Mansfield University

It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.

An efficient and intuitive algorithm is presented for the design of vector quantizers based either on a known probabilistic model or on a long training sequence of data. The basic properties of the algorithm are discussed and demonstrated by examples. Quite general distortion measures and long blocklengths are allowed, as exemplified by the design of parameter vector quantizers of ten-dimensional vectors arising in Linear Predictive Coded (LPC) speech compression with a complicated distortion measure arising in LPC analysis that does not depend only on the error vector.

ABSTRACT Modelling strategies for predicting the potential impacts of climate change on the natural distribution of species have often focused on the characterization of a species’ bioclimate envelope. A number of recent critiques have questioned the validity of this approach by pointing to the many factors other than climate that play an important part in determining species distributions and the dynamics of distribution changes. Such factors include biotic interactions, evolutionary change and dispersal ability. This paper reviews and evaluates criticisms of bioclimate envelope models and discusses the implications of these criticisms for the different modelling strategies employed. It is proposed that, although the complexity of the natural system presents fundamental limits to predictive modelling, the bioclimate envelope approach can provide a useful first approximation as to the potentially dramatic impact of climate change on biodiversity. However, it is stressed that the spatial scale at which these models are applied is of fundamental importance, and that model results should not be interpreted without due consideration of the limitations involved. A hierarchical modelling framework is proposed through which some of these limitations can be addressed within a broader, scale‐dependent context.

Layered double hydroxides (LDHs) are a class of ionic lamellar compounds made up of positively charged brucite-like layers with an interlayer region containing charge compensating anions and solvation molecules. Delamination of LDHs is an interesting route for producing positively charged thin platelets with a thickness of a few atomic layers, which can be used as nanocomposites for polymers or as building units for making new designed organic-inorganic or inorganic-inorganic nanomaterials. The synthesis of nanosized LDH platelets can be generally classified into two approaches, bottom-up and top-down. It requires modification of the LDH interlamellar environment and then selection of an appropriate solvent system. In DDS intercalated LDHs, the aliphatic tails of the DDS- anions exhibit a high degree of interdigitation in order to maximize guest-guest dispersive interactions. Bellezza reported that the LDH colloids can also been obtained by employing a reverse microemulsion approach.

The objective of the U.K. Prospective Diabetes Study is to determine whether improved blood glucose control in type II diabetes will prevent the complications of diabetes and whether any specific therapy is advantageous or disadvantageous. The study will report in 1998, when the median duration from randomization will be 11 years. This report is on the efficacy of therapy over 6 years of follow-up and the overall incidence of diabetic complications. Subjects comprised 4,209 newly diagnosed type II diabetic patients who after 3 months' diet were asymptomatic and had fasting plasma glucose (FPG) 6.0–15.0 mmol/l. The study consists of a randomized controlled trial with two main comparisons: 1) 3,867 patients with 1,138 allocated to conventional therapy, primarily with diet, and 2,729 allocated to intensive therapy with additional sulfonylurea or insulin, which increase insulin supply, aiming for FPG <6 mmol/l; and 2) 753 obese patients with 411 allocated to conventional therapy and 342 allocated to intensive therapy with metformin, which enhances insulin sensitivity. In the first comparison, in 2,287 subjects studied for 6 years, intensive therapy with sulfonylurea and insulin similarly improved glucose control compared with conventional therapy, with median FPG at 1 year of 6.8 and 8.2 mmol/l, respectively (P < 0.0001). and median HbA1c of 6.1 and 6.8%, respectively (P < 0.0001). During the next 5 years, the FPG increased progressively on all therapies (P < 0.0001) with medians at 6 years in the conventional and intensive groups, FPG 9.5 and 7.8 mmol/l, and HbA1c 8.0 and 7.1%, respectively. The glycemic deterioration was associated with progressive loss of β-cell function. In the second comparison, in 548 obese subjects studied for 6 years, metformin improved glucose control similarly to intensive therapy with sulfonylurea or insulin. Metformin did not increase body weight or increase the incidence of hypoglycemia to the same extent as therapy with sulfonylurea or insulin. A high incidence of clinical complications occurred by 6-year follow-up. Of all subjects, 18.0% had suffered one or more diabetes-related clinical endpoints, with 12.1% having a macrovascular and 5.7% a microvascular endpoint. Sulfonylurea, metformin, and insulin therapies were similarly effective in improving glucose control compared with a policy of diet therapy. The study is examining whether the continued improved glucose control, obtained by intensive therapy compared with conventional therapy (median over 6 years HbA1c 6.6% compared with 7.4%), will be clinically advantageous in maintaining health.

Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.

Bandwidth-efficient data transmission over telephone and radio channels is made possible by the use of adaptive equalization to compensate for the time dispersion introduced by the channel Spurred by practical applications, a steady research effort over the last two decades has produced a rich body of literature in adaptive equalization and the related more general fields of reception of digital signals, adaptive filtering, and system identification. This tutorial paper gives an overview of the current state of the art in adaptive equalization. In the first part of the paper, the problem of intersymbol interference (ISI) and the basic concept of transversal equalizers are introduced followed by a simplified description of some practical adaptive equalizer structures and their properties. Related applications of adaptive filters and implementation approaches are discussed. Linear and nonlinear receiver structures, their steady-state performance and sensitivity to timing phase are presented in some depth in the next part. It is shown that a fractionally spaced equalizer can serve as the optimum receive filter for any receiver. Decision-feedback equalization, decision-aided ISI cancellation, and adaptive filtering for maximum-likelihood sequence estimation are presented in a common framework. The next two parts of the paper are devoted to a discussion of the convergence and steady-state properties of least mean-square (LMS) adaptation algorithms, including digital precision considerations, and three classes of rapidly converging adaptive equalization algorithms: namely, orthogonalized LMS, periodic or cyclic, and recursive least squares algorithms. An attempt is made throughout the paper to describe important principles and results in a heuristic manner, without formal proofs, using simple mathematical notation where possible.

This paper revisits the concept of refugee labelling I elaborated nearly two decades ago. In radically different conditions, the contemporary relevance and utility of the concept are re-examined and re-established. Formulated at a time of regionally contained, mass refugee migration in the south during the late 1970s and early 1980s, the paper argues that the concept still offers vital insights into the impacts of institutional and bureaucratic power on the lives of refugees in a globalized era of transnational social transformations, mixed migration flows, and the continuing presence of large scale refugee migration. The core of the paper argues that the ‘convenient images’ of refugees, labelled within a co-opting humanitarian discourse in the past, have been displaced by a fractioning of the label which is driven by the need to manage globalized processes and patterns of migration and forced migration in particular. The paper re-evaluates the concept using the three original axioms—forming, transforming and politicizing the label ‘refugee’. The core argument is that in the contemporary era: a) the formation of the refugee label reflects causes and patterns of forced migration which are much more complex than in the past, contrasting with an essentially homogeneous connotation in the past; b) responding to this complexity, the refugee label is transformed by an institutional ‘fractioning’ in order to manage the new migration; c) governments, rather than NGOs as in the past, are the pre-eminent agency in the contemporary processes of transforming the refugee label, a process driven by northern interests; d) the refugee label has become politicized by the reproduction of institutional fractioning and by embedding the wider political discourse of resistance to migrants and refugees.

Abstract Although concepts of space and time are socially constructed, they operate with the full force of objective fact and play a key role in processes of social reproduction. Conceptions of space and time are inevitably, therefore, contested as part and parcel of processes of social change, no matter whether that change is superimposed from without (as in imperialist domination) or generated from within (as in the conflict between environmentalist and economic standards of decision making). A study of the historical geography of concepts of space and time suggests that the roots of the social construction of these concepts lie in the mode of production and its characteristic social relations. In particular, the revolutionary qualities of a capitalistic mode of production, marked by strong currents of technological change and rapid economic growth and development, have been associated with powerful revolutions in the social conceptions of space and time. The implications of these revolutions, implying as they do the “annihilation of space by time'’and the general speed-up and acceleration of turnover time of capital, are traced in the fields of culture and politics, aesthetic theory and, finally, brought home within the discipline of geography as both a problem and a stimulus for rethinking the role of the geographical imagination in contemporary social life.

The crystallographically determined bond length, valence angle, and torsion angle information in the Cambridge Structural Database (CSD) has many uses. However, accessing it by means of conventional substructure searching requires nontrivial user intervention. In consequence, these valuable data have been underutilized and have not been directly accessible to client applications. The situation has been remedied by development of a new program (Mogul) for automated retrieval of molecular geometry data from the CSD. The program uses a system of keys to encode the chemical environments of fragments (bonds, valence angles, and acyclic torsions) from CSD structures. Fragments with identical keys are deemed to be chemically identical and are grouped together, and the distribution of the appropriate geometrical parameter (bond length, valence angle, or torsion angle) is computed and stored. Use of a search tree indexed on key values, together with a novel similarity calculation, then enables the distribution matching any given query fragment (or the distributions most closely matching, if an adequate exact match is unavailable) to be found easily and with no user intervention. Validation experiments indicate that, with rare exceptions, search results afford precise and unbiased estimates of molecular geometrical preferences. Such estimates may be used, for example, to validate the geometries of libraries of modeled molecules or of newly determined crystal structures or to assist structure solution from low-resolution (e.g. powder diffraction) X-ray data.

Vision Science: Photons to Phenomenology Steven E. Palmer. Cambridge, MA: The MIT Press, 1999. Pages: 810. Price: $70.00. ISBN 0-262-16183-4 This book is an extremely well written, and eminently readable, soup-to-nuts textbook on how we see. The text is enhanced by liberal use of illustrations that are among the best I have seen in any textbook on vision. The material in this book is drawn from a wide range of disciplines in vision science—philosophy, psychology, computer science, linguistics, and the neurosciences—and the resulting treatment of visual perception and cognition is remarkably broad in scope. Because of the author’s excellent exposition, the book functions well as an introductory text, although some of the material that he covers is quite sophisticated.FIGUREFigurePalmer’s goal is the examination of vision from three different theoretical perspectives: inferential (advocated by the 19th-century physicist and physiologist Herman von Helmholtz), ecological (advocated by the 20th-century psychologist James J. Gibson), and computational (advocated by the 20th-century physiologist and computer scientist David Marr). Although Palmer promises to be even-handed in his assessment of these perspectives, he seems to have stacked the deck slightly in favor of the inferential perspective. According to the inferential perspective, visual scene analysis is an underconstrained problem: there is not enough information in the visual data received through the eyes for perception to occur. For example, the spectral composition of the light reaching the eye from an apple depends only partly on the spectral reflectance of the apple’s surface. It also depends greatly on the illuminant, which may vary considerably even under natural conditions. Therefore, the observer needs more information if the apple is to continue to look “red” under most natural illuminants, a phenomenon known as “color constancy.” Helmholtz argued that this additional information is obtained by logical “unconscious inference,” based upon our knowledge of the properties of apples acquired from prior experience. Almost everyone who studies vision would agree that perception of the visual world cannot proceed without some underlying assumptions. However, there is currently much debate regarding the form of these assumptions and the level(s) at which they operate within the visual process of scene analysis. Adherents to the ecological view argue that the sensory data already contain much of this additional information. This information is in the form of invariant properties in the spatiotemporal patterns of stimulation that occur as the observer interacts with his environment. According to Gibson, these invariant properties can be detected directly, without the recourse to high level rule-based operations. Much of the present work on computational vision is explicitly directed toward identifying and understanding how the human visual system extracts these invariants from sensory data and exploits them in the perceptual process. Palmer clearly acknowledges this point. However, the sophisticated reader may feel that although knowledge and inferential processes undoubtedly play important roles in visual cognition, Palmer is sometimes too quick to invoke rule-based processes to explain the occurrence of certain visual phenomena, when lower-level computational strategies may work equally well or even better. The book is divided into three sections. In the first section, Foundations, Palmer defines the domain of visual perception and lays the groundwork for the discussions of theory and empirical findings that form the backbone of the book. In the concluding chapter of the Foundations section, Palmer uses color vision as the exemplar for his interdisciplinary treatment of visual perception. The second section of the book, Spatial Vision, concerns seeing things in the world based on processes that recover the image-, surface-, object-, and category-based properties of those things. This section focuses on many of the fundamental issues in classical visual space and form perception. These include image segmentation, surface reconstruction, depth perception, the perception of form and two- and three-dimensional shape, and the spatial visual constancies. A weakness in this section of the book is that it all but ignores much of the modern computational literature on three-dimensional shape and the factors that influence its perception. The influential theoretical work in this area by Jan Koenderink and Andrea van Doorn is mentioned but not developed in any depth. The final section, Visual Dynamics, is concerned with motion perception, eye movements and attention, interactions between vision and memory, and visual awareness. The treatment of many topics is delightfully interdisciplinary. For example, like most other textbook authors, Palmer begins his treatment of color vision with a discussion of traditional psychophysical and neurobiological topics: trichromacy, color-opponency, color and lightness contrast effects, hue and lightness constancy, and so forth. But, unlike most authors, Palmer then plunges into an extensive discussion of the work of Berlin & Kay and Rosch in color categorization, the Sapir-Whorf hypotheses of linguistic relativity, and determinism, and even, later in the book, an engaging discussion of that old philosophical chestnut, the “reversed spectrum” problem. I thoroughly enjoyed this aspect of the book. Vision Science: Photons to Phenomenology is a huge book, in both size (over 760 very large pages) and scope. The highly motivated student will be rewarded for his/her efforts in reading this volume with an extraordinarily broad introduction to vision science. However, there are two “down sides” to Palmer’s approach to writing this book. First, to reach a broad audience, he included almost no mathematics. This severely limits the impact of much of the modern formal work in computational vision. Second, because he wrote about visual perception on so broad a scale, Palmer had to limit his development of any given topic. Sophisticated readers are likely to find his treatments of some individual topics to be too incomplete or imprecise to be satisfying. Nonetheless, Palmer has written a remarkable book, and it will certainly have an important impact on the new generation of vision scientists.

For more than 100 years, the fruit fly Drosophila melanogaster has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula Drosophilae , that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type–related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the Drosophila community and serves as a reference to study genetic perturbations and disease models at single-cell resolution.

Simulation work is reported indicating that packet reservation multiple access (PRMA) allows a variety of information sources to share the same wireless access channel. Some of the sources, such as speech terminals, are classified as periodic and others, such as signaling, are classified as random. Packets from all sources contend for access to channel time slots. When a periodic information terminal succeeds in gaining access, it reserves subsequent time slots for uncontested transmission. Both computer simulations and a listening test reveal that PRMA achieves a promising combination of voice quality and bandwidth efficiency.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

The authors study the performance of four different approaches for providing the queuing necessary to smooth fluctuations in packet arrivals to a high-performance packet switch. They are (1) input queuing, where a separate buffer is provided at each input to the switch; (2) input smoothing, where a frame of b packets is stored at each of the input line to the switch and simultaneously launched into a switch fabric of size Nb*Nb; (3) output queuing, where packets are queued in a separate first-in first-out (FIFO) buffer located at each output of the switch; and (4) completely shared buffering, where all queuing is done at the outputs and all buffers are completely shared among all the output lines. Input queues saturate at an offered load that depends on the service policy and the number of inputs N, but is approximately 0.586 with FIFO buffers when N is large. Output queuing and completely shared buffering both achieve the optimal throughput-delay performance for any packet switch. However, compared to output queuing, completely shared buffering requires less buffer memory at the expense of an increase in switch fabric size.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Several researchers conducted studies to demonstrate metal catalyzed alkene and alkyne hydrocylation. A team of researchers developed a method for the synthesis of cyclooctenones using the intramolecular hydrogenation. Eight-membered ring formation was achieved by the incorporation of a cyclopropane ring in the substrate to demonstrate metal catalyzed alkene and alkyne hydrocylation. The key step of the method involved the fragmentation and isomerization of rhodacycle 25 into ring-expanded rhodacycle 26. The researchers investigated the reactions of the two isomers of a deuterium-labeled substrate to explore the mechanism in operation. Another team of researchers prepared a series of medium-ring sulfur heterocycles using intramolecular hydroacylation to demonstrate the investigations.

The requirements for high level expression of three foreign proteins using the polyhedrin gene promoter of Autographa californica nuclear polyhedrosis virus (AcNPV, Baculoviridae) have been investigated. In Spodoptera frugiperda cells infected with the appropriate recombinant baculoviruses, the synthesis of the two S RNA coded genes of lymphocytic choriomeningitis virus (LCMV; i.e. the nucleoprotein, N, and glycoprotein precursor, GPC), or the haemagglutinin gene of influenza A virus, appears to be related to the degree of integrity of the 5' upstream sequence of the polyhedrin gene. No effect on the level of N protein expression was detected when all the polyhedrin gene coding sequences or some of the immediate 3' downstream sequences were deleted. Using the most efficient expression viruses derived from a new transfer vector, pAcYM1, it has been estimated that LCMV N protein represented approximately 50% of the total cellular protein, an observation consistent with the presence of numerous inclusion bodies in the cytoplasm of infected cells. For recombinant viruses derived from the pAcYM1 transfer vector containing the LCMV GPC gene, the level of synthesis of the arenavirus glycoprotein was equivalent to approximately 20% of the cellular protein. Thin sections of cells infected with the GPC recombinant revealed a highly vacuolated cytoplasm.

A reduced-state sequence estimator for linear intersymbol interference channels is described. The estimator uses a conventional Viterbi algorithm with decision feedback to search a reduced-state subset trellis that is constructed using set-partitioning principles. The complexity of maximum-likelihood sequence estimation (MLSE) due to the length of the channel memory and the size of the signal set is systematically reduced. An error probability analysis shows that a good performance/complexity tradeoff can be obtained. In particular, the results indicate that the required complexity to achieve the performance of MLSE is independent of the size of the signal set for large enough signal sets. Simulation results are provided for two partial-response systems. A simple technique for quadrature partial-response signaling (QPRS) is described that eliminates the quasicatastrophic nature of the ML trellis.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Shannon's determination of the capacity of the linear Gaussian channel has posed a magnificent challenge to succeeding generations of researchers. This paper surveys how this challenge has been met during the past half century. Orthogonal minimum-bandwidth modulation techniques and channel capacity are discussed. Binary coding techniques for low-signal-to-noise ratio (SNR) channels and nonbinary coding techniques for high-SNR channels are reviewed. Recent developments, which now allow capacity to be approached on any linear Gaussian channel, are surveyed. These new capacity-approaching techniques include turbo coding and decoding, multilevel coding, and combined coding/precoding for intersymbol-interference channels.

The sixth blind test of organic crystal structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, a polymorphic former drug candidate, a chloride salt hydrate, a co-crystal and a bulky flexible molecule. This blind test has seen substantial growth in the number of participants, with the broad range of prediction methods giving a unique insight into the state of the art in the field. Significant progress has been seen in treating flexible molecules, usage of hierarchical approaches to ranking structures, the application of density-functional approximations, and the establishment of new workflows and `best practices' for performing CSP calculations. All of the targets, apart from a single potentially disordered Z' = 2 polymorph of the drug candidate, were predicted by at least one submission. Despite many remaining challenges, it is clear that CSP methods are becoming more applicable to a wider range of real systems, including salts, hydrates and larger flexible molecules. The results also highlight the potential for CSP calculations to complement and augment experimental studies of organic solid forms.

In this paper I critically assess the alleged process of globalisation of the world economy. Five interrelated themes are addressed. First, I argue that the ‘real’ myth of the globalisation discourse is part of an intensifying ideological, political, socioeconomic, and cultural struggle over the organisation of society and the position of the citizen therein. Second, the ‘mythical’ resurrection of the ‘local’ or ‘regional’ scale—both in theory and in practice—is an integral part of the ‘myth’ of globalisation. Third, the preeminence of the ‘global’ in much of the literature and political rhetoric obfuscates, marginalises, and silences an intense and ongoing sociospatial struggle in which the reconfiguration of spatial scales of governance takes a central position. Fourth, the ‘rhetoric’ of globalisation is paralleled by and facilitates the emergence of more authoritarian or at least autocratic forms of governance. Fifth, the proliferation of new modes and forms of resistance to the restless process of deterritorialisation-reterritorialisation of capital requires greater attention to ‘spatial scale’ in order to assess how the emerging new ‘gestalt of scale’ could be turned into an emancipatory and empowering process.