Are there changes in characteristics of UK higher education around the time of the 2006 Reforms (BIS research paper no. 14)

Analysis of Higher Education Statistics Agency (HESA) data, 2002/3 to 2007/8 in response to the research question 'Are there any changes in the Characteristics of UK Higher Education around the time of the 2006 Reforms?' In analysing trends in student characteristics over the period between 2002 and 2007 the researchers identify areas where the 2006 reforms may have had an effect. It should be noted that the tables and charts presented in the report are descriptive

Equitable Representation in the Councils of the United Nations: Theory and Application

We develop a theoretical framework for equity in council voting games (CVGs). In a CVG, a fully representative voting body delegates decision-making to a subset of the members, as describes, e.g., the United Nations Security Council (UNSC). Three equity concepts are proposed: ex-ante (procedural) equity, ex-post (outcome) equity and regional equity. The last two concepts are consistent with a new square-root rule on the probability of council membership, but no CVG can meet all three concepts. We apply our framework to evaluate the equitability of the UNSC, and the claims of those who seek to reform it

Voluntary Disclosure Schemes for Offshore Tax Evasion: An Analysis

In recent years tax authorities worldwide have implemented voluntary disclosure schemes to recover tax on offshore investments. Such Schemes are characterized by the acquisition of non-audit information on offshore holdings, and a subsequent opportunity for affected taxpayers to make a voluntary disclosure. Accepted disclosures are subject to a discounted .ne rate, but verified under-disclosure attracts a higher penalty. We characterize the optimal Scheme and show that an optimal Scheme can generate a Pareto-improvement over the optimal auditing equilibrium without a Scheme, and can stimulate legitimate offshore investment activity. We show when a tax authority optimally gives incentives for truthful disclosure, and when it does not. The analysis yields practical design insights for policymakers

Advanced Lease Caching

Since the dawn of computing, CPU performance has continually grown, buoyed by Moore\u27s Law. Execution speed for parallelizable programs in particular has massively increased with the now widespread employment of GPUs, TPUs, and FPGAs, capable of preforming hundreds of computations simultaneously, for data processing. A major bottleneck for further performance increases, which has impeded speedup of sequential programming in particular, is the processor memory performance gap. One of the approaches to address this block is improving cache management algorithms. Caching is transparent to software, but traditional caching algorithms forgo hardware-software collaboration. Previous work introduced the idea of assigning leases to cache blocks as a form of collaborative cache eviction policy and introduced two lease-caching algorithms, Compiler Lease of cAche Memory (CLAM) and Phased Reference Leasing (PRL), evaluating them over 7 benchmarks from the Polybench benchmark suite. This work evaluates CLAM and PRL over all thirty benchmarks of the Polybench suite for multiple dataset sizes. Additionally, to address the flaws CLAM and PRL, two new lease-caching algorithms have been developed: Scoped Hooked Eviction Lease (SHEL) and Cross-Scope Eviction Lease (C-SHEL). These algorithms are evaluated not just for a single-level cache, typically found in embedded systems, but also for a multi-level cache as exists in more high-performance systems including multi-core CPUs. The test system uses a RISCV architecture to run benchmarks. All four lease caching algorithms outperform the baseline Pseudo Least Recently Used (PLRU) policy at both levels of the cache hierarchy. Further, SHEL and C-SHEL display significant performance increases over PRL for certain benchmarks, demonstrating the value of scoped leasing in addressing complex reuse interval (RI) behavior

Reform of the United Nations Security Council: Equity and Efficiency

Twenty years of negotiations over reform of the United Nations Security Council (UNSC) are yet to bear fruit. We use recent advances in the theory of a-priori voting power to present a formal quantitative appraisal of the structural reforms contained within eleven current reform proposals, and the separate effect of expansion of the UNSC membership. Only two reform proposals - the EU acting as a single entity, or a weakening of the veto power for permanent members - robustly dominate the status quo against our measures of equity and efficiency. Several proposals may actually worsen the issues they ostensibly claim to resolve

Emotional distress may increase risk for self-medication and lower risk for mood-related drinking consequences in adolescents

The current study examines indicators of emotional distress and coping that may define sub-populations of adolescents at risk for two potential affect-related mechanisms underlying substance misuse: self-medication and mood-related drinking consequences. Although theory and empirical evidence point to the salience of affect-related drinking to current and future psychopathology, we have little knowledge of whether or for whom such mood-related processes exist in adolescents because few studies have used methods that optimally match the phenomenon to the level of analysis. Consequently, the current study uses multi-level modeling in which daily reports of negative mood and alcohol use are nested within individuals to examine whether adolescents with more emotional distress and poorer coping skills are more likely to evidence self-medication and moodrelated drinking consequences. Seventy-five adolescents participated in a multi-method, multi-reporter study in which they completed a 21-day experience sampling protocol assessing thrice daily measures of mood and daily measures of alcohol use. Results indicate that adolescents reporting greater anger are more likely to evidence self-medication. Conversely, adolescents displaying lower emotional distress and more active coping are more likely to evidence mood-related drinking consequences. Implications for identifying vulnerable sub-populations of adolescents at risk for these mechanisms of problematic alcohol use are discussed.peer-reviewe

Putative phosphodiesterase inhibitors as potential new chemotherapies against African Trypanosomiasis

African trypanosomiasis is a disease caused by the Kinetoplastida parasites Trypanosoma brucei rhodesiense and T. b. gambiense. The distribution of the disease is split geographically with T. b. rhodesiense found in eastern sub-Saharan Africa and T. b. gambiense in the west of the continent. Current treatment for this fatal disease is wholly unsatisfactory with problems such as extreme toxicity, affordability and the emergence of resistance. The case for the generation of new potential chemotherapies is compelling and urgent. Phosphodiesterase (PDE) enzymes degrade the secondary signalling molecule cyclic adenosine monophosphate (cAMP) to AMP by hydrolysis, thereby modulating and regulating the signal transduction to the effector proteins. The phosphodiesterase enzymes in the PDEB family in T. brucei were shown to be essential to the host-infective bloodstream forms and validated as good drug targets using RNA-interference (Zoraghi, R. and Seebeck, T., 2002; Oberholzer, M., 2007). Prompted by these findings, two series of putative trypanosomal PDE inhibitors, from different sources, were thoroughly assessed in this project for their anti-trypanosomal activity and their intracellular effects on the trypanosome. The whole-cell in vitro efficacy for each compound, against T. brucei wildtype and the drug-resistant strain TbAT1 knockout, was established by the standard resazurin reduction assay. 25 compounds from Series 1 had EC50 values below 0.5 µM, with 7 under 100 nM and the most active having an EC50 value of 5.8 ± 3.4 nM. For the much smaller Series 2 (GJS Compounds), the most active compound was GJS-128 with an EC50 value of 79.4 ± 10.3 nM. This demonstrates that a number of compounds from both series have potent in vitro activity against trypanosomes that is better than or equal to the current chemotherapeutic compound diminazene, and some Series 1 compounds are on a par with pentamidine and melarsoprol. No major cross-resistance was displayed by the TbAT1 knockout strain to either Series 1 or the GJS series. Similarly, a panel of Series 1 compounds tested against the B48 strain (resistant to pentamidine and melaminophenyl arsenical drugs), and also against Trypanosoma equiperdum wildtype and diminazene resistant (PBR) strains, showed no major cross-resistance displayed by the other resistant strains. This suggests that there would also be little or no cross-resistance from refractory strains in the field, and also that the compounds are active against multiple Trypanosoma species. A small panel of Series 1 compounds were also tested for efficacy against trypanosomes in infected mice. 4 daily doses of 20 mg/kg bodyweight of Compound 48 significantly reduced parasitaemia by approximately 60% compared to untreated controls, however higher concentrations were not tolerated by the mice so a cure could not be demonstrated. A high-throughput method for monitoring the speed of action of test compounds on trypanosomes in real time was developed, based on the fluorescence of propidium iodide when bound with DNA. Optimisation of the protocol to 96-well plates and low cell densities provided higher resolution and accurate traces of the lysis of trypanosomes in a cell suspension compared to previously used methods, as well as a greatly increased capacity. The propidium iodide assay could also be converted to provide end-point EC50 values that were directly comparable to those established by the standard resazurin reduction assay. The majority of Series 1 compounds did not increase the intracellular concentration of cAMP on incubation with bloodstream form trypanosomes; those that did only induced a minor elevation of the intracellular concentration of the signalling molecule. Since genetic disruption to phosphodiesterase enzymes resulted in large increases in cAMP levels (Oberholzer, M. et al, 2007; Zoraghi, R. and Seebeck, T., 2002), the lack of increase in cAMP by the Series 1 compounds strongly suggest that they do not sufficiently inhibit the PDEs in live trypanosomes and kill the cells via an alternative pathway. In contrast, incubation with the GJS compounds did result in significant increases in intracellular cAMP concentration with the most active being GJS-128 recording an approximately 3-fold increase in cAMP over 3 hours at just 30 nM. The concentrations that begin to increase cAMP level are consistent with the EC50 values for trypanosomes cultured in vitro (this study), and is also in line with inhibition data of recombinant TbrPDEB enzymes (work conducted by Dr. Herrmann Tenor, ALTANA Pharma, and Prof. Thomas Seebeck, University of Bern). This gives a clear and consistent link between the cause of cAMP rise (inhibition of PDEB by GJS compounds) and the effect of that concentration increase on bloodstream form trypanosomes (cell death), demonstrating that the GJS series are inhibitors of trypanosomal PDEs and chemically validate PDEs as drug targets for potential new chemotherapies against African trypanosomiasis. The effect of PDE inhibition on the physiology of the bloodstream form trypanosomes was also investigated. Flow cytometry analysis and the assessment of DNA configuration by fluorescence microscopy after DAPI staining determined that PDE inhibition by GJS-128 resulted in a precise block of the cell cycle in cytokinesis. The replicating trypanosome synthesized and segregated its DNA into two nuclei and kinetoplasts as normal and proceeded to initiate the physical separation of mother and daughter cells. The cleavage furrow between the old and new flagella progressed normally until the point of abscission, at which point division was halted with only a small section of plasma membrane connecting the two almost separated cells. Both cells appeared viable and underwent subsequent rounds of DNA replication, segregation and attempted physical separation that was always blocked near completion. This indicates cAMP signalling plays an important role in the correct physical separation of the replicating bloodstream form trypanosomes. A trypanosome cell line resistant to GJS-128 was developed by chemical mutagenesis and continuous culture with gradually increasing, but sub-lethal concentrations of the PDE inhibitor. This cell line, termed R0.8, was >15-fold less sensitive to GJS-128 and displayed significant cross-resistance to the other GJS compounds, as well as to stable, membrane permeable cAMP analogues. The mode of resistance was investigated by comparing the cAMP profile of the R0.8 and parental wildtype strains on incubation with GJS-128. No major differences were observed suggesting that both the adenylyl cyclase and phosphodiesterase activities remained unchanged in the PDE inhibitor-resistant strain. In support of this, the sequencing of TbrPDEB1 and TbrPDEB2 in both strains, while uncovering the loss of heterozygosity in the R0.8 line, revealed no mutations that would impact on enzyme function or inhibitor binding in the resistant cell line. These data strongly suggest that the adaptation resulting in resistance to PDE inhibitors is located in the effector proteins downstream of the PDEs and adenylyl cyclases in the cAMP signalling pathway. Identifying a compound that inhibits phosphodiesterases in trypanosomes and elevates cAMP concentrations, along with the generation of a PDE inhibitor-resistant cell line will allow more detailed examination of all aspects of the cAMP signalling pathway in T. brucei and across the Kinetoplastida. Phosphodiesterases have also been demonstrated to be chemically inhibitable in trypanosomes and could prove to be the target of a new generation of chemotherapies against African trypanosomiasis

Military identities, conventional capability and the politics of NATO standardisation at the beginning of the Second Cold War, 1970-1980

This paper uses equipment standardisation as a lens for examining power relationships and the importance of military identity in framing the development of NATO conventional capability. In the face of the Warsaw Pact's overwhelming military capacity the logic of standardisation was compelling. Standardising equipment and making military forces interoperable reduced logistics overlap, increased the tempo of operations and allowed partners to optimise manufacturing capacity. Applied carefully, standardisation would help NATO mount a successful conventional defence of Western Europe, a crucial aspect of the Alliance's flexible response strategy. In this paper we apply Actor Network Theory to standardisation discussions thereby revealing the incoherence and volatility of NATO's collective strategic thinking and the vast networks of countervailing interests on which this is based