This thesis examines how individuals signal their social status by sharing sustainable dining experiences on social media, focusing on tourists. By integrating impression management theories and status signalling, this thesis examines how sustainable dining is perceived and portrayed as prestigious and desirable on Instagram. Analysing user-generated content shows that social media posts from sustainable restaurants serve as status symbols, with users carefully curating their online identities to reflect environmental awareness and boost their social reputation. Despite the increasing importance of sustainability, the articles are primarily concerned with self-promotion and food quality, while little attention is paid to ethical aspects. This superficial commitment suggests that sustainable food is often more about status symbols than genuine ethical commitment. The results show that the tourism industry can capitalise on the prestige of sustainable cuisine to promote broader environmental awareness. However, it is crucial to critically examine the motivations behind individuals' sustainable behaviours to comprehend the evenness between representative and intrinsic values. Future studies should conduct longitudinal and cross-cultural analyses to investigate these challenging dynamics further.

No / Carbon monoxide (CO) is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins, it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, NO and cGMP levels, as well as regulate MAPK signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+-sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

No / Purpose- Promoting a safe workplace for everyone is a key tenet of Sustainable Development Goal 8 (SDG-8), which focuses on promoting inclusive and sustainable economic growth, employment, and decent work for all. Therefore, this study explores how responsible leadership ensures a psychologically safe workplace for everyone, leveraging employee-oriented human resource management. Specifically, drawing on signalling theory, this study aims to examine the impact of responsible leadership on employee-oriented HRM and the subsequent effect of employee-oriented HRM on employees' psychological safety. Furthermore, it investigates the mediating role of employee-oriented HRM in the relationship between responsible leadership and psychological safety. Design/methodology/approach- Data was collected from banking professionals through a survey questionnaire. A total of 270 samples were collected using both online and face-to-face data collection strategies. The data was analysed using the Partial Least Squares Structural Equation Modelling (PLS-SEM) approach. Findings- The findings reveal that responsible leadership significantly ensures employee-oriented HRM, which subsequently enhances employees' psychological safety. Further, the results suggest that employee-oriented HRM acts as a mediator between responsible leadership and psychological safety. Originality/value- Past studies have often emphasized HRM practices as antecedents of various attitudes and behaviours. The present study offers a novel contribution by conceptualizing and empirically validating employee-oriented HRM as a mechanism that links responsible leadership and psychological safety. It stands as the first of its kind to establish this significant relationship, shedding new light on the dynamics between responsible leadership, HRM practices, and employees' sense of psychological safety.

No / Bone morphogenetic proteins (BMPs) play essential roles in the control of skin development, postnatal tissue remodelling and tumorigenesis. To explore whether some of the effects of BMP signalling are mediated by microRNAs, we performed genome-wide microRNA (miRNA) screening in primary mouse keratinocytes after BMP4 treatment. Microarray analysis revealed substantial BMP4-dependent changes in the expression of distinct miRNAs, including miR-21. Real-time PCR confirmed that BMP4 dramatically inhibits miR-21 expression in the keratinocytes. Consistently, significantly increased levels of miR-21 were observed in transgenic mice overexpressing the BMP antagonist noggin under control of the K14 promoter (K14-noggin). By in situ hybridization, miR-21 expression was observed in the epidermis and hair follicle epithelium in normal mouse skin. In K14-noggin skin, miR-21 was prominently expressed in the epidermis, as well as in the peripheral portion of trichofolliculoma-like hair follicle-derived tumours that contain proliferating and poorly differentiated cells. By transfecting keratinocytes with a miR-21 mimic, we identified the existence of two groups of the BMP target genes, which are differentially regulated by miR-21. These included selected BMP-dependent tumour-suppressor genes (Pten, Pdcd4, Timp3 and Tpm1) negatively regulated by miR-21, as well as miR-21-independent Id1, Id2, Id3 and Msx2 that predominantly mediate the effects of BMPs on cell differentiation. In primary keratinocytes and HaCaT cells, miR-21 prevented the inhibitory effects of BMP4 on cell proliferation and migration. Thus, our study establishes a novel mechanism for the regulation of BMP-induced effects in the skin and suggests miRNAs are important modulators of the effects of growth factor signalling pathways on skin development and tumorigenesis.

Yes / Wnt signalling and its downstream effectors are well known for their roles in embryogenesis and tumourigenesis, including the regulation of cell proliferation, survival and differentiation. In the nervous system, Wnt signalling has been described mainly during embryonic development, although accumulating evidence suggests that it also plays a major role in adult brain morphogenesis and function. Studies have predominantly concentrated on memory formation in the hippocampus, although recent data indicate that Wnt signalling is also critical for neuroendocrine control of the developed hypothalamus, a brain centre that is key in energy balance regulation and whose dysfunction is implicated in metabolic disorders such as type 2 diabetes and obesity. Based on scattered findings that report the presence of Wnt molecules in the tanycytes and ependymal cells lining the third ventricle and arcuate nucleus neurones of the hypothalamus, their potential importance in key regions of food intake and body weight regulation has been investigated in recent studies. The present review brings together current knowledge on Wnt signalling in the hypothalamus of adult animals and discusses the evidence suggesting a key role for members of the Wnt signalling family in glucose and energy balance regulation in the hypothalamus in diet-induced and genetically obese (leptin deficient) mice. Aspects of Wnt signalling in seasonal (photoperiod sensitive) rodents are also highlighted, given the recent evidence indicating that the Wnt pathway in the hypothalamus is not only regulated by diet and leptin, but also by photoperiod in seasonal animals, which is connected to natural adaptive changes in food intake and body weight. Thus, Wnt signalling appears to be critical as a modulator for normal functioning of the physiological state in the healthy adult brain, and is also crucial for normal glucose and energy homeostasis where its dysregulation can lead to a range of metabolic disorders.

Yes / The antidiuretic hormone arginine vasopressin (AVP) regulates water homeostasis, blood pressure and a range of stress responses. It is synthesized in the hypothalamus and released from the posterior pituitary into the general circulation upon a range of stimuli. While the mechanisms leading to AVP secretion have been widely investigated, the molecular mechanisms regulating AVP gene expression are mostly unclear. Here we investigated the neurotransmitters and signal transduction pathways that activate AVP gene expression in the paraventricular nucleus (PVN) of the rat using acute brain slices and quantitative real-time PCR. We show that stimulation with l-glutamate robustly induced AVP gene expression in acute hypothalamic brain slices containing the PVN. More specifically, we show that AVP transcription was stimulated by NMDA. Using pharmacological treatments, our data further reveal that the activation of ERK1/2 (PD184352), CaMKII (KN-62) and PI3K (LY294002; 740 Y-P) is involved in the NMDA-induced AVP gene expression in the PVN. Together, this study identifies NMDA-mediated cell signalling pathways that regulate AVP gene expression in the rat PVN. / Supported by a generous donation from Jonathan Feuer.

Yes / The Cdc42- and Rac-interactive binding motif (CRIB) of coronin binds to Rho GTPases with a preference for GDP-loaded Rac. Mutation of the Cdc42- and Rac-interactive binding motif abrogates Rac binding. This results in increased 1evels of activated Rac in coronin-deficient Dictyostelium cells (corA−), which impacts myosin II assembly. corA− cells show increased accumulation of myosin II in the cortex of growth-phase cells. Myosin II assembly is regulated by myosin heavy chain kinase–mediated phosphorylation of its tail. Kinase activity depends on the activation state of the p21-activated kinase a. The myosin II defect of corA− mutant is alleviated by dominant-negative p21-activated kinase a. It is rescued by wild-type coronin, whereas coronin carrying a mutated Cdc42- and Rac-interactive binding motif failed to rescue the myosin defect in corA− mutant cells. Ectopically expressed myosin heavy chain kinases affinity purified from corA− cells show reduced kinase activity. We propose that coronin through its affinity for GDP–Rac regulates the availability of GTP–Rac for activation of downstream effectors. / This work was supported by Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich 670 (SFB 670) and Köln Fortune (to A.A.N.). A.M.-T. acknowledges support by the SFB 914, and J.F. acknowledges support by Grant FA330/6-1 within the framework of the DFG priority programme “Principles and Evolution of Actin Nucleator Complexes” (SPP1464). Work in F.R. lab is supported by grants from the Hull York Medical School.

Two-pore channels (TPCs, gene name Tpcn) have recently been identified as endolysosomal cation channels modulated by the potent calcium (Ca2+) releasing messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Gene knockout (KO) and RNA knockdown studies have implicated TPCs in fundamental cellular processes, including secretion, of insulin in pancreatic islets, and differentiation, of skeletal myoblasts and osteoclasts. Investigations of Tpcn1 and Tpcn2 mRNA expression have indicated widespread tissue distribution, but a lack of suitable antibodies has impeded study of the endogenous proteins. In this study, an anti-TPC1 antibody was purified from immune sera and used in immunoblotting investigations to demonstrate TPC1 protein expression in a wide range of mouse tissues, with highest expression levels observed in kidney, liver and adipose tissue. Endogenous mouse TPC1 was demonstrated to be glycosylated, with apparent differences in the extent of glycosylation in different tissues based on the indicated molecular weight before and after treatment with a deglycosylating enzyme, which may have implications for the functional regulation of channel activity. Given the increasing prevalence of type 2 diabetes and obesity, an understanding of the molecular basis of glucose homeostasis and adipose tissue formation and function is an important scientific goal. Tpcn KO mice have been developed; in both Tpcn1 KOs and Tpcn2 KOs, impaired pancreatic β-cell Ca2+ signalling and reduced insulin secretion from the whole pancreas were demonstrated. However, the whole-animal phenotype has not been extensively researched. In this study, intraperitoneal glucose tolerance tests were conducted in Tpcn KO mice. These indicated that glucose homeostasis was not significantly affected in Tpcn2 KOs or Tpcn1/2 double KOs (DKOs), and only mildly impaired in Tpcn1 KOs, despite the defects previously observed at the cellular and tissue level. In addition, body composition was investigated in Tpcn1 KO, Tpcn2 KO and Tpcn1/2 DKO animals using magnetic resonance spectroscopy and time domain-nuclear magnetic resonance. Single Tpcn KOs were found to have lower adipose tissue levels as a percentage of body composition, while Tpcn1/2 DKOs were shown to have increased bodyweight but normal body composition. To investigate potential roles for TPCs in adipose tissue formation, Tpcn expression during adipogenesis was investigated using an in vitro multipotent mesenchymal stem cell line model of adipogenic differentiation. Tpcn2 mRNA levels were demonstrated by quantitative PCR to be transiently increased during the early stages of adipogenic differentiation, and cyclic AMP (cAMP) was identified as the factor that induced this upregulation. Lentiviruses were developed to express fluorescently-tagged TPCs, and overexpression of TPC2 was demonstrated to partially overcome the requirement for the cAMP-inducing agent in the medium used for the induction of adipogenesis. Collectively, these data suggest that TPCs may play a role in the formation and/or function of adipose tissue.

This study consists of two pieces of work investigating haematological malignancies; Acute Lymphoblastic Leukaemia (ALL) and Diffuse Large B Cell Lymphoma (DLBCL). Firstly, Pre-B ALL represents the most common paediatric malignancy and despite increasingly improved outcomes for patients, ~ 20% of all patients diagnosed with ALL relapse. Activating mutations in the RAS pathway are common (~50%) and result in hyperactivation of the MAPK pathway. I identified Erk negative feedback control via DUSP6 to be crucial for NRASG12D-mediated pre-B cell transformation and investigated its potential as a therapeutic target. I showed that a small molecule inhibitor of DUSP6 (BCI) selectively induced cell death in patient-derived pre-B ALL cells; with a higher sensitivity observed in relapse pre-B ALL. I also discovered that a high level of Erk activity is required for proliferation of normal pre-B cells, but dispensable in leukemic pre-B ALL cells. In addition, I found that human B cell malignancies can be grouped into three categories that fundamentally differ in their ability to control Erk signalling strength. Secondly, DLBCL is the most common haematological malignancy and although potentially curable with chemotherapy, 40% of patients still succumb from their disease. Recent exome sequencing studies have identified hundreds of genetic alterations but, for most, their contribution to disease, or their importance as therapeutic targets, remains uncertain. I optimised a novel approach to screen the functional importance of these mutations. This was achieved by reconstituting non-malignant, primary, human germinal centre B cells (GC B cells) with combinations of wildtype and mutant genes to recapitulate the genetic events of DLBCL. When injected into immunodeficient mice, these oncogene-transduced GC B cells gave rise to tumours that closely resemble human DLBCL, reinforcing the biological relevance of this system. To screen potential tumour suppressor mutations in this system in a high throughput fashion, I developed a lymphoma-focused CRISPR library of 692 genes recurrently altered in B cell lymphomas. These experiments identified GNA13 as an unexpectedly potent tumour suppressor in human GC B cells and provided new understanding to its mechanism of action. These findings provide novel understanding of the complexity of oncogenic mechanisms in human B cell malignancies.

Ovarian Cancer is the 5th most common cause of cancer death in women and the second most common gynaecological cancer in the UK. Worldwide, around 152,000 women were estimated to have died from ovarian cancer in 2012. Survival rates for women with epithelial ovarian cancer have not significantly changed since platinum-based treatment was introduced over 30 years ago. This is particularly disconcerting considering the fact that there is a less than 5% five year survival rate for patients diagnosed with late stage high grade serous ovarian cancer. This thesis examines the role of BMP signalling in ovarian cancer using in vitro cancer cell models. It builds upon the initial published work by the Inman lab identifying autocrine BMP9 as a promoter of ovarian cancer cell proliferation. The findings of Chapters 3-5 provide strong evidence indicating BMP9 as a context specific modulator of ovarian cancer cell proliferation. This significantly builds upon on the sole pro-proliferative BMP9 growth response previously described. Responding cell lines were subjected to a microarray with and without BMP9 treatment In order to determine early BMP target genes which were subsequently transiently knocked down in order to determine their role in the aetiology of said growth phenotype. ID1 gene expression was found to significantly contribute to the BMP9 proproliferative phenotype. Moreover several other BMP genes identified significantly alter basal cell proliferation. It was subsequently determined that BMP9 implemented a cell growth phenotype by negating apoptosis. .Excitingly, preliminary evidence suggests a marked reduction in detectable levels of a recently described Bax isoform, Bax β that coincide with BMP9 addition and the resultant anti-apoptotic phenotype observed. This is very interesting as no prior evidence correlating the BMP family and Bax β currently exists. These findings provide an enhanced understanding of BMP9s contribution to ovarian cancer pathogenesis that may result in the development of effective and targeted therapeutic interventions upon further stratification of the contextuality of the BMP induced growth response.