever failing to support me in all my pursuits. MiR-302a and b expression was validated by qRT-PCR in the clonally derived cell lines and in primary MSC cultures. To determine the role of the miR-302 family during MSC differentiation, their functional activity was tested by knock-down and over expression, via transfection of a ▇▇▇▇▇-302 family inhibitor or individual miR-302a and miR-302b mimics into MSCs and the cells were treated with osteogenic, adipogenic or growth medium as control for 14 days. Then lineage specific gene expression was measured by qRT-PCR. Expression patterns of the 9 candidate genes showed no reproducible significant effects during osteoblastic or adipocytic differentiation. ▇▇▇▇▇-302a and b were both down regulated during differentiation of MSCs into both osteogenic and adipogenic lineages. Knock-down of ▇▇▇▇▇-302 family in MSCs caused a significant upregulation of between 2-5 times of RUNX2 expression and between 3-10 times of ALP expression during osteogenic differentiation of MSCs. Overexpression of miR-302b did not have any significant reproducible effects on osteogenic differentiation of MSCs. In contrast, over expression of miR-302a resulted in increased RUNX2 expression by 1.5-2 fold on day 2 and ALP expression by almost 50 fold after day 4. Inhibition or over expression of miR-302 family had no early effects on adipogenesis of MSCs, but at day 14 FAB4 was upregulated nearly 40% in inhibited cells and between 20-30% in miR-302a overexpressed cells. In contrast overexpression of miR-302b downregulated FAB4 by a range of between 10-80% at day 14. ALP enzyme activity rose at day 7 after inhibition of miR-302 and decreased at day 10 and 14 after miR-302a over expression significantly. The results suggest that ▇▇▇▇▇-302 acts to maintain MSC phenotype by specific repression of osteogenic differentiation. The results also suggest that this may be specifically due to the action of miR-302a. In contrast the miR-302 family had little or no effects on adipogenic differentiation of MSCs, with the exception of a transient upregulation of FAB4 at a late stage of differentiation due to miR-302 inhibition.TABLE OF CONTENTS SYSTEMATIC REVIEW 4 MAIN RESEARCH PROJECT 43 SERVICE EVALUATION PROJECT 79