Algorithms and architectures for the multirate additive synthesis of musical tones

In classical Additive Synthesis (AS), the output signal is the sum of a large number of independently controllable sinusoidal partials. The advantages of AS for music synthesis are well known as is the high computational cost. This thesis is concerned with the computational optimisation of AS by multirate DSP techniques. In note-based music synthesis, the expected bounds of the frequency trajectory of each partial in a finite lifecycle tone determine critical time-invariant partial-specific sample rates which are lower than the conventional rate (in excess of 40kHz) resulting in computational savings. Scheduling and interpolation (to suppress quantisation noise) for many sample rates is required, leading to the concept of Multirate Additive Synthesis (MAS) where these overheads are minimised by synthesis filterbanks which quantise the set of available sample rates. Alternative AS optimisations are also appraised. It is shown that a hierarchical interpretation of the QMF filterbank preserves AS generality and permits efficient context-specific adaptation of computation to required note dynamics. Practical QMF implementation and the modifications necessary for MAS are discussed. QMF transition widths can be logically excluded from the MAS paradigm, at a cost. Therefore a novel filterbank is evaluated where transition widths are physically excluded. Benchmarking of a hypothetical orchestral synthesis application provides a tentative quantitative analysis of the performance improvement of MAS over AS. The mapping of MAS into VLSI is opened by a review of sine computation techniques. Then the functional specification and high-level design of a conceptual MAS Coprocessor (MASC) is developed which functions with high autonomy in a loosely-coupled master- slave configuration with a Host CPU which executes filterbanks in software. Standard hardware optimisation techniques are used, such as pipelining, based upon the principle of an application-specific memory hierarchy which maximises MASC throughput

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Global variability in leaf respiration in relation to climate, plant functional types and leaf traits

• Leaf dark respiration (Rdark) is an important yet poorly quantified component of the global carbon cycle. Given this, we analyzed a new global database of Rdark and associated leaf traits. • Data for 899 species were compiled from 100 sites (from the Arctic to the tropics). Several woody and nonwoody plant functional types (PFTs) were represented. Mixed-effects models were used to disentangle sources of variation in Rdark. • Area-based Rdark at the prevailing average daily growth temperature (T) of each site increased only twofold from the Arctic to the tropics, despite a 20°C increase in growing T (8–28°C). By contrast, Rdark at a standard T (25°C, Rdark25) was threefold higher in the Arctic than in the tropics, and twofold higher at arid than at mesic sites. Species and PFTs at cold sites exhibited higher Rdark25 at a given photosynthetic capacity (Vcmax25) or leaf nitrogen concentration ([N]) than species at warmer sites. Rdark25 values at any given Vcmax25 or [N] were higher in herbs than in woody plants. • The results highlight variation in Rdark among species and across global gradients in T and aridity. In addition to their ecological significance, the results provide a framework for improving representation of Rdark in terrestrial biosphere models (TBMs) and associated land-surface components of Earth system models (ESMs)

Transcriptional analysis of quiescent and proliferating CD34+human hemopoietic cells from normal and chronic myeloid leukemia sources

Quiescent and dividing hemopoietic stem cells (HSC) display marked differences in their ability to move between the peripheral circulation and the bone marrow. Specifically, long-term engraftment potential predominantly resides in the quiescent HSC subfraction, and G-CSF mobilization results in the preferential accumulation of quiescent HSC in the periphery. In contrast, stem cells from chronic myeloid leukemia (CML) patients display a constitutive presence in the circulation. To understand the molecular basis for this, we have used microarray technology to analyze the transcriptional differences between dividing and quiescent, normal, and CML-derived CD34+ cells. Our data show a remarkable transcriptional similarity between normal and CML dividing cells, suggesting that the effects of BCR-ABL on the CD34+ cell transcriptome are more limited than previously thought. In addition, we show that quiescent CML cells are more similar to their dividing counterparts than quiescent normal cells are to theirs. We also show these transcriptional differences to be reflected in the altered proliferative activity of normal and CML CD34+ cells. Of the most interest is that the major class of genes that is more abundant in the quiescent cells compared with the dividing cells encodes members of the chemokine family. We propose a role for chemokines expressed by quiescent HSC in the orchestration of CD34+ cell mobilization

Learning and Change in 20th-Century British Economic Policy

Despite considerable interest in the means by which policy learning occurs, and in how it is that the framework of policy may be subject to radical change, the “black box” of economic policy making remains surprisingly murky. This article utilizes Peter Hall’s concept of “social learning” to develop a more sophisticated model of policy learning; one in which paradigm failure does not necessarily lead to wholesale paradigm replacement, and in which an administrative battle of ideas may be just as important a determinant of paradigm change as a political struggle. It then applies this model in a survey of U.K. economic policy making since the 1930s: examining the shift to “Keynesianism” during the 1930s and 1940s; the substantial revision of this framework in the 1960s; the collapse of the“Keynesian-plus” framework in the 1970s; and the major revisions to the new “neoliberal” policy framework in the 1980s and 1990s