Showing papers by "University of Birmingham published in 1996"

Rapid least-squares inversion of apparent resistivity pseudosections by a quasi-Newton method1

Abstract: A fast inversion technique for the interpretation of data from resistivity tomography surveys has been developed for operation on a microcomputer. This technique is based on the smoothness-constrained least-squares method and it produces a two-dimensional subsurface model from the apparent resistivity pseudosection. In the first iteration, a homogeneous earth model is used as the starting model for which the apparent resistivity partial derivative values can be calculated analytically. For subsequent iterations, a quasi-Newton method is used to estimate the partial derivatives which reduces the computer time and memory space required by about eight and twelve times, respectively, compared to the conventional least-squares method. Tests with a variety of computer models and data from field surveys show that this technique is insensitive to random noise and converges rapidly. This technique takes about one minute to invert a single data set on an 80486DX microcomputer.

The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus.

Abstract: Objective. To develop and perform an initial validation of a damage index for systemic lupus erythematosus (SLE). Methods. A list of items considered to reflect damage in SLE was generated through a nominal group process. A consensus as to which items to be included in an index was reached, together with rules for ascertainment. Each center submitted 2 assessments, 5 years apart, on 2 patients with active and 2 with inactive disease, of whom 1 had increased damage and the other had stable disease. Analysis of variance was used to test the factors physician, time, amount of damage, and activity status. Results. Nineteen physicians completed the damage index on 42 case scenarios. The analysis revealed that the damage index could identify changes in damage seen in patients with both active and inactive disease. Patients who had active disease at both time points had a higher increase in damage. There was good agreement among the physicians on the assessment of damage in these patients. Conclusion. This damage index for SLE records damage occurring in patients with SLE regardless of its cause. The index was demonstrated to have content, face, criterion, and discriminant validity.

Who Learns What from Whom: a Review of the Policy Transfer Literature

Abstract: It has always existed but there can be no doubt that the rapid growth in communications of all types since the Second World War has accelerated the process. Not surprisingly, the increase in policy transfer has led to the development of interest in the topic among students of comparative politics and public policy. This article reviews this literature which is of two types. First, there are studies which do not use the concept but which often throw considerable light on policy transfer. Second, there is a growing body of material dealing specifically with the process. Both types of study are now common. As an example, the June 1994 edition of Political Studies included two articles dealing with the issues discussed here. Walsh’s examination of exchange rate policy in France and Germany is a good representative of the first type of study. He does not discuss transfer, but shows how international capital flows gave rise to tensions in the European Monetary System which, in turn, led to policy convergence. In contrast, Coleman’s analysis of policy convergence in banking directly addressed the question of how international economic changes affect policy goals, policy content, policy instruments and policy style. The aim of this article is to present a critical review of the literature on policy transfer in order to both introduce the topic to a wider audience and contribute to its development. Our review is both narrower and broader than the major existing review by Bennett.* Bennett’s approach is broader in that he concentrates upon the general pattern of convergence between the policies adopted by nations. In contrast, our focus is more narrowly upon the transfer of specific policies as a result of strategic decisions taken by actors inside and outside government. At the same time however, our approach is broader, particularly because we:

Self-Assembly in Natural and Unnatural Systems

Abstract: Although there are no fundamental factors hindering the development of nanoscale structures, there is a growing realization that “engineering down” approaches, in other words a reduction in the size of structures generated by lithographic techniques below the present lower limit of roughly 1 μm, may become impractical. It has, therefore, become increasingly clear that only by the development of a fundamental understanding of the self-assembly of large-scale biological structures, which exist and function at and beyond the nanoscale, downwards, and the extension of our knowledge regarding the chemical syntheses of small-scale structures upwards, can the gap between the promise and the reality of nanosystems be closed. This kind of construction of nanoscale structures and nanosystems represents the so-called “bottom up” or “engineering up” approach to device fabrication. Significant progress can be made in the development of nanoscience by transferring concepts found in the biological world into the chemical arena. Central to this mission is the development of simple chemical systems capable of instructing their own organization into large aggregates of molecules through their mutual recognition properties. The precise programming of these recognition events, and hence the correct assembly of the growing superstructure, relies on a fundamental understanding and the practical exploitation of non-covalent bonding interactions between and within molecules. The science of supramolecular chemistry—chemistry beyond the molecule in its very broadest sense—has started to bridge the yawning gap between molecular and macro-molecular structures. By utilizing inter-actions as diverse as aromatic π–π stacking and metal–ligand coordination for the information source for assembly processes, chemists have, in the last decade, begun to use biological concepts such as self-assembly to construct nanoscale structures and superstructures with a variety of forms and functions. Here, we provide a flavor of how self-assembly operates in natural systems and can be harnessed in unnatural ones.

Source Apportionment of Atmospheric Polycyclic Aromatic Hydrocarbons Collected from an Urban Location in Birmingham, U.K.

Abstract: Intensive seasonal sampling campaigns were undertaken at an urban location in Birmingham, U.K., in which high-volume samplers were used to collect particulate- and vapor-phase polycyclic aromatic hydrocarbons (PAHs) by means of filter papers and polyurethane foam plugs. Eighteen PAH species were determined by reversed-phase HPLC. Additionally, the suspended particle loading of the air was measured gravimetrically. Dichotomous stacked filter units (DSFUs) were run simultaneously with the high-volumes enabling the collection of particulate matter representative of fine (<2.1 μm) and coarse sized (2.1−10 μm) fractions. Filters from the DSFUs were analyzed for 19 metal species [by proton induced X-ray emission (PIXE)], ammonium, elemental carbon, and various anions. Metal and PAH concentrations were observed to be broadly in line with concentrations measured at other urban areas throughout the U.K. Chemical source apportionment studies took the form of principal component analysis (PCA) followed by multi-line...

Couplings of microstrip square open-loop resonators for cross-coupled planar microwave filters

Abstract: A new type of cross-coupled planar microwave filter using coupled microstrip square open-loop resonators is proposed. A method for the rigorous calculation of the coupling coefficients of three basic coupling structures encountered in this type of filter is developed. Simple empirical models are derived for estimation of the coupling coefficients. Experiments are performed to verify the theory. A four-pole elliptic function filter of this type is designed and fabricated. Both the theoretical and experimental performance is presented.

Facility Location: A Survey of Applications and Methods

Abstract: (1996). Facility Location: A Survey of Applications and Methods. Journal of the Operational Research Society: Vol. 47, No. 11, pp. 1421-1422.

The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry

Abstract: Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell-mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ-specific autoimmune disease.

International Union of Pharmacology. XII. Classification of opioid receptors

Abstract: Facing the rapidly spreading novel coronavirus disease (COVID-19), evidence to inform decision-making at both the clinical and policy-making level is highly needed. Based on the results of a study by Petrilli et al, we have developed a calculator using patient data at admission to predict the risk of critical illness (intensive care unit admission, use of mechanical ventilation, discharge to hospice, or death). We report a retrospective validation of the risk calculator on 145 consecutive patients admitted with COVID-19 to a single hospital in Israel. Of the 18 patients with critical illness, 17 were correctly identified by the model(sensitivity: 94.4%, 95% CI, 72.7% to 99.9%; specificity: 81.9%, 95% CI, 74.1% to 88.2%). Of the 127 patients with non-critical illness, 104 were correctly identified. This, despite considerable differences between the original and validation study populations. Our results show that data from published knowledge can be used to provide reliable, patient level, automated risk assessment, potentially reducing the cognitive burden on physicians and helping policy makers better prepare for future needs.

A mechanism for generation of long-range synchronous fast oscillations in the cortex.

Abstract: Synchronous neuronal oscillations in the 30-70 Hz range, known as gamma oscillations, occur in the cortex of many species. This synchronization can occur over large distances, and in some cases over multiple cortical areas and in both hemispheres; it has been proposed to underlie the binding of several features into a single perceptual entity. The mechanism by which coherent oscillations are generated remains unclear, because they often show zero or near-zero phase lags over long distances, whereas much greater phase lags would be expected from the slow speed of axonal conduction. We have previously shown that interneuron networks alone can generate gamma oscillations; here we propose a simple model to explain how an interconnected chain of such networks can generate coherent oscillations. The model incorporates known properties of excitatory pyramidal cells and inhibitory interneurons; it predicts that when excitation of interneurons reaches a level sufficient to induce pairs of spikes in rapid succession (spike doublets), the network will generate gamma oscillations that are synchronized on a millisecond time-scale from one end of the chain to the other. We show that in rat hippocampal slices interneurons do indeed fire spike doublets under conditions in which gamma oscillations are synchronized over several millimetres, whereas they fire single spikes under other conditions. Thus, known properties of neurons and local synaptic circuits can account for tightly synchronized oscillations in large neuronal ensembles.

Practical techniques for 3D resistivity surveys and data inversion1

Abstract: Techniques to reduce the time needed to carry out 3D resistivity surveys with a moderate number (25 to 100) of electrodes and the computing time required to interpret the data have been developed. The electrodes in a 3D survey are normally arranged in a square grid and the pole-pole array is used to make the potential measurements. The number of measurements required can be reduced to about one-third of the maximum possible number without seriously degrading the resolution of the resulting inversion model by making measurements along the horizontal, vertical and 45° diagonal rows of electrodes passing through the current electrode. The smoothness-constrained least-squares inversion method is used for the data interpretation. The computing time required by this technique can be greatly reduced by using a homogeneous half-space as the starting model so that the Jacobian matrix of partial derivatives can be calculated analytically. A quasi-Newton updating method is then used to estimate the partial derivatives for subsequent iterations. This inversion technique has been tested on synthetic and field data where a satisfactory model is obtained using a modest amount of computer time. On an 80486DX2/66 microcomputer, it takes about 20 minutes to invert the data from a 7 by 7 electrode survey grid. using the techniques described below, 3D resistivity surveys and data inversion can be carried out using commercially available field equipment and an inexpensive microcomputer.

Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition.

Abstract: We have performed a Phase I clinical trial with the naturally occurring flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone). Quercetin has antiproliferative activity in vitro and is known to inhibit signal transduction targets including tyrosine kinases, protein kinase C, and phosphatidyl inositol-3 kinase. Quercetin was administered by short i.v. infusion at escalating doses initially at 3-week intervals. The first dose level was 60 mg/m2; at the 10th dose level of 1700 mg/m2, dose-limiting nephrotoxicity was encountered, but no myelosuppression. At the preceding dose level of 1400 mg/m2, five patients were treated at 3-week intervals, and another eight patients were treated on a once-weekly schedule; overall, 2 of 10 evaluable patients had renal toxicity, 1 at grade 2 and 1 at grade 4. We therefore treated other patients at 945 mg/m2 (eight at 3-week intervals and six at weekly intervals); 3 of 14 patients had clinically significant renal toxicity, 2 patients with grade 2 and 1 patient with grade 3. Patients treated on the weekly schedule did not have cumulative renal impairment but did have a fall in the glomerular filtration rate of 19 +/- 8% in the 24 h after drug administration. We recommend 1400 mg/m2 as the bolus dose, which may be given either in 3-week or weekly intervals, for Phase II trials. Quercetin pharmacokinetics were described by a first-order two-compartment model with a median t(1/2)alpha of 6 min and median t(1/2)beta of 43 min. The median estimated clearance was 0.28 liter/min/m2, and median volume of distribution at steady state was 3.7 liter/m2. In 9 of 11 patients, lymphocyte protein tyrosine phosphorylation was inhibited following administration of quercetin at 1 h, which persisted to 16 h. In one patient with ovarian cancer refractory to cisplatin, following two courses of quercetin (420 mg/m2), the CA 125 had fallen from 295 to 55 units/ml, and in another patient with hepatoma, the serum alpha-fetoprotein fell. In conclusion, quercetin can be safely administered by i.v. bolus at a dose injection. The plasma levels achieved inhibited lymphocyte tyrosine kinase activity, and evidence of antitumor activity was seen.

Cellular Interactions in Thymocyte Development

Abstract: Interactions between stromal cells and thymocytes play a crucial role in T cell development. The thymic stroma is complex and consists of epithelial cells derived from the pharyngeal region during development, together with macrophages and dendritic cells of bone marrow origin. In addition, fibroblasts and matrix molecules permeate the whole framework. It is now apparent that these individual stromal components play specialized roles at different stages of T cell differentiation. Thus, at the early CD4-8- stage of development, T cell precursors require fibroblast as well as epithelial cell interactions. Later, at the CD4+8+ stage, as well as providing low avidity TCR/MHC-peptide interactions, thymic epithelial cells have been shown to possess unique properties essential for positive selection. Dendritic cells, on the other hand, are probably efficient mediators of negative selection, but they may not be solely responsible for this activity. Alongside the functional roles of stromal cells, considerable progress is being made in unraveling the nature of the signaling pathways involved in T cell development. Identification of the pre-T cell receptor (pre-TCR) and associated signaling molecules marks an important advance in understanding the mechanisms that control gene rearrangement and allelic exclusion. In addition, a better understanding of the signaling pathways that lead to positive selection on the one hand and negative selection on the other is beginning to emerge. Many issues remain unresolved, and some are discussed in this review. What, for example, is the nature of the chemotactic factor(s) that attract stem cells to the thymus? What is the molecular basis of the essential interactions between early thymocytes and fibroblasts, and early thymocytes and epithelial cells? What is special about cortical epithelial cells in supporting positive selection? These and other issues are ripe for analysis and can now be approached using a combination of modern molecular and cellular techniques.

Large clonal expansions of CD8 + T cells in acute infectious mononucleosis

Abstract: Primary infection with Epstein–Barr virus often results in the clinical syndrome of acute infectious mononucleosis (glandular fever). This illness is characterized by a striking lymphocytosis, the nature of which has been controversial. We show that large monoclonal or oligoclonal populations of CD8+ T cells account for a significant proportion of the lymphocytosis and provide molecular evidence that these populations have been driven by antigen. The results suggest that the selective and massive expansion of a few dominant clones of CD8+ T cells is an important feature of the primary response to this virus.

Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study.

Abstract: The trends in treatment and outcome of 13560 patients with pancreatic cancer, and in incidence of the disease, in the West Midlands health region were determined between 1957 and 1986 using data from the West Midlands Region Cancer Registry. Patients were divided into those diagnosed in the first 20 years (19570–1976, n = 7888) and the most recent 10 years (1977–1986, n = 5672). The disease was more common in men and the incidence increased up to 1970 after which it levelled off. In the 1977–1986 period a lower proportion of patients had laparotomy alone (825 (14·5 per cent) versus 1552 (19·7 per cent)), a similar proportion had bypass surgery (2010 (35·4 per cent) versus 2760 (35·0 per cent)), while a greater proportion had supportive care (2710 (47·8 per cent) versus 3368 (42·7 per cent)) but the resection rates were the same (145 (2·6 per cent) versus 208 (2·6 per cent)). The 30-day mortality rates between the two periods unproved for resection (40 (27·6 per cent) versus 94 (45·2 per cent)), bypass surgery (436 (21·7 percent) versus 691 (25·0 per cent)) and laparotomy (372 (45·1 per cent) versus 873 (56·3 per cent)). The 12-month survival rate for bypass did not significantly differ during the study (14·9 per cent versus 12·4 per cent) but there was a significant improvement in the 5-year survival for resection (9·7 per cent versus 2·6 per cent, P < 0·015). The resection rates were low and 30-day mortality rates for surgery were high compared with those of other published series.

High‐ and low‐frequency fatigue revisited

Abstract: Changes in excitation-contraction coupling have long been recognized as possible causes of the failure in function which occurs in fatigued muscle. High-frequency fatigue is characterized by an excessive loss of force at high frequencies of stimulation and rapid recovery when the frequency is reduced. Frequencies in excess of 50 Hz are rarely seen with voluntary activation of human muscle, and for this reason there has been some doubt as to whether high-frequency fatigue is a significant feature of normal activity. Recent experiments have shown that with 30 Hz stimulation there is a more rapid loss of force if the muscle is held isometric in a shortened position and the fatigue is rapidly reversed if the muscle is re-extended, even under ischaemic conditions. These findings are consistent with the accumulation of K+ in the t-tubules and interfibre spaces of the muscle. Low-frequency fatigue is characterized by a relative loss of force at low frequencies of stimulation and a slow recovery over the course of hours or even days. There is evidence from intracellular measurements that low-frequency fatigue is due to a reduction in Ca2+ release. However, there is a possibility that in the fatiguing exercise, the end sarcomeras of the fibre overextend and damage those in the middle section of the fibre. In this situation the active sarcomas would be working at a shorter length than predicted from the overall fibre length and the force-frequency curve will be shifted to the right. Measurements of the length-tension relationship of muscles damaged by stretching are consistent with this happening.

Characterization of Vectors for Gene Therapy Formed by Self-Assembly of DNA with Synthetic Block Co-Polymers

Abstract: Cationic polymers can self-assemble with DNA to form polyelectrolyte complexes capable of gene delivery, although biocompatibility of the complexes is generally limited. Here we have used A-B type cationic-hydrophilic block co-polymers to introduce a protective surface hydrophilic shielding following oriented self-assembly with DNA. Block co-polymers of poly(ethylene glycol)–poly-l-lysine (pEG-pLL) and poly-N-(2-hydroxypropyl)methacrylamide–poly(trimethylammonioethyl methacrylate chloride) (pHPMA–pTMAEM) both show spontaneous formation of complexes with DNA. Surface charge measured by zeta potential is decreased compared with equivalent polycation–DNA complexes in each case. Atomic force microscopy shows that pHPMA–pTMAEM/DNA complexes are discrete spheres similar to those formed between DNA and simple polycations, whereas pEG–pLL/DNA complexes adopt an extended structure. Biological properties depend on the charge ratio of formation. At optimal charge ratio, pEG–pLL/DNA complexes show efficient ...

Contributions of individual mechanisms to fluoroquinolone resistance in 36 Escherichia coli strains isolated from humans and animals.

Abstract: Twenty-eight human isolates of Escherichia coli from Argentina and Spain and eight veterinary isolates received from the Ministry of Agriculture Fisheries and Foods in the United Kingdom required 2 to > 128 micrograms of ciprofloxacin per ml for inhibition. Fragments of gyrA and parC encompassing the quinolone resistance-determining region were amplified by PCR, and the DNA sequences of the fragments were determined. All isolates contained a mutation in gyrA of a serine at position 83 (Ser83) to an Leu, and 26 isolates also contained a mutation of Asp87 to one of four amino acids: Asn (n = 14), Tyr (n = 6), Gly (n = 5), or His (n = 1). Twenty-four isolates contained a single mutation in parC, either a Ser80 to Ile (n = 17) or Arg (n = 2) or a Glu84 to Lys (n = 3). The role of a mutation in gyrB was investigated by introducing wild-type gyrB (pBP548) into all isolates; for three transformants MICs of ciprofloxacin were reduced; however, sequencing of PCR-derived fragments containing the gyrB quinolone resistance-determining region revealed no changes. The analogous region of parE was analyzed in 34 of 36 isolates by single-strand conformational polymorphism analysis and sequencing; however, no amino acid substitutions were discovered. The outer membrane protein and lipopolysaccharide profiles of all isolates were compared with those of reference strains, and the concentration of ciprofloxacin accumulated (with or without 100 microM carbony cyanide m-chlorophenylhydrazone [CCCP] was determined. Twenty-two isolates accumulated significantly lower concentrations of ciprofloxacin than the wild-type E. coli isolate; nine isolates accumulated less then half the concentration. The addition of CCCP increased the concentration of ciprofloxacin accumulated, and in all but one isolate the percent increase was greater than that in the control strains. The data indicate that high-level fluoroquinolone resistance in E. coli involves the acquisition of mutations at multiple loci.

Interleukin-2 receptor common γ-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: Selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression

Abstract: Cytokine deprivation from activated T cells leads to apoptosis associated with down-regulation of the bcl-2 gene product. It is not clear, however, how cytokines other than interleukin-2 (IL-2) may affect this process and regulate the involvement of other apoptosis-modulating genes. We show that a group of cytokines including IL-2 (IL-2R gamma), prevent the apoptosis of IL-2-deprived activated T cells. This rescue involves the induction of the anti-apoptosis genes bcl-2 and bcl-xL), but causes little change in expression of bax and bcl-xS, which promote apoptosis. Furthermore, the prevention of apoptosis and induction of proliferation by the common gamma chain cytokines can be dissociated. Thus, when proliferation is blocked, the common gamma chain cytokines still induce up-regulation of bcl-2 relative to bax and retard apoptosis. These cytokines can thus regulate the persistence or removal of effector T cells by coordinating the balance between genes which promote and those which inhibit apoptosis, events which are probably mediated at least in part by signals through the common gamma chain. These data also implicate inappropriate T cell apoptosis resulting from a dysfunctional common gamma-chain as part of the pathophysiological defect in patients with X-linked severe-combined immunodeficiency (SCID).

A framework for the dimensions of quality in higher education

Abstract: In any quality improvement programme, measurement plays a vital role as it provides information for decision making. Finding the characteristics of quality is a prerequisite for the measurement process. Despite recent research on general service’s quality dimensions, little work has been concentrated on public services and in particular higher education. Examines conceptual models proposed for different environments for consistency with higher education. Reviews quality factors found in the relevant literature and presents a new framework for the dimensions of quality in higher education.

Accelerated telomere shortening in ataxia telangiectasia

Abstract: Ataxia telangiectasia (AT) is characterized by neurological deterioration, immunodeficiency, spontaneous chromosomal instability, hypersensitivity to ionizing radiation, predisposition to cancer, particularly T cell leukaemia and lymphoma, and premature ageing. The most commonly observed defect affecting telomeres in humans is telomeric fusions, particularly in T lymphocytes in AT patients. Rarely, some tumour cells, like senescent cells, have dicentric chromosomes that may arise as a result of telomeric sequence loss. We show that the AT mutation in the homozygous state confers a predisposition to accelerated telomere shortening with increasing age in peripheral blood lymphocytes (PBLs), which may be linked to premature senescence. We also show that telomeric fusions are associated with large (> 90%) preleukaemic translocation clones in T cells. We propose that these fusions may result from a compound effect of accelerated telomere shortening, together with a growth advantage of cells in large clones which leads to further telomere loss. Fusions are not observed in leukaemic cells in these patients. There is no evidence that either accelerated telomere loss per se or telomeric fusions are important in tumourigenesis. Telomerase is present in both normal and AT lymphocytes and so neither telomere shortening nor telomeric fusions can be explained by the absence of telomerase.

Selbstorganisation in natürlichen und in nichtnatürlichen Systemen

Abstract: Zwar steht der Entwicklung von nanometergrosen Strukturen prinzipiell nichts im Wege, doch setzt sich immer mehr die Auffassung durch, das sich Strukturminiaturisierungen unter die gegenwartig durch lithographische Techniken erreichbare 1-μ-Grenze als nicht mehr praktikabel erweisen werden. Es wurde daher deutlich, das nur durch ein grundlegendes Verstandnis der Selbstorganisation von funktionellen makroskopischen biologischen Strukturen mit Abmessungen im Nanometerbereich und sogar darunter (Verkleinerungsansatz) und durch die Erweiterung unseres Wissens uber die chemische Synthese von mikroskopischen Strukturen (Vergroserungsansatz) die Brucke zwischen Anspruch und Wirklichkeit bei Nanosystemen geschlagen werden kann. Die Konstruktion von Nanostrukturen und -systemen aus kleinen Molekulbausteinen ist das „engineering-up” zum Aufbau von molekularen Funktionseinheiten. Bedeutende Fortschritte konnen auf dem Gebiet der Nanowissenschaften erzielt werden, wenn die Konzepte, die in der Biologie gefunden wurden, auf die Chemie ubertragen werden. Im Zentrum dieser Aufgabe steht die Entwicklung von einfachen chemischen Systemen, die sich selbst durch gegenseitige Erkennung zu groseren Molekulaggregaten organisieren konnen. Die genaue Programmierung derartiger Erkennungsprozesse und somit auch der korrekte Aufbau der Uberstrukturen setzen ein fundamentales Verstandnis und die Nutzung inter- sowie intramolekularer nichtkovalenter bindender Wechselwirkungen voraus. Die supramolekulare Chemie – eine Chemie, die in jeder Hinsicht uber die Chemie der Molekule hinausgeht – hat begonnen, den grosen Graben zwischen molekularen und makromolekularen Strukturen zu schliesen. Durch Nutzung von so unterschiedlichen Wechselwirkungen wie aromatischen π-Stapel- und Metall-Ligand-Koordinationswechselwirkungen als Informationsquellen der Aufbauprozesse haben Chemiker in den letzten zehn Jahren biologische Konzepte wie die Selbstorganisation zur Konstruktion von Nanostrukturen und Uberstrukturen mit einer Vielzahl von Formen und Funktionen herangezogen. Wir wollen hier einen Eindruck davon vermitteln, wie die Selbstorganisation in naturlichen Systemen funktioniert und wie diese Prinzipien nutzbringend auf nichtnaturliche Systeme angewendet werden konnen.

A light microscopic atlas of meiosis in Arabidopsis thaliana.

Abstract: An atlas of meiosis in Arabidopsis thaliana, encompassing all stages from preleptotene to telophase II and early microspore formation, is presented in detail for the first time. The photomicrographs and descriptions are based on staining with the DNA fluorochrome 4',6-diamidino-2-phenylindole (DAPI) combined with a spreading procedure, or haematoxylin-iron alum (HIA) staining. Despite previous reservations about the practicality of cytogenetic meiotic analysis in Arabidopsis due to its small genome size, good-quality and clearly analysable preparations of all meiotic stages were obtained. This atlas of normal, wild-type meiosis is considered an essential prerequisite to informed analyses of meiotic mutants. Furthermore, extended prophase I chromosomes, particularly at the pachytene stage, offer considerable potential for producing a detailed cytogenetic map (karyotype) of Arabidopsis chromosomes with the additional prospect of high-resolution physical mapping based on fluorescence in situ hybridization (FISH) of defined DNA probes to these extended chromosomes.

Cellular consequences of thrombin-receptor activation.

Abstract: To say that thrombin is a multi-functional protein is rather to understate the case. It is the key enzyme involved in haemostasis, playing important roles at all levels of complexity. First, in the coagulation cascade, thrombin converts fibrinogen into fibrin, which is readily cross-linked to form a clot (reviewed in [1,2]) ; secondly, thrombin activates blood platelets, causing aggregation and secretion [3,4] ; and thirdly, thrombin can elicit mitogenic responses from vascular smooth-muscle cells [5,6]. This latter property is probably most significant in the renewal of damaged blood-vessel walls. Additionally, thrombin is able to elicit responses from cell types as diverse as macrophages [7], monocytes [8] and neutrophils [9]. Perhaps more surprisingly, it is able to regulate neurite outgrowth from cells of neuronal origin [10] and initiate resorption of bone cells [11]. All of these properties of thrombin appear to rely on its action as a serine proteinase, since modification (either chemically [12–14] or mutationally [15–17]) which destroys its proteolytic activity leads to a loss of biological activity. These crucial findings have been explained to a large extent by the recent elegant characterization of a novel, widely expressed thrombin receptor which is activated by proteolytic cleavage rather than by ligand (protein) binding [18,19]. At the same time as elucidation of the mechanism of thrombin signalling there has been a dramatic increase in our understanding of how thrombin signals are mediated within the cell. This therefore seems an appropriate time to assess our current knowledge and perhaps to try to predict areas where the greatest advances will be made in the immediate future. In this review, because of limitations in length, emphasis will be placed on recent advances, in particular on the characterization of the thrombin receptor and in the mechanisms of intracellular signalling. Whilst most studies of thrombin have concentrated on its action on cells involved in blood clotting and wound healing, it is now becoming apparent that it can modulate the growth and differentiation status of cells of neuronal origin. A consideration of recent advances in this area of study will form the third major theme of this review.

A ROSAT survey of Hickson's compact galaxy groups

Abstract: We report the results of an almost complete survey of the X-ray properties of Hickson's compact galaxy groups with the ROSAT PSPC. Diffuse X-ray emission is detected from 22 groups. We infer that hot intragroup gas is present in $\gtsimm 75\%$ of these systems and derive their X-ray luminosity function. Earlier reports that only spiral-poor systems exhibit diffuse X-ray emission are found to be incorrect. Strong correlations are found between the X-ray luminosity and both the gas temperature and the velocity dispersion of the group galaxies. We argue that these properties provide strong evidence that most of these groups are genuinely compact configurations, rather than line-of-sight superpositions. Comparison with the X-ray properties of galaxy clusters indicate a significant steepening of the $L:T$ relation below $T\sim1$\keV, which may result from the action of galaxy winds.

Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors

Abstract: Crystal structures of HIV-1 reverse transcriptase (RT) complexed with a range of chemically diverse non-nucleoside inhibitors (NNIs) have shown a single pocket in which the inhibitors bind and details of the inhibitor-protein interactions. To delineate the structural requirements for an effective inhibitor, we have determined the structures of three closely related NNIs which vary widely in their potencies. Crystal structures of HIV-1 RT complexed with two very potent inhibitors, MKC-442 and TNK-651, at 2.55 angstroms resolution complement our previous analysis of the complex with the less effective inhibitor, HEPT. These structures reveal conformational changes which correlate with changes in potency. We suggest that a major determinant of increased potency in the analogues of HEPT is an improved interaction between residue Tyr181 in the protein and the 6-benzyl ring of the inhibitors which stabilizes the structure of the complex. This arises through a conformational switching of the protein structure triggered by the steric bulk of the 5-substituent of the inhibitor pyrimidine ring.