Showing papers by "University of Hertfordshire published in 1998"

RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor.

Abstract: Calcitonin-gene-related peptide (CGRP) and adrenomedullin are related peptides with distinct pharmacological profiles. Here we show that a receptor with seven transmembrane domains, the calcitonin-receptor-like receptor (CRLR), can function as either a CGRP receptor or an adrenomedullin receptor, depending on which members of a new family of single-transmembrane-domain proteins, which we have called receptor-activity-modifying proteins or RAMPs, are expressed. RAMPs are required to transport CRLR to the plasma membrane. RAMP1 presents the receptor at the cell surface as a mature glycoprotein and a CGRP receptor. RAMP2-transported receptors are core-glycosylated and are adrenomedullin receptors.

Toxicity of heavy metals to microorganisms and microbial processes in agricultural soils: a review.

Abstract: An increasing body of evidence suggests that microorganisms are far more sensitive to heavy metal stress than soil animals or plants growing on the same soils. Not surprisingly, most studies of heavy metal toxicity to soil microorganisms have concentrated on effects where loss of microbial function can be observed and yet such studies may mask underlying effects on biodiversity within microbial populations and communities. The types of evidence which are available for determining critical metal concentrations or loadings for microbial processes and populations in agricultural soil are assessed, particularly in relation to the agricultural use of sewage sludge. Much of the confusion in deriving critical toxic concentrations of heavy metals in soils arises from comparison of experimental results based on short-term laboratory ecotoxicological studies with results from monitoring of long-term exposures of microbial populations to heavy metals in field experiments. The laboratory studies in effect measure responses to immediate, acute toxicity (disturbance) whereas the monitoring of field experiments measures responses to long-term chronic toxicity (stress) which accumulates gradually. Laboratory ecotoxicological studies are the most easily conducted and by far the most numerous, but are difficult to extrapolate meaningfully to toxic effects likely to occur in the field. Using evidence primarily derived from long-term field experiments, a hypothesis is formulated to explain how microorganisms may become affected by gradually increasing soil metal concentrations and this is discussed in relation to defining “safe” or “critical” soil metal loadings for soil protection.

RECAPRetrosynthetic Combinatorial Analysis Procedure: A Powerful New Technique for Identifying Privileged Molecular Fragments with Useful Applications in Combinatorial Chemistry

Abstract: The use of combinatorial chemistry for the generation of new lead molecules is now a well established strategy in the drug discovery process. Central to the use of combinatorial chemistry is the design and availability of high quality building blocks which are likely to afford hits from the libraries that they generate. Herein we describe “RECAP” (Retrosynthetic Combinatorial Analysis Procedure), a new computational technique designed to address this building block issue. RECAP electronically fragments molecules based on chemical knowledge. When applied to databases of biologically active molecules this allows the identification of building block fragments rich in biologically recognized elements and privileged motifs and structures. This allows the design of building blocks and the synthesis of libraries rich in biological motifs. Application of RECAP to the Derwent World Drug Index (WDI) and the molecular fragments/building blocks that this generates are discussed. We also describe a WDI fragment knowle...

Circular polarization in star-formation regions: implications for biomolecular homochirality.

Abstract: Strong infrared circular polarization resulting from dust scattering in reflection nebulae in the Orion OMC-1 star-formation region has been observed. Circular polarization at shorter wavelengths might have been important in inducing chiral asymmetry in interstellar organic molecules that could be subsequently delivered to the early Earth by comets, interplanetary dust particles, or meteors. This could account for the excess of L-amino acids found in the Murchison meteorite and could explain the origin of the homochirality of biological molecules.

Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression

Abstract: In situ killing of tumor cells using suicide gene transfer to generate death by a non-apoptotic pathway was associated with high immunogenicity and induction of heat shock protein (hsp) expression. In contrast, a syngeneic colorectal tumor line, CMT93, killed predominantly by apoptosis, showed low levels of hsp expression and less immunogenicity. When apoptosis was inhibited in CMT93 cells by overexpression of bcl-2, hsp was also induced. Furthermore, when cDNA encoding hsp70 was stably transfected into BT6 and CMT93 cells, its expression significantly enhanced the immunogenicity of both tumors. Increased levels of hsp, induced by non-apoptotic cell killing, may provide an immunostimulatory signal in vivo which helps break tolerance to tumor antigens. These findings have important implications for the development of novel anti-cancer therapies aimed at promoting patients' immune responses to their own tumors.

Continuous Time Active Filter Design

Abstract: Fundamentals Introduction Filter Characterization Types of Filters Steps in Filter Design Analysis Continuous-Time Filter Functions Stability Passivity for One- and Two-Port Networks Reciprocity The Approximation Problem Introduction Filter Specifications and Permitted Functions Formulation of the Approximation Problem Approximation to the Ideal Lowpass Filter Filters with Linear Phase: Delays Bessel-Thomson Delay Approximation Delay Equalization Frequency Transformations Design Tables of Passive LC Ladder Filters Impedance Scaling Predistortion Active Elements Introduction Ideal Controlled Sources Impedance Transformation (Generalized Impedance Converters and Inverters) Negative Resistance Ideal Operational Amplifier The Ideal Operational Transconductance Amplifier (OTA) Realization of 1st- and 2nd-Order Functions Using Opamps Introduction Realization of 1st-Order Functions The General 2nd-Order Filter Function Sensitivity of 2nd-Order Filters Realization of Biquadratic Functions Using SABs Realization of a Quadratic with a Positive Real Zero Biquads Obtained Using the Twin-Tee RC Network Two Opamp Biquads Three Opamp Biquads Realization of High-Order Functions Using Opamps Introduction Selection Criteria for High-Order Function Realizations Mutliparameter Sensitivity High-Order Function Realization Methods Cascade Connection of 2nd-Order Sections Mutli-Loop Feedback Filters Cascade of Biquartics Simulation of LC Ladder Filters Using Opamps Introduction Resistively Terminated Lossless LC ladder Filters Methods of LC Ladder Filter Simulation The Gyrator Generalized Impedance Converter FDNRs Complex Impedance Scaling Functional Simulation Wave Active Filters Introduction Wave Active Filters Wave Active Equivalents (WAE) Economical Wave Active Filters Sensitivity of WAFs Operation of WAFs at Higher Frequencies Complementary Transfer Functions Wave Simulation of Inductance Linear Transformation Active Filters (LTA Filters)

Measures of spatial pattern for counts

Abstract: SADIE (Spatial Analysis by Distance IndicEs) is a new methodology to detect and measure the degree of nonrandomness in the two-dimensional spatial patterns of populations. It applies the same principles to data in the form of maps as to data in the form of counts at specified locations, but with different techniques. This paper considers data in the form of counts such as occur commonly in ecology. For such data the method has an advantage over traditional approaches that measure only statistical variance heterogeneity, because all the spatial information in the sample is used. Two indices and associated tests are reviewed, one based on the total distance of the sample from a completely regular arrangement, the other from a completely crowded arrangement. A new diagnostic plot is presented to aid interpretation. Results from some artificial data are studied to survey the properties of both indices for defined patterns of clustering. Indices based on the distance to regularity are powerful at detecting aggregation when several clusters are present; those based on the distance to crowding have the power to detect aggregation only when a single cluster is present. Methods are presented to estimate the typical cluster size and intercluster distance, suitable for data from sample units in the form of a contiguous grid. Examples are given for cyst-nematode field data and plant virus disease.

Nitrogen deposition and its contribution to nitrogen cycling and associated soil processes

Abstract: Human activity has greatly perturbed the nitrogen cycle through increased fixation by legumes, by energy and fertilizer production, and by the mobilization of N from long-term storage pools. This extra reactive N is readily transported through the environment, and there is increasing evidence that it is changing ecosystems through eutrophication and acidification. Rothamsted Experimental Station, UK has been involved in research on N cycling in ecosystems since its inception in 1843. Measurements of precipitation composition at Rothamsted, made since 1853, show an increase of nitrate and ammonium N in precipitation from 1 and 3 kg Nha -1 yr -1 , respectively, in 1855 to a maximum of 8 and 10 kg N ha -1 yr -1 in 1980, decreasing to 4 and 5 kg N ha -1 yr -1 today. Nitrogen inputs via dry deposition do, however, remain high. Recent measurements with diffusion tubes and filter packs show large concentrations of nitrogen dioxide of c. 20 μg m -3 in winter and c. 10 μg m -3 in summer; the difference is linked to the use of central heating, and with variations in wind direction and pollutant source. Concentrations of nitric acid and particulate N exhibit maxima of 1.5 and 2 μg m -3 in summer and winter, respectively. Concentrations of ammonia are small, barely rising above 1 μg m -3 . Taking deposition velocities from the literature gives a total deposition of all measured N species to winter cereals of 43.3 kg N ha -1 yr -1 , 84 % as oxidized species, 79 % dry deposited. The fate of this N deposited to the very long-term Broadbalk Continuous Wheat Experiment at Rothamsted has been simulated using the SUNDIAL N-cycling model: at equilibrium, after 154 yr of the experiment and with N deposition increasing from c. 10 kg ha -1 yr -1 in 1843 to 45 kg ha -1 yr -1 today, c. 5% is leached, 12% is denitrified, 30% immobilized in the soil organic matter and 53 % taken off in the crop. The 'efficiency of use' of the deposited N decreases, and losses and immobilization increase as the amount of fertilizer N increases. The deposited N itself, and the acidification that is associated with it (from the nitric acid, ammonia and ammonium), has reduced the number of plant species on the 140-yr-old Park Grass hay meadow. It has also reduced methane oxidation rates in soil by c. 15% under arable land and 30 % under woodland, and has caused N saturation of local woodland ecosystems: nitrous oxide emission rates of up to 14 kg ha -1 yr -1 are equivalent to those from arable land receiving > 200 N ha -1 yr -1 , and in proportion to the excess N deposited; measurements of N cycling processes and pools using 15 N pool dilution techniques show a large nitrate pool and enhanced rates of nitrification relative to immobilization. Ratios of gross nitrification: gross immobilization might prove to be good indices of N saturation.

Exploring the conformational space of protein side chains using dead-end elimination and the A* algorithm.

Abstract: We describe an algorithm which enables us to search the conformational space of the side chains of a protein to identify the global minimum energy combination of side chain conformations as well as all other conformations within a specified energy cutoff of the global energy minimum. The program is used to explore the side chain conformational energy surface of a number of proteins, to investigate how this surface varies with the energy model used to describe the interactions within the system and the rotamer library. Enumeration of the rotamer combinations enables us to directly evaluate the partition function, and thus calculate the side chain contribution to the conformational entropy of the folded protein. An investigation of these conformations and the relationships between them shows that most of the conformations near to the global energy minimum arise from changes in side chain conformations that are essentially independent; very few result from a concerted change in conformation of two or more residues. Some of the limitations of the approach are discussed. Proteins 33:227–239, 1998. © 1998 Wiley-Liss, Inc.

An Extremely Powerful Acylation Reaction of Alcohols with Acid Anhydrides Catalyzed by Trimethylsilyl Trifluoromethanesulfonate

Abstract: Trimethylsilyl trifluoromethanesulfonate is an excellent catalyst for the acylation of alcohols with acid anhydrides. Highly functionalized primary, secondary, tertiary, and allylic alcohols, and phenols, were acylated cleanly and efficiently and in a fraction of the time used under the standard DMAP conditions.

Molecular markers in entomology

Abstract: A diverse range of novel molecular (DNA) markers are now available for entomological investigations. Both DNA and protein markers have revolutionized the biological sciences and have enhanced many fields of study, especially ecology. Relative to DNA markers, allozymes are cheap, often much quicker to isolate and develop, even from minute insects (aphids, thrips, parasitic wasps, etc.), and subsequently easy to use. They display single or multi-locus banding patterns of a generally easily interpretable Mendelian nature, and the statistics for their analysis are well established. DNA markers are also suitable for use with small amounts of insect material and can be used with stored, dry or old samples. They have an expanding range of applications, many involving intra- and interspecific discriminations. Like allozymes, they can be single or multilocus, whilst methods for their statistical analysis have recently been published. However, they can be considerably more expensive than allozymes, require more complex preparatory protocols, expensive equipment, may involve lengthy development procedures (e.g. isolating cloned oligonucleotides to develop primers to detect microsatellite regions) and some have complex multi-locus banding patterns which may be of a non-Mendelian nature (e.g. RAPDs, randomly amplified polymorphic DNA), and are in some cases, not easily repeatable. In this review, we hope to inform the general reader about the methodology and scope of the main molecular markers commonly in use, along with brief details of some other techniques which show great promise for entomological studies. Thereafter, we discuss their applications including suitability for particular studies, the methods used to load and run samples, subsequent band detection, band scoring and interpretation, the reliability of particular techniques, the issues of safety involved, cost effectiveness and the statistical analyses utilized.

Disruption of retinoid‐related orphan receptor β changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice

Abstract: The orphan nuclear receptor RORβ is expressed in areas of the central nervous system which are involved in the processing of sensory information, including spinal cord, thalamus and sensory cerebellar cortices. Additionally, RORβ localizes to the three principal anatomical components of the mammalian timing system, the suprachiasmatic nuclei, the retina and the pineal gland. RORβ mRNA levels oscillate in retina and pineal gland with a circadian rhythm that persists in constant darkness. RORβ −/− mice display a duck‐like gait, transient male incapability to sexually reproduce, and a severely disorganized retina that suffers from postnatal degeneration. Consequently, adult RORβ −/− mice are blind, yet their circadian activity rhythm is still entrained by light–dark cycles. Interestingly, under conditions of constant darkness, RORβ −/− mice display an extended period of free‐running rhythmicity. The overall behavioral phenotype of RORβ −/− mice, together with the chromosomal localization of the RORβ gene, suggests a close relationship to the spontaneous mouse mutation vacillans described >40 years ago.

Patient participation — a review of the literature

Abstract: This article presents a critical review of the concept of patient participation. The concept of patient participation has become widely accepted in contemporary nursing practice. It is now part of the vocabulary of professional nurses and has been heralded as a means of enhancing decision making and human dignity and enriching quality of life. Patient participation in care is emerging as a growing movement wherein patients are assuming more responsibility for the prevention, detection and treatment of health problems in a manner that supplements or substitutes for professional services. The review concludes with some recommendations for nursing practice, education and research.

Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and sialidase from influenza virus types A and B.

Abstract: The first paper in this series (see previous article) described structure−activity studies of carboxamide analogues of zanamivir binding to influenza virus sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein−ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme. It is proposed that the unexpected strong binding of these inhibitors is a result of the burial of hydrophobic surface area and salt-bridge formation in an environment of low dielectric. In sialidase from type A virus, binding of the carboxamide moeity and salt-bridge formation have only a minor effect on the positions of the surrounding residues, ...

Distribution of Sulfur within Oilseed Rape Leaves in Response to Sulfur Deficiency during Vegetative Growth

Abstract: The distribution of S to sulfate, glucosinolates, glutathione, and the insoluble fraction within oilseed rape (Brassica napus L.) leaves of different ages was investigated during vegetative growth. The concentrations of glutathione and glucosinolates increased from the oldest to the youngest leaves, whereas the opposite was observed for SO42-. The concentration of insoluble S was similar among all of the leaves. At sufficient S supply and in the youngest leaves, 2% of total S was allocated to glutathione, 6% to glucosinolates, 50% to the insoluble fraction, and the remainder accumulated as SO42-. In the middle and oldest leaves, 70% to 90% of total S accumulated as SO42-, whereas glutathione and glucosinolates together accounted for less than 1% of S. When the S supply was withdrawn (minus S), the concentrations of all S-containing compounds, particularly SO42-, decreased in the youngest and middle leaves. Neither glucosinolates nor glutathione were major sources of S during S deficiency. Plants grown on nutrient solution containing minus S and low N were less deficient than plants grown on solution containing minus S and high N. The effect of N was explained by differences in growth rate. The different responses of leaves of different ages to S deficiency have to be taken into account for the development of field diagnostic tests to determine whether plants are S deficient.

Psychological development of prematurely born children

Abstract: Improvements in antenatal care and advances in neonatal medicine have resulted in increased survival of infants, in particular those of very low birthweight (VLBW) (< 1500 g) and extremely low birthweight (ELBW) (< 1000 g). If simple gain in life years is taken as a standard, then neonatal care is the most successful discipline in medicine today.1 The psychological development and quality of life of VLBW and ELBW children has become an increasing focus of recent research.2 #### Key messages The psychological development of the preterm child has been considered in four main domains: (a) cognitive development (for example, intelligence, memory, language); (b) behavioural and emotional status ranging from individual differences such as temperament to behavioural problems such as hyperactivity, phobias, or enuresis; (c) social functioning—that is, the ability to form and maintain social relationships with adults and peers and to reflect on these relationships (for example, self concept); and (d) school adaptation and failure. To provide reliable, valid, and generalisable information on the psychological developmental outcome of VLBW infants the ideal study should: (a) be prospective; (b) be based on large populations (geographical, epidemiological, or multicentre studies); (c) have few infants lost to follow up or good documentation of the dropouts; (d) include full term control groups for cohort specific comparisons; (e) be long term …

Spontaneous play in children with autism : A reappraisal

Abstract: Much controversy remains regarding the ability of children with autism to engage in spontaneous play. In this study children with autism, Down syndrome and typical development with verbal mental ages of approximately 2 years were assessed for play abilities at three data points. Even in this group of children with autism, who had relatively low verbal mental ages, symbolic play skills were not totally absent. However, it was possible to distinguish their pattern of play behaviors from the other two groups. Consequentially, it is argued that there are unusual features in early spontaneous play in children with autism and these atypical patterns are not restricted to their difficulties in the production of symbolic play. Such differences in early spontaneous play raise interesting questions about the etiology of autism, the direction of future research, and the theoretical models that can account for the condition.

Global change, soil biodiversity, and nitrogen cycling in terrestrial ecosystems: three case studies

Abstract: The relative contribution of different soil organism groups to nutrient cycling has been quantified for a number of ecosystems. Some functions, particularly within the N-cycle, are carried out by very specific organisms. Others, including those of decomposition and nutrient release from organic inputs are, however, mediated by a diverse group of bacteria, protozoa, fungi and invertebrate animals. Many authors have hypothesized that there is a high degree of equivalence and flexibility in function within this decomposer community and thence a substantial extent of redundancy in species richness and resilience in functional capacity. Three case studies are presented to examine the relationship between soil biodiversity and nitrogen cycling under global change in ecosystem types from three latitudes, i.e. tundra, temperate grassland and tropical rainforest. In all three ecosystems evidence exists for the potential impact of global change factors (temperature change, CO2 enrichment, land-use-change) on the composition and diversity of the soil community as well as on various aspects of the nitrogen and other cycles. There is, however, very little unequivocal evidence of direct causal linkage between species richness and nutrient cycling efficiency. Most of the changes detected are shifts in the influence of major functional groups of the soil biota (e.g. between microflora and fauna in decomposition). There seem to be few data, however, from which to judge the significance of changes in diversity within functional groups. Nonetheless the soil biota are hypothesized to be a sensitive link between plant detritus and the availability of nutrients to plant uptake. Any factors affecting the quantity or quality of plant detritus is likely to change this link. Rigorous experimentation on the relationships between soil species richness and the regulation or resilience of nutrient cycles under global change thus remains a high priority.

Haptic virtual reality for blind computer users

Abstract: This paper describes a series of studies involving a haptic device which can display virtual textures and 3-D objects. The device has potential for simulating real world objects and assisting in the navigation of virtual environments. Three experiments investigated: (a) whether previous results from experiments using real textures could be replicated using virtual textures; (b) whether participants perceived virtual objects to have the intended size and angle; and (c) whether simulated real objects could be recognised. In all the experiments differences in perception by blind and sighted people were also explored. The results have implications for the future design of VEs in that it cannot be assumed that virtual textures and objects will feel to the user as the designer intends. However, they do show that a haptic interface has considerable potential for blind computer users.

Mortality during dispersal and the cost of host‐specificity in parasites: how many aphids find hosts?

Abstract: 1. For a full assessment of explanations for the evolution of host-specificity it is necessary to estimate the probability that a dispersing parasite finds a host. We develop a method of estimating this success rate from samples of dispersing parasites and populations resident on hosts. 2. Applying this method to data on the bird cherry-oat aphid, Rhopalosiphum padi (L.), from southern Scotland in 1984-92, we estimate that 0.6% of the autumn migrants find hosts. 3. With such a low success rate, there should be selection for a broadening of host range, to include any host on which the colonist's fitness is more than about 0.6% of that on the normal hosts. We argue that neither nutrition nor the need for 'enemy-free space' are sufficient explanations of the host-specificity of this animal, and propose instead that it is the host's role as a rendezvous for mating that constrains the migrants to their costly host-specificity. 4. We also discuss the implications of this low success rate for the hypothesis that aphids speciate sympatrically through the formation of host races.

Delineation of the Cdc42/Rac-binding domain of p21-activated kinase.

Abstract: p21-activated kinases (PAKs) serve as effector proteins for the GTP-binding proteins Cdc42 and Rac. They are serine/threonine kinases containing the Cdc42/Rac interactive binding (CRIB) motif. The main aim of this study was to define the minimal domain of alphaPAK required for Cdc42/Rac binding. Eight stable PAK fragments of varying lengths, each containing the CRIB motif (residues 75-88), were expressed in Escherichia coli, and their ability to interact with Cdc42 and Rac was assessed using scintillation proximity assays, isothermal titration calorimetry, and fluorescence techniques. The shortest fragments examined (residues 70-94 and 75-94) bound only weakly to either Cdc42 or Rac. A longer fragment starting at residue 75 and ending at residue 105 showed binding to Q61L Rac.GTP with Kd = 1.9 microM. Highest affinity binding (Kd approximately 0.05 microM) was seen with longer fragments ending at residue 118 or 132. A small increase in affinity was seen with those fragments starting at residue 70 rather than residue 75. PAK fragments bound with approximately 3-10-fold higher affinity to Cdc42 than to Rac and bound Q61L variants with 5-10-fold higher affinity than wild type. The dissociation rates of Q61L Rac.mant-GTP and of Q61L Cdc42. mant-GTP from PAK fragment residues 70-132 were measured to be 0.66 and 0.25 min-1, respectively, which are 100-fold lower than dissociation rates for Ras:Ras-effector domains, although their affinities are similar. Calorimetric measurements revealed that binding was associated with a relatively slow heat change. It is suggested that these PAK fragments (in the absence of Cdc42 or Rac) might exist predominantly in an inactive conformation that slowly interconverts with an active conformation and/or a slow conformational change may occur upon binding to Cdc42/Rac. In conclusion, the PAK CRIB motif itself is insufficient for high-affinity binding to Cdc42/Rac, but a 30 amino acid region of PAK (residues 75-105), containing this motif, is sufficient.

Remobilisation of vacuolar stored nitrate in barley root cells

Abstract: Double-barrelled nitrate-selective microelectrodes have been used to measure the time course of the remobilisation of vacuolar stored nitrate in barley (Hordeum vulgare L. cv. Klaxon) root cells during 24 h of nitrate deprivation. These measurements showed that there are different time courses for this process in epidermal and cortical cells of the same root. The remobilisation was much slower from cortical cell vacuoles and had a time course which was similar to that obtained for tissue digests of the roots. The microelectrodes were also used to measure the nitrate concentration in sap exuding from detopped seedlings. These measurements showed that there was a gradual decrease in the delivery of nitrate to the shoot during this time. Root nitrate reductase activity of neither shoots nor roots changed significantly during the first 24 h. Direct measurement of the cytosolic nitrate in a root epidermal cell showed that during short-term changes, such as a 20-min exposure to zero external nitrate supply, cytosolic nitrate was maintained relatively unchanged. Net nitrate efflux from the roots was measurable during the initial 5 h of the zero-nitrate incubation period; after this time no further nitrate efflux was detectable. These measurements are discussed in relation to the nitrate budget of a root cell and we conclude that during the first 24 h of nitrate withdrawal vacuolar nitrate can be readily mobilised to supply the nitrogen demands of the seedling and to maintain the cytosolic nitrate concentration.