Search

Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the

The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo CTP production relies on CTP synthetases 1 and 2 (CTPS1 and 2) that catalyze the conversion of UTP into CTP. CTP synthetase activity is high in proliferating cells including cancer cells, however, the respective roles of CTPS1 and CTPS2 in cell proliferation are not known. By inactivation of CTPS1 and/or CTPS2 and complementation experiments, we showed that both CTPS1 and CTPS2 are differentially required for cell proliferation. CTPS1 was more efficient in promoting proliferation than CTPS2, in association with a higher intrinsic enzymatic activity that was more resistant to inhibition by 3-Deaza-uridine, an UTP analog. The contribution of CTPS2 to cell proliferation was modest when CTPS1 was expressed, but essential in absence of CTPS1. Public databases analysis of more than 1,000 inactivated cancer cell lines for CTPS1 or CTPS2 confirmed that cell growth is highly dependent of CTPS1 but less of CTPS2. Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation.

PurposeThe purpose of this paper is to explore the aims, objectives and approach to change adopted by the e3i CETL for Employability at Sheffield Hallam University and illustrates the impact of change via three thematic case studies and an organising framework for understanding the locus of change with respect to work‐related learning: module curriculum and pedagogy (micro level), Faculty and Departmental strategies and operations, course design, structure and delivery (meso level), and institutional policies and processes (the macro level). These experiences are distilled to formulate recommendations for a modus operandi for those interested or involved with transforming higher education institutions (HEIs) to create a greater emphasis on and enhanced opportunities for students to engage with work‐related learning.DesignA case studies approach is utilised to illustrate the work of the CETL in practice and generate insights.FindingsFindings suggest that HEIs can successfully embrace the WRL agenda and make a significant contribution to achieving its aims and objectives. Central to this success is encouraging institutions to absorb WRL into their mission in an overt manner, providing guidance, support, encouragement, inspiration, resources and reward to colleagues involved in creating and facilitating WRL, and adopting a modus operandi with regards to change that resonates with institutional academic culture.Practical implicationsThe paper suggests an approach to strategic and transformative change in HEIs that will be of interest to change agents across the sector.Originality/valueThe paper adds insights to the expanding literature on managing large‐scale change initiatives in HEIs.

Carbonate sands undergo degradation when transported hydraulically from a dredging vessel to the reclamation site. Risks involved in the production of fines during hydraulic transport are a deterioration of the mechanical properties of the fill in certain areas of the reclamation area where these fines concentrate. In order to assess sand degradation in the concrete and road construction industry, the Micro-Deval test for fine aggregates was developed in France and Canada. During Micro-Deval testing, aggregates degrade when tumbled in a rotating steel drum with water and steel balls. In the Canadian standard, the steel charge is lower than in the French standard and balls have the diameter of the smallest balls used in the French test. During testing, the quantity of fines produced is measured. This makes the Micro-Deval test an option for assessing the degradation of sand during hydraulic transportation of slurries in the dredging industry. Three sands are tested: two shelly carbonate sands and one quartzic river sand for comparison. The carbonate sands were sampled on reclaimed land and had been subjected to hydraulic transportation in pipeline before artificial deposition. Due to differences in particle shape, the carbonate sands and the quartz sand have a different number of contacts with the steel charge in the drum of the Micro-Deval and are not exposed to the same degradation forces during testing. It was found that the quartzic sand suffers relatively much degradation as compared to the carbonate sands, despite its greater hardness and resistance to crushability. The French test appears to create turbulence that promotes floatation of the curved shells of the carbonate sands instead of shell grinding at the bottom of the drum by contact with the steel balls. Microscopic observations of sand samples before and after testing showed that the French Micro-Deval test is too destructive. The test leads to the fragmentation by impact of the quartz sands and the destruction of certain particle types that had survived hydraulic transportation. With respect to the Canadian test, microscopic examination of sand grains before and after testing shows there is still much fragmentation of quartz grains. A lower rotational speed combined with a limited steel charge made of uniform balls of a smaller diameter, reduces turbulence, shell floatability and last but not the least, impact forces. It produces the desired result: a high Micro-Deval loss for the carbonate sands in comparison to that for the quartz sands and a very limited fragmentation of the quartz grains. Once the slurry reaches its destination, the grain size distribution of the fines fraction will influence the mechanical behaviour of mixed sands. A procedure is proposed to measure the particle size distribution of the fines fraction produced during Micro-Deval testing. Field validation is needed to validate preliminary laboratory results.

A novel series of small molecule C5a antagonists is reported. In particular, in vitro metabolic studies and solution based combinatorial synthesis are demonstrated as useful tools for the rapid identification of antagonists with low in vitro clearance. Members of this series specifically inhibited the binding of (125)I-labeled C5a to human recombinant C5a receptor (C5aR). In functional cell assays these compounds displayed surmountable antagonism against C5a and did not demonstrate any detectable agonist activity.

The development of corporate leadership skills is seen as a crucial ingredient of management education programmes in higher education. Moreover, with the increasing globalisation of business activity, the education of those who will ultimately occupy positions of authority within organisations must take into account cross-cultural differences in the interpretation and conceptualisation of leadership. A key task for educators in this respect is to design and deliver programmes that facilitate an understanding and enhanced competence in the exercise of relevant skills that are sensitive to the complexity of the notion of leadership in a cross-cultural environment. The manner in which such objectives have been pursued on the full-time MSc in International Business and Management course, jointly run by Sheffield Business School, United Kingdom, and the International Business School at Groningen in the Netherlands, is the theme of this article. Working within an action research paradigm, the tutor responsible for the International Management Competencies module has sought, through three cycles, to plan and hone an approach designed to help students develop a cross-cultural perspective on corporate leadership. The nature of the challenge is analysed – specifically the generic nature of the treatment of leadership skills in much of the literature and the difficulties students face in relating what they learn to their own experiences. The three cycles are described. Consideration is also given to the lessons learnt both in terms of the treatment of leadership as a concept and as an international management competence and of further potential refinements in the learning and teaching process.

This article will review and evaluate the response of academics working in higher education institutions (HEIs) in the UK to the experience of teaching quality review. It will do so by gathering the viewpoints and opinions of academics from a particular source over a specific time period: the Times Higher Education Supplement (THES) between January and August of 2001. Before presenting and then evaluating these viewpoints, the paper will discuss the development of teaching quality assessment methodologies in UK HE within the context of the increasing importance and embededness of quality assurance and enhancement values and processes within the practices of HEIs. It is argued that this is both a recent and contested phenomenon. The article finds that the concerns of academics with the teaching quality review exercise fall under a number of headings: (1) administrative/cost burden; (2) grade inflation/gamesmanship/ organisational learning; (3) elitist bias within the system; (4) system impact of quality re...

The increasing globalization of business means that those responsible for educating tomorrow's managers must give priority to the development of “cross-cultural capability,” comprising an ...

Immunization with dendritic cells (DCs) transfected with genes encoding tumor-associated antigens (TAAs) is a highly promising approach to cancer immunotherapy. We have developed a system, using complexes of plasmid DNA expression constructs with the cationic peptide CL22, that transfects human monocyte-derived DCs much more efficiently than alternative nonviral agents. After CL22 transfection, DCs expressing antigens stimulated autologous T cells in vitro and elicited primary immune responses in syngeneic mice, in an antigen-specific manner. Injection of CL22-transfected DCs expressing a TAA, but not DCs pulsed with a TAA-derived peptide, protected mice from lethal challenge with tumor cells in an aggressive model of melanoma. The CL22 system is a fast and efficient alternative to viral vectors for engineering DCs for use in immunotherapy and research.

Draws on relevant academic literature to explore the nature of cross‐cultural capability and goes on to consider its implications for the student experience in British undergraduate business education. Some of the key issues concerning the design of mechanisms and strategies for integrating cross‐cultural capability within the curriculum are highlighted and discussed with a view to informing what needs to be done to prepare undergraduates for the international business world of tomorrow

As part of their attempt to embed their teaching more firmly in the ‘real world’ of business, some university tutors have incorporated ‘commissioned’ or ‘live’ projects into their learning and teaching strategies. These projects enable students to make a direct contribution to their business clients while simultaneously fulfilling key educational objectives. Drawing on their experience of the use of commissioned projects on an MSc in International Business (MSclB) course, the authors analyse in detail both the potential benefits and the problems that arise in implementing such schemes. In this paper, they outline some of the key features of the MSclB course, focusing on the commissioned project component; indicate the reasons for using commissioned projects from the point of view of both tutors and students; describe and evaluate the methodology used to generate data for informing the identification and discussion of issues; and explore a number of key factors for tutors and students in the use of commissioned projects. The paper thus raises awareness of the nature of commissioned projects as a pedagogic tool and of what needs to be done if their contribution to the enhancement of students' understanding of the business world is to be maximized.

Examines the nature of commissioned projects in business education and the value they hold for key stakeholder groups: students, tutors and clients. Identifies the essence of commissioned projects as being a unique fusion of vocational and pedagogic (problem‐based learning) perspectives. Describes the structure of commissioned projects and argues that this is a necessary but not sufficient condition for their success. Argues that the key to their successful utilisation is the establishment of effective foundations. Identifies these as a strategy for curriculum support; a commitment to the integration of skills and knowledge; a negotiated approach to the specification of learning outcomes; a recognition of the importance of process issues; the development of a framework for applying learning; and an emphasis on the concept of reflective practice.

The neutrophil enzyme myeloperoxidase (MPO) promotes oxidative stress in numerous inflammatory pathologies by producing hypohalous acids. Its inadvertent activity is a prime target for pharmacological control. Previously, salicylhydroxamic acid was reported to be a weak reversible inhibitor of MPO. We aimed to identify related hydroxamates that are good inhibitors of the enzyme. We report on three hydroxamates as the first potent reversible inhibitors of MPO. The chlorination activity of purified MPO was inhibited by 50% by a 5 nm concentration of a trifluoromethyl-substituted aromatic hydroxamate, HX1. The hydroxamates were specific for MPO in neutrophils and more potent toward MPO compared with a broad range of redox enzymes and alternative targets. Surface plasmon resonance measurements showed that the strength of binding of hydroxamates to MPO correlated with the degree of enzyme inhibition. The crystal structure of MPO-HX1 revealed that the inhibitor was bound within the active site cavity above the heme and blocked the substrate channel. HX1 was a mixed-type inhibitor of the halogenation activity of MPO with respect to both hydrogen peroxide and halide. Spectral analyses demonstrated that hydroxamates can act variably as substrates for MPO and convert the enzyme to a nitrosyl ferrous intermediate. This property was unrelated to their ability to inhibit MPO. We propose that aromatic hydroxamates bind tightly to the active site of MPO and prevent it from producing hypohalous acids. This mode of reversible inhibition has potential for blocking the activity of MPO and limiting oxidative stress during inflammation.

Although BTEC has considerably refined its approach to the development and embedding of common skills (core skills) within its Higher National Programmes in recent years, argues that there are still a number of problems associated with the practical operation of this strategy and obstacles to a deeper acceptance of the common skills pedagogy within a higher education context remain. From a survey of students who completed a Higher National Diploma at Sheffield Business School in 1993 the crucial issues in this respect were seen to be the complexity of the common skills strategy, difficulties in the area of assessment, the value placed on subject knowledge by students, the lack of an acceptance of a common skills profile when applying for jobs, interviews, and further study, the fact that students thought some skills to be more important than others, and the fact that the development of skills was not undertaken with sufficient reference to probable future contexts where they could be utilized.

The role of work-based learning (WBL) in the development of student employability skills is well researched. Although universities have responded positively to both the opportunities and challenges of WBL, there is still a sense that demand outstrips supply for WBL opportunities in higher education. Many institutions, therefore, are offering work-related learning (WRL) as a substitute for WBL. An interesting question is to what extent WRL can generate similar learning outcomes to WBL, given the role of WBL in bridging the gap between higher education and the workplace and providing real world authentic learning experiences. This chapter will review an approach to WRL within the “Venture Matrix” (VM) at Sheffield Hallam University in the UK, and compare and contrast student learning outcomes with those identified in the WBL literature. The chapter will reflect upon the common approaches to WRL in business education, the nature of knowledge and skills development in these approaches, and the extent to which WRL can be used as a substitute for WBL.

This chapter argues that one of the key criticisms of contemporary business education relates to its approach to knowledge construction, and the prioritising and privileging of disciplinary-based propositional knowledge in the core curriculum. It is suggested that, in general, business education has been slow to respond to the changing conditions and nature of knowledge creation outside of the academy, and it is posited that a recognition of this “new knowledge” is crucial when developing the skills and attributes identified as being important in the workplace. It is further argued that, although project and work-based learning opportunities should be expanded within the higher education (HE) curriculum as a way of making learning more relevant to the business world, of equal importance is how this knowledge is fused with disciplinary-based propositional knowledge within the majority of modules or educational experiences a student is exposed to. By way of illustration, the findings of a small scale research project examining student learning from a “live” company project will be examined. It is concluded that by incorporating authentic learning approaches more extensively within the curriculum, which expose students to or enable them to develop aspects of the “new knowledge”, and then leveraging these broadly across the curriculum, business educators can forge a knowledge synthesis and support skills development that will go some way to bridging the expectations gap between universities and business.

We describe the discovery of small molecule benzazepine derivatives as agonists of human peroxisome proliferator-activated receptor δ (PPARδ) that displayed excellent selectivity over the PPARα and PPARγ subtypes. Compound 8 displayed good PK in the rat and efficacy in upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) mRNA in human primary myotubes, a biomarker for increased fatty acid oxidation.

The polymerase chain reaction was used to screen human peripheral blood mononuclear cells (PBMC) and Jurkat cells for the presence of GABAA receptor subunit mRNAs. Positive signals were detected for the alpha1, alpha3, beta2, beta3, delta and epsilon subunit mRNAs in both cell populations, with the Jurkat cells giving a positive signal for some additional species. Real-time PCR was used to confirm that PBMC, lymphocytes and monocytes contained significant levels of the alpha1 subunit mRNA and that PBMC and lymphocytes contained low levels of beta2 mRNA. The alpha1 subunit was detected in PBMC and fractionated T-cell populations, as well as Jurkat and HL-60 cell lines, by Western blotting and immunofluorescence using a specific antibody. The application of 1mM GABA reduced the specific increase in intracellular PBMC Ca2+ levels produced by addition of 1 nM fMLP: this effect was mimicked by muscimol, but not glycine, and was blocked by bicuculline. The inhibitory effect of GABA was limited to a subset of PBMC. We conclude that cells within the human PBMC population, including lymphocytes, express functional GABAA receptors and these receptors may modulate immune responses.

This paper is part of an overall programme to investigate how to distill the massive amounts of technical information that are generated in the analysis of any upstream petroleum asset into suitable formats for use in "complete" decision tree analyses of the design, management and value of that asset. A complete decision tree analyses future flexibility in response to all dynamic uncertain variables, including prices, throughout the life cycle of the asset. The first part of the paper explains how and why we have set up this programme. The second part of the paper begins an examination of a particular issue where we need to distill technical detail for use in a complete decision tree. The upstream petroleum asset life cycle is usually divided into discrete phases. However, the actual situation is more fluid. For example, information arrives, and can be collected, throughout the life of the asset. In this sense, appraisal never stops, and, in principle, development and production activities should be tuned to take into account the value of the information that can be collected as a result of these activities. We begin to explore this by examining, in an integrated fashion, the appraisal and development phases of the asset life cycle, using a model of an offshore oil-field development lease as an example. We presume that drilling and facilities construction are the only two activities during this part of the life cycle. Drilling can give information about the asset ("appraisal drilling") or provide production capability ("production drilling") or both. Investment in production facilities begins at sanction, which can occur in any year until the end of the lease. In our initial exploration of this issue, we have found situations where an asset manager can add value by considering the option to have mixed appraisal and production drilling programmes before and after sanction.