21,026 research outputs found

    2022-1 A Partial Identification Approach to Identifying the Determinants of Human Capital Accumulation: An Application to Teachers

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    This paper views teacher quality through the human capital perspective. Teacher quality exhibits substantial growth over teachers’ careers, but why it improves is not well understood. I use a human capital production function nesting On-the-Job-Training (OJT) and Learning-by-Doing (LBD) and experimental variation from Glewwe et al. (2010), a teacher incentive pay experiment in Kenya, to discern the presence and relative importance of these forces. The identified set for the OJT and LBD components has a closed-form solution, which depends on experimentally estimated average treatment effects. The results provide evidence of an LBD component, as well as an informative upper bound on the OJT component

    Preferentialism and the conditionality of trade agreements. An application of the gravity model

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    Modern economic growth is driven by international trade, and the preferential trade agreement constitutes the primary fit-for-purpose mechanism of choice for establishing, facilitating, and governing its flows. However, too little attention has been afforded to the differences in content and conditionality associated with different trade agreements. This has led to an under-considered mischaracterisation of the design-flow relationship. Similarly, while the relationship between trade facilitation and trade is clear, the way trade facilitation affects other areas of economic activity, with respect to preferential trade agreements, has received considerably less attention. Particularly, in light of an increasingly globalised and interdependent trading system, the interplay between trade facilitation and foreign direct investment is of particular importance. Accordingly, this thesis explores the bilateral trade and investment effects of specific conditionality sets, as established within Preferential Trade Agreements (PTAs). Chapter one utilises recent content condition-indexes for depth, flexibility, and constraints on flexibility, established by Dür et al. (2014) and Baccini et al. (2015), within a gravity framework to estimate the average treatment effect of trade agreement characteristics across bilateral trade relationships in the Association of Southeast Asian Nations (ASEAN) from 1948-2015. This chapter finds that the composition of a given ASEAN trade agreement’s characteristic set has significantly determined the concomitant bilateral trade flows. Conditions determining the classification of a trade agreements depth are positively associated with an increase to bilateral trade; hereby representing the furthered removal of trade barriers and frictions as facilitated by deeper trade agreements. Flexibility conditions, and constraint on flexibility conditions, are also identified as significant determiners for a given trade agreement’s treatment effect of subsequent bilateral trade flows. Given the political nature of their inclusion (i.e., the appropriate address to short term domestic discontent) this influence is negative as regards trade flows. These results highlight the longer implementation and time frame requirements for trade impediments to be removed in a market with higher domestic uncertainty. Chapter two explores the incorporation of non-trade issue (NTI) conditions in PTAs. Such conditions are increasing both at the intensive and extensive margins. There is a concern from developing nations that this growth of NTI inclusions serves as a way for high-income (HI) nations to dictate the trade agenda, such that developing nations are subject to ‘principled protectionism’. There is evidence that NTI provisions are partly driven by protectionist motives but the effect on trade flows remains largely undiscussed. Utilising the Gravity Model for trade, I test Lechner’s (2016) comprehensive NTI dataset for 202 bilateral country pairs across a 32-year timeframe and find that, on average, NTIs are associated with an increase to bilateral trade. Primarily this boost can be associated with the market access that a PTA utilising NTIs facilitates. In addition, these results are aligned theoretically with the discussions on market harmonisation, shared values, and the erosion of artificial production advantages. Instead of inhibiting trade through burdensome cost, NTIs are acting to support a more stable production and trading environment, motivated by enhanced market access. Employing a novel classification to capture the power supremacy associated with shaping NTIs, this chapter highlights that the positive impact of NTIs is largely driven by the relationship between HI nations and middle-to-low-income (MTLI) counterparts. Chapter Three employs the gravity model, theoretically augmented for foreign direct investment (FDI), to estimate the effects of trade facilitation conditions utilising indexes established by Neufeld (2014) and the bilateral FDI data curated by UNCTAD (2014). The resultant dataset covers 104 countries, covering a period of 12 years (2001–2012), containing 23,640 observations. The results highlight the bilateral-FDI enhancing effects of trade facilitation conditions in the ASEAN context, aligning itself with the theoretical branch of FDI-PTA literature that has outlined how the ratification of a trade agreement results in increased and positive economic prospect between partners (Medvedev, 2012) resulting from the interrelation between trade and investment as set within an improving regulatory environment. The results align with the expectation that an enhanced trade facilitation landscape (one in which such formalities, procedures, information, and expectations around trade facilitation are conditioned for) is expected to incentivise and attract FDI

    In vitro investigation of the effect of disulfiram on hypoxia induced NFκB, epithelial to mesenchymal transition and cancer stem cells in glioblastoma cell lines

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    A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.Glioblastoma multiforme (GBM) is one of the most aggressive and lethal cancers with a poor prognosis. Advances in the treatment of GBM are limited due to several resistance mechanisms and limited drug delivery into the central nervous system (CNS) compartment by the blood-brain barrier (BBB) and by actions of the normal brain to counteract tumour-targeting medications. Hypoxia is common in malignant brain tumours such as GBM and plays a significant role in tumour pathobiology. It is widely accepted that hypoxia is a major driver of GBM malignancy. Although it has been confirmed that hypoxia induces GBM stem-like-cells (GSCs), which are highly invasive and resistant to all chemotherapeutic agents, the detailed molecular pathways linking hypoxia, GSC traits and chemoresistance remain obscure. Evidence shows that hypoxia induces cancer stem cell phenotypes via epithelial-to-mesenchymal transition (EMT), promoting therapeutic resistance in most cancers, including GBM. This study demonstrated that spheroid cultured GBM cells consist of a large population of hypoxic cells with CSC and EMT characteristics. GSCs are chemo-resistant and displayed increased levels of HIFs and NFκB activity. Similarly, the hypoxia cultured GBM cells manifested GSC traits, chemoresistance and invasiveness. These results suggest that hypoxia is responsible for GBM stemness, chemoresistance and invasiveness. GBM cells transfected with nuclear factor kappa B-p65 (NFκB-p65) subunit exhibited CSC and EMT markers indicating the essential role of NFκB in maintaining GSC phenotypes. The study also highlighted the significance of NFκB in driving chemoresistance, invasiveness, and the potential role of NFκB as the central regulator of hypoxia-induced stemness in GBM cells. GSC population has the ability of self-renewal, cancer initiation and development of secondary heterogeneous cancer. The very poor prognosis of GBM could largely be attributed to the existence of GSCs, which promote tumour propagation, maintenance, radio- and chemoresistance and local infiltration. In this study, we used Disulfiram (DS), a drug used for more than 65 years in alcoholism clinics, in combination with copper (Cu) to target the NFκB pathway, reverse chemoresistance and block invasion in GSCs. The obtained results showed that DS/Cu is highly cytotoxic to GBM cells and completely eradicated the resistant CSC population at low dose levels in vitro. DS/Cu inhibited the migration and invasion of hypoxia-induced CSC and EMT like GBM cells at low nanomolar concentrations. DS is an FDA approved drug with low toxicity to normal tissues and can pass through the BBB. Further research may lead to the quick translation of DS into cancer clinics and provide new therapeutic options to improve treatment outcomes in GBM patients

    Mutational Profile of Human Papilloma Virus (HPV) Induced and Non-HPV Induced Head and Neck Squamous Cell Carcinoma

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    Head and Neck cancer accounts for approximately 900,000 cases and over 400,000 deaths annually worldwide. The primary risk factors associated with Head and Neck cancer include usage of tobacco, alcohol consumption, Human Papillomavirus (HPV) infection and Epstein-Barr virus (EBV) infection. Few subsites of Head and Neck Squamous Cell Carcinoma (HNSCC) are associated with Human Papilloma Virus (HPV) while others remain non-associated. The anatomical, physiological, genetic, protein profile and epigenetic changes that occur in both HPV-positive and HPV-negative HNSCC has been discussed in this chapter. The mutational profile plays a crucial role in the treatment of the HNSCC patients as the HPV-positive HNSCC patients have a better prognosis compared to the HPV-negative HNSCC patients. This chapter mainly focusses on the mutational profile of both HPV-associated and non-HPV associated HNSCC tumours

    Incentivising research data sharing : a scoping review

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    Background: Numerous mechanisms exist to incentivise researchers to share their data. This scoping review aims to identify and summarise evidence of the efficacy of different interventions to promote open data practices and provide an overview of current research. Methods: This scoping review is based on data identified from Web of Science and LISTA, limited from 2016 to 2021. A total of 1128 papers were screened, with 38 items being included. Items were selected if they focused on designing or evaluating an intervention or presenting an initiative to incentivise sharing. Items comprised a mixture of research papers, opinion pieces and descriptive articles. Results: Seven major themes in the literature were identified: publisher/journal data sharing policies, metrics, software solutions, research data sharing agreements in general, open science ‘badges’, funder mandates, and initiatives. Conclusions: A number of key messages for data sharing include: the need to build on existing cultures and practices, meeting people where they are and tailoring interventions to support them; the importance of publicising and explaining the policy/service widely; the need to have disciplinary data champions to model good practice and drive cultural change; the requirement to resource interventions properly; and the imperative to provide robust technical infrastructure and protocols, such as labelling of data sets, use of DOIs, data standards and use of data repositories

    Embodying entrepreneurship: everyday practices, processes and routines in a technology incubator

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    The growing interest in the processes and practices of entrepreneurship has been dominated by a consideration of temporality. Through a thirty-six-month ethnography of a technology incubator, this thesis contributes to extant understanding by exploring the effect of space. The first paper explores how class structures from the surrounding city have appropriated entrepreneurship within the incubator. The second paper adopts a more explicitly spatial analysis to reveal how the use of space influences a common understanding of entrepreneurship. The final paper looks more closely at the entrepreneurs within the incubator and how they use visual symbols to develop their identity. Taken together, the three papers reject the notion of entrepreneurship as a primarily economic endeavour as articulated through commonly understood language and propose entrepreneuring as an enigmatic attractor that is accessed through the ambiguity of the non-verbal to develop the ‘new’. The thesis therefore contributes to the understanding of entrepreneurship and proposes a distinct role for the non-verbal in that understanding

    RNA pull-down-confocal nanoscanning (RP-CONA), a novel method for studying RNA/protein interactions in cell extracts that detected potential drugs for Parkinson’s disease targeting RNA/HuR complexes

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    MicroRNAs (miRNAs, miRs) are a class of small non-coding RNAs that regulate gene expression through specific base-pair targeting. The functional mature miRNAs usually undergo a two-step cleavage from primary miRNAs (pri-miRs), then precursor miRNAs (pre-miRs). The biogenesis of miRNAs is tightly controlled by different RNA-binding proteins (RBPs). The dysregulation of miRNAs is closely related to a plethora of diseases. Targeting miRNA biogenesis is becoming a promising therapeutic strategy. HuR and MSI2 are both RBPs. MiR-7 is post-transcriptionally inhibited by the HuR/MSI2 complex, through a direct interaction between HuR and the conserved terminal loop (CTL) of pri-miR-7-1. Small molecules dissociating pri-miR-7/HuR interaction may induce miR-7 production. Importantly, the miR-7 levels are negatively correlated with Parkinson’s disease (PD). PD is a common, incurable neurodegenerative disease causing serious motor deficits. A hallmark of PD is the presence of Lewy bodies in the human brain, which are inclusion bodies mainly composed of an aberrantly aggregated protein named α-synuclein (α-syn). Decreasing α-syn levels or preventing α-syn aggregation are under investigation as PD treatments. Notably, α-syn is negatively regulated by several miRNAs, including miR-7, miR-153, miR-133b and others. One hypothesis is that elevating these miRNA levels can inhibit α-syn expression and ameliorate PD pathologies. In this project, we identified miR-7 as the most effective α-syn inhibitor, among the miRNAs that are downregulated in PD, and with α-syn targeting potentials. We also observed potential post-transcriptional inhibition on miR-153 biogenesis in neuroblastoma, which may help to uncover novel therapeutic targets towards PD. To identify miR-7 inducers that benefit PD treatment by repressing α-syn expression, we developed a novel technique RNA Pull-down Confocal Nanoscaning (RP-CONA) to monitor the binding events between pri-miR-7 and HuR. By attaching FITC-pri-miR-7-1-CTL-biotin to streptavidin-coated agarose beads and incubating them in human cultured cell lysates containing overexpressed mCherry-HuR, the bound RNA and protein can be visualised as quantifiable fluorescent rings in corresponding channels in a confocal high-content image system. A pri-miR-7/HuR inhibitor can decrease the relative mCherry/FITC intensity ratio in RP-CONA. With this technique, we performed several small-scale screenings and identified that a bioflavonoid, quercetin can largely dissociate the pri-miR-7/HuR interaction. Further studies proved that quercetin was an effective miR-7 inducer as well as α-syn inhibitor in HeLa cells. To understand the mechanism of quercetin mediated α-syn inhibition, we tested the effects of quercetin treatment with miR-7-1 and HuR knockout HeLa cells. We found that HuR was essential in this pathway, while miR-7 hardly contributed to the α-syn inhibition. HuR can directly bind an AU-rich element (ARE) at the 3’ untranslated region (3’-UTR) of α-syn mRNA and promote translation. We believe quercetin mainly disrupts the ARE/HuR interaction and disables the HuR-induced α-syn expression. In conclusion, we developed and optimised RP-CONA, an on-bead, lysate-based technique detecting RNA/protein interactions, as well as identifying RNA/protein modulators. With RP-CONA, we found quercetin inducing miR-7 biogenesis, and inhibiting α-syn expression. With these beneficial effects, quercetin has great potential to be applied in the clinic of PD treatment. Finally, RP-CONA can be used in many other RNA/protein interactions studies

    An investigation of the relationship between perioperative characteristics and perioperative anaesthesia on the postoperative systemic inflammatory response and clinical outcome in patients undergoing surgery for colorectal cancer

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    In UK, colorectal cancer (CRC) is the fourth most common cancer and the second most common cause of cancer death. Until now, surgical resection remains the cornerstone for the management of CRC in all stages, however, stress response elicit from surgery may cause different changes through multiple systems in human body including neural, endocrine, metabolic, inflammatory, and immunological changes. In addition, other perioperative factors such as volatile anaesthetic and opioids may induce the immunosuppression. There is a proportional correlation between the stress response and the magnitude of the inflammatory immune response, invasiveness, and duration of surgery. The pre-operative and post-operative status of patients are important when considering the prognosis. The systemic inflammatory response (SIR) has been recognised to correlate with tumour progression and the prognosis of CRC. An exaggerated postoperative SIR is associated with postoperative infective complications and poor survival. Several predictive markers of the SIR have been used, such as the neutrophil to lymphocyte ratio (NLR), serum C-reactive protein (CRP) level, and Glasgow prognostic score (GPS). Some evidence reported that general anaesthesia (GA) combined with regional anaesthesia (RA) are better than the single use of general anaesthesia in reducing the post-operative immuno-suppression in some degrees. Furthermore, the peri-operative inflammatory process may be affected by the choice of anaesthetic technique, with propofol reported to have anti-inflammatory effect by targeting neutrophil activity. Up to now, there is insufficient evidence to recommend any specific anaesthetic or analgesic technique for patients undergoing surgery for tumour resection based on inflammatory response, recurrence, and metastasis. The work presented in this thesis further examines the relationship between the perioperative characteristics, perioperative anaesthesia, and the postoperative systemic inflammatory response following surgery for colorectal cancer. Several preoperative medications along with anaesthesia might influence the postoperative systemic inflammatory response but the question is whether the post-operative systemic inflammatory response affected by the administration of different types of anaesthesia or not following surgery for colorectal cancer. Chapter 1 discusses the epidemiology, aetiology, carcinogenesis, risk factors of colorectal cancer, pro-carcinogenic factors, anti-carcinogenic agents, inflammation and cancer, the post-operative systemic inflammatory response, tumour staging, screening, and diagnosis of colorectal cancer. Chapter 2 discusses the treatment of colorectal cancer. Chapter 3 discusses different anaesthetic techniques and agents. Chapter 4 provides summary and aims of the thesis. Chapter 5 represents findings from a systematic review and meta-analysis about the effect of anaesthesia on the postoperative systemic inflammatory response in patients undergoing surgery. The results conclude that there was some evidence that anaesthetic regimens may reduce the magnitude of the post-operative SIR. However, the studies identified in this systematic review were heterogeneous and generally of low quality. Chapter 6 represents a retrospective cohort study about the relationship between anaesthetic technique, clinicopathological characteristics and the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colon cancer. The results show that the type of anaesthesia varied over time and appears to influence the magnitude of the postoperative SIR on post-operative day 2 for those patients who underwent for open surgery but not laparoscopic surgery. Chapter 7 represents a prospective cohort study about the effect of anaesthesia on the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colorectal cancer in the context of an enhanced recovery pathway. The results show that there was a modest but an independent association between regional anaesthesia (RA) and a lower magnitude of the postoperative SIR. Chapter 8 represents the relationship between pre-operative medications, the type of anaesthesia and post-operative sequelae in patients undergoing surgery for colorectal cancer. The results show that there was no association between the preoperative administration of aspirin, statins and ACE inhibitors and anaesthesia. Chapter 9 represents the relationship between nutritional status, anaesthetic approach, and peri-operative characteristics of patients undergoing surgery for colorectal cancer. The results show that there was no significant association between measures of nutritional status and anaesthetic approach. Chapter 10 represents the relationship between opioid administration, type of anaesthesia and clinicopathological characteristics in patients undergoing surgery for colorectal cancer. The results show that opioid administration was independently associated with both anaesthetic and operative factors. Chapter 11 represents the main findings of the thesis and some recommendation for a future work
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