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Experimental and theoretical studies were carried out to interrogate the effect of an imidazole substituent in each of the ortho, meta, and para positions on the pKa, E°, and O−H BDE of phenol. The results reveal that imidazole substitution lowers the pKa of phenol and increases the E° of phenoxide due to its σ-electron withdrawing ability (σp^- = +0.21, σm^- = +0.45) but decreases the O−H BDE and E° of phenol due to its π-electron-donating ability (σp⁺ = −0.45).

The adenosine 5‘-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O⁶-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC50 = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N²-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N²-NH group and the requirement for an aromatic N²-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4‘-position, for example, the 4‘-hydroxy derivative (25, IC50 = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4‘-monomethylsulfonamide derivative (28, IC50 = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4‘-carboxamide derivative (34, IC50 = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.

The Hammett equation correlates the effects of Y on many different chemical properties of YC6H4ZX families of compounds. One of the most surprising is that the Z−X bond dissociation enthalpy (BDE), a homolytic property, can be correlated for some 4-YC6H4ZX families with electrophilic substituent constants, %@mt;sys@%σ%@sx@%p%@be@%+%@sxx@%%@mx@% (Y), which were largely derived from the rates of the heterolytic SN1 solvolyses of para-substituted cumyl chlorides. Although there is no Hammett correlation of the C−X BDEs in 4-YC6H4CH2X (X = H, halide, OPh) families, there are good correlations of N−X BDEs with %@mt;sys@%σ%@sx@%p%@be@%+%@sxx@%%@mx@% (Y) in 4-YC6H4NHX (X = H, CH3, OH, F) and excellent correlations of O−X BDEs with %@mt;sys@%σ%@sx@%p%@be@%+%@sxx@%%@mx@% (Y) in 4-YC6H4OX (X = H, CH3, CH2Ph) families. The reasons for this varied behavior are discussed.

An automated liquid column height measurement technique using the total internal reflection of a collimated laser beam from the convex meniscus surface is proposed. This new technique can alleviate the shortcomings of the traditional cathetometer that tends to introduce user bias. Experimental measurements and theoretical predictions have been conducted to examine the detected signal broadening and measurement uncertainties of the proposed technique, resulting from (1) the finite laser-beam diameter, (2) the capillary pore diameter, (3) the beam steering by thermal gradients, and (4) the beam steering by density variations of the liquid inside a capillary pore. For the collimated 52.6-μm diameter laser beam, for three different tested pores of 0.5, 1.0, and 2.0 mm diameter, the overall uncertainty of the wicking height measurement is estimated to be ±12 μm in the case of on-axis detection, and ±24 μm in the case of off-axis detection.An automated liquid column height measurement technique using the total internal reflection of a collimated laser beam from the convex meniscus surface is proposed. This new technique can alleviate the shortcomings of the traditional cathetometer that tends to introduce user bias. Experimental measurements and theoretical predictions have been conducted to examine the detected signal broadening and measurement uncertainties of the proposed technique, resulting from (1) the finite laser-beam diameter, (2) the capillary pore diameter, (3) the beam steering by thermal gradients, and (4) the beam steering by density variations of the liquid inside a capillary pore. For the collimated 52.6-μm diameter laser beam, for three different tested pores of 0.5, 1.0, and 2.0 mm diameter, the overall uncertainty of the wicking height measurement is estimated to be ±12 μm in the case of on-axis detection, and ±24 μm in the case of off-axis detection.

Theoretical calculations of carbon−oxygen bond dissociation enthalpies in substituted methylperoxyl radicals (YCH2OO^•) reveal that bond strengths are not governed solely by the stability of YCH2^• radicals but are largely affected by hyperconjugation when Y is electron-donating or conjugating. In many cases, this hyperconjugative effect is greater than stabilization of the methyl radical by Y. All electron-withdrawing Y exert small destabilizing effects via inductive withdrawal of electrons from the polarized C−OO^• bond.

Density functional theory indicates that the minimum energy structure of the diphenylaminyl radical, Ph2N^•, has a “staggered” conformation in which the two phenyl rings are twisted relative to each other by an angle, φ, of 40°. In this conformation, the aromatic rings are oriented so as to maximize interaction with the unpaired electron while minimizing repulsion between the 2- and 2‘-hydrogen atoms. This calculated ground state structure of Ph2N^• differs from that, which has been accepted for the past 15 years, which had the two rings orthogonal (φ = 90°) with one ring conjugating with the nitrogen's lone pair and the other conjugating with the unpaired electron. This structure was based on unexpected differences between the UV−vis absorption spectra of Ph2N^• and the diphenylmethyl radical. However, our calculations indicate that this orthogonal structure lies 3.5 kcal/mol above the global minimum. Further support for the staggered conformation of Ph2N^• is provided by the similarities between absorption transition wavelengths determined theoretically and the experimental absorption bands of Ph2N^• and other diarylaminyl radicals generated by laser flash photolysis. The long wavelength transition of Ph2N^•, resulting in a structure that can be represented as (Ph2)⁺N^-, is red-shifted as compared to the related transition from Ph2CH^• to (Ph2)⁺CH^- due to the electronegativity of the N atom. The absorption bands for PhCH2^•, PhNH^•, and PhO^• in the 300−450 nm region are similar in position, which has been taken to indicate that for isoelectronic species the electronic transition energies should be little affected by heteroatom substitution. Our calculations show, however, that these sets of absorption bands arise from different transitions. Therefore, the experimentally similar 300−450 nm absorption bands for these three radicals are fortuitous and do not reflect some common, unifying traits, a fact that further serves to emphasize the importance of theory in the assignment of bands due to electronic transitions.

High resolution, rotationally resolved electronic spectra of 2-hydroxypyridine (2HP) and 2-aminopyridine (2AP; at ~277 and ~299 nm, respectively) have been observed and fit using rigid-rotor Hamiltonians to within lifetime-limited resolutions of 170 and 120 MHz, respectively. The derived values of the rotational constants are very similar to those of phenol and aniline. However, 2HP and 2AP each exhibit inertial axis tilting, large rotations of their S1−S0 electronic transition moments, and intramolecular hydrogen bonds, making them very different from their hydrocarbon analogues. Possible reasons for this behavior are discussed.

ABSTRACTThe Leishmania pifanoiamastigote antigen P-8 has been previously shown to induce protective immunity in a murine model of cutaneous leishmaniasis (L. Soong, S. M. Duboise, P. Kima, and D. McMahon-Pratt, Infect. Immun. 63:3559–3566, 1995). As this antigen is of interest for further vaccine studies, the biochemical characterization of P-8 was undertaken. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western-blot analysis, and gel filtration chromatography revealed that P-8 antigen consisted of two proteoglycolipid complexes. The P-8 epitope is associated with theL. pifanoiamastigote-specific glycolipid components found in the two complexes. The P-8 complex 1 (P-8c1) consists of a 56-kDa serine metalloproteinase, apolipoprotein E (derived from fetal bovine serum), and amastigote-specific glycolipids. The P-8 complex 2 (P-8c2) consists of a 31-kDa cysteine proteinase associated with amastigote glycolipids. Biochemical analyses suggest that the P-8 antigenic glycolipids may be distinct from previously describedLeishmaniaglycolipids (glycosylinositolphospholipids and sphingoglycolipids). Protective immunity studies revealed that P-8c1 (serine metalloproteinase-glycolipid complex) confers comparable protection against infection as immunopurified P-8. The isolated P-8c2 (cysteine proteinase-glycolipid complex) does not provide significant protection, nor does stimulation with P-8c2 result in significant T-cell activation in P-8- or P-8c2-vaccinated mice. Consequently, the P-8c1 complex appears to be the immunodominant component of P-8.

Pathogenic trypanosomatids cause a plethora of diseases marked by the lack of efficient vaccines and therapies. As a consequence, studies are being conducted that are geared towards the understanding of basic mechanisms and various biological aspects of these parasites that might be used as targets for new developments in these areas. One such aspect is the understanding of specific cellular trafficking mechanisms that might be attacked with the intention of disease control. In this paper, we give an overview of our current knowledge of cellular targeting mechanisms in trypanosomatids, with special emphasis on our data related to lysosomal targeting of cysteine proteinases in Leishmania.

Rotationally resolved S1←S0 fluorescence excitation spectra of three methylindoles and their single atom van der Waals complexes with argon have been obtained. Each spectrum is extensively perturbed by the hindered internal rotation of the methyl group. Analyses of these perturbations show that the barriers to such motion are substantially increased by complex formation. Barriers of this type are primarily electronic in origin. Thus, even at the relatively large distances (3.5 Å) found in van der Waals complexes, the attachment of a weakly bound argon atom has a significant effect on the electron distribution in the indole ring.

This paper summarises the many activities that formed a vigorous and innovative phase of understanding 3rd generation systems and their potential service/product offering. Experience from the introduction of 2nd generation GSM systems showed that, even though based upon strong standards, real hands-on development to validate the design activities was essential for both a workable standard and a smooth and successful service deployment. Trials activities are used to overcome the lack of validation and to bring innovation through integration of capabilities and devices — they consist of two areas. Firstly, a number of test radio systems were examined and used in the validation of network planning tools plus measurement or real throughput figures, and, secondly, some service scenarios were developed and implemented on an all-IP network to demonstrate that IP can deliver a marketable services level. The interaction with wireless systems and the impact of that on the application were also examined.

The thermal decomposition of di(trifluoromethyl) peroxide (between 575 and 900 K) and di-tert-butyl peroxide (between 425 and 650 K) has been investigated by means of a very low pressure pyrolysis method. The Arrhenius equations for homolytic oxygen−oxygen bond rupture obey log(k1/s^-1) = 15.30−45.0 kcal mol^-1/2.303RT for CF3O−OCF3 and log(k2/s^-1) = 15.30−37.4 kcal mol^-1/2.303RT for Me3CO−OCMe3. The oxygen−oxygen bond dissociation enthalpies, BDE(O−O), at 298 K for the peroxides are derived to be 47.5 ± 0.5 (CF3O−OCF3) and 38.9 ± 0.5 kcal mol^-1 (Me3CO−OCMe3). Various density functional theory calculations have been utilized to compute the BDEs for XO−H, XO−OH, and XO−OX, with X = H, CF3, and Me3C. Expansion of the basis set and the application of the restricted open-shell (RO) formalism for the radical species affords better agreement with experimental values. Using isodesmic reactions, a convergence is obtained for the BDE(O−H) in trifluoromethanol (CF3O−H) toward 118.8 ± 0.5 kcal mol^-1. Reevaluation of literature thermokinetic data leads to BDE(F−CF2O^•) of 27 ± 1, and BDE(CF3O−F) of 48 ± 1 kcal mol^-1.

The bond dissociation enthalpies for a set of 30 compounds containing X−Y (X, Y = C, N, O, S, halogen) bonds are computed using density functional theory based model approaches with the B3P86 functional. These types of bonds were chosen because of their particular importance in free radical organic and bio-organic chemistry, specifically redox chemistry and atom transfer reactions. A series of test calculations on hydrogen peroxide, propane, and methyl chloride led to the choice of the 6-311G(d,p) basis set for optimum performance in terms of speed and accuracy. Three models are defined and tested. The lowest level model, which is capable of treating systems containing more than 30 non-hydrogen atoms, predicts bond dissociation enthalpies with a mean absolute deviation of 2.38 kcal/mol relative to experiment. For a subset of 21 molecules, the two higher-level models predict results with mean absolute deviations of 1.88 and 2.19 kcal/mol relative to experiment. Test calculations on X−H bond energetics indicate that two separate approaches are required for the accurate treatment of both X−Y and X−H bonds.

A mathematical model capable of predicting the wicking height formed by a wetting liquid in a vertical, heated capillary tube was developed. The model incorporates the disjoining pressure, the fluid flow and heat transfer in the thin film region, and the thermocapillary effects. Evaluation of the modeling predictions indicates the meniscus radius of curvature at the vapor - liquid interface increases significantly with increasing heat flux, resulting in an increase in the contact angle due to the surface tension variation, disjoining pressure, and fluid flow in the evaporating thin film. The increase in the contact angle is shown to be the principal reason that the static wicking height in capillary tubes is typically greater than the dynamic wicking height observed during dynamic flow conditions. In addition to the individual contributions of the dynamic flow effect and the contact angle variation, both of these parameters are presented and discussed as a function of the tube diameter. In order to verify the analytical model, comparisons with previously obtained experimental data are made. The verified analytical model presented and developed here provides a better understanding of the wetting phenomena occurring in a heated capillary tube and has applicability in a wide range of applications.

Described herein are the rotationally resolved one-photon fluorescence excitation spectra of several vibronic bands in the S1 ← S0 electronic transitions of three linear polyenes in the gas phase, 1,3,5,7-octatetraene (OT), 1,3,5,7-nonatetraene (NT), and 2,4,6,8-decatetraene (DT). Several of the spectra are significantly perturbed by an apparent centrifugal distortion in the S1 state of OT, owing to the high frequency of rotations parallel to a and the low frequency of an in-plane bending mode (ν48), by Coriolis coupling in the S1 state of NT, involving ν48 and a nearby methyl torsional level, and by torsion−rotation coupling in the S1 states of NT and DT, owing to a significant reduction in the excited-state torsional barrier(s) compared to the ground state. Nonetheless, the inertial parameters of eight different S0 and S1 vibronic levels have been determined, from which it is concluded that the carriers of the spectra are in all cases the trans,trans isomers. The important role of ν48 as a promoting mode for S1−S2 vibronic coupling, the source of the S1 ← S0 oscillator strength, is confirmed. Finally, the measured differences in the rotational constants of the S0 and S1 states (e.g., ΔA = 2532, ΔB = −11.7, and ΔC = −11.0 MHz for the vibronic origin of OT) provide new information about the changes in geometry that occur when the photon is absorbed.

Bond dissociation energies, electron affinities, and proton affinities are computed for a variety of molecules containing C−H, N−H, O−H, and S−H bonds using density functional theory with the B3LYP functional. Thermochemistry in which these bonds are broken or ions are formed is particularly relevant to understanding proton transfer (acid−base), electron transfer (redox), and H-atom transfer (free radical) reactions. A series of basis set experiments has led to an optimum compromise between computational speed and accuracy. Several theoretical models are defined and tested, and the medium and higher-level models approach an accuracy of 1 kcal/mol. Use of the above methodology to obtain absolute bond dissociation energies for X−H bonds, isodesmic reaction schemes, substituent effects, redox potentials, and gas-phase acid dissociation constants shows the usefulness of this approach.

Folded chromosome phenotypes have been examined and compared in four cell-division-cycle (cdc) mutants during transitions between cycling and non-cycling states. The two start mutants, cdc 28 and cdc 25, can undergo G0 arrest at the restrictive temperature. Arrest at start, defined by the cdc 28 and cdc 25 block points, is distinguishable from G0 arrest. Arrest at the cdc 28 and cdc 25 block points can also be distinguished from each other: folded chromosomes appear to be destabilized at the cdc 25 block, but are stable at the cdc 28 arrest point. On the other hand, folded chromosomes from cdc 28 in sporulation medium at the restrictive temperature appear unstable, while chromosomes from cdc 25 are stable. The G1 arrest mutants, cdc 4 and cdc 7, can undergo G0 arrest at the restrictive temperature. In sporulation medium no meiotic replication form is detected at the restrictive temperature, although incorporation of labeled precursors into nuclear DNA does take place. A schematic model incorporating these various findings is presented.

A group of children aged 9 and 10 were asked what signified Christmas to them. The children had all English as a mother tongue and were in the traditional mainstream English culture pattern. The children were asked: (1) to write random ideas on Christmas; (2) to define certain terms used in the nativity story, otherwise seldom used; (3) to identify unmarked greetings cards, isolating if possible reasons for their identification.Afterwards, they heard a reminiscence of Christmas in another land, and applied their imagination to drawing cards appropriate to that.The whole exercise was in the context of trying to give explicit reasons for signs which have implicit basic cultural significance, and the authors raise the question of whether at least partial knowledge of reasons is important in this type of semiological context, and whether making intuitive knowledge explicit could make a difference to learning.

We studied the organization and arrangement of the genes encoding beta-tubulin in the protozoan parasite Leishmania tropica and examined the structure and orientation of the beta-tubulin mRNA relative to the gene. There were found to be eight to nine beta-tubulin genes arranged in an array of direct tandem repeat units with a length of 3.8 kilobase pairs, and they were extremely homologous, if not identical, in sequence. These repeat units did not contain the alpha-tubulin genes. The transcribed sequences within the beta-tubulin genes were localized, and the orientation of the major alpha-tubulin mRNA was mapped on the gene by S1 nuclease analysis.

Clinically normal, bovine viral diarrhea virus (BVDV)-seronegative, 7 to 9-month-old steers were inoculated intranasally with NY-1. a noncytopathic strain of BVDV, or exposed intramuscularly to killed BVDV. Indirect immunofluorescence staining with monoclonal antibodies specific for bovine leukocyte subsets followed by flow cytometric analysis was used to monitor subsequent hematologic alterations. Infection with BVDV resulted in a transient leukopenia which was characterized by decreases in the absolute numbers of circulating T lymphocytes, including BoT4+ (“helper”) and BoT8+ (“cytotoxic/suppressor”) subsets, B lymphocytes, and neutrophils. There was no significant variation in numbers of non-T, non-B (“null”) lymphocytes or monocytes. Exposure to inactivated BVDV in a combination vaccine did not cause significant alteration in the circulating numbers of any major leukocyte subset; however, significant variation was seen in the BoT4/BoT8 ratios and in the numbers of cells expressing major histocompatibility complex (MHC) class II antigens.

BS5750 is the British Standard on “Quality Systems”. Its equivalent in European Standards is EN29000 and in the International Standards Organisation ISO9000. This paper points out that these standards lay down formalised procedures and require documentation but do not ipso facto lead to quality assurance.The author points to the Japanese post-war industrial success as being an example of Total Quality Management within the framework provided by the philosophy of Dr. W. Edwards Deming (1988 and 1993). This philosophy on the management of “systems” to provide high quality products and services is briefly outlined.The author argues that improvement in prosthetic and orthotic services will not be reached through implementation of BS5750 but rather through radical rethinking and the adoption and application of the Deming philosophy.

Tomato callus clones selected for the ability to grow at paraquat concentrations lethal to wild-type cells were found at an approximate frequency of 5×10-8 per viable cell. Diploid plants were regenerated from nine of the nineteen paraquat-tolerant callus clones isolated. Although some of these plants appeared normal, others had altered morphology and reduced vigor and fertility. New callus cultures initiated from these regenerated plants typically had at least a 30-fold increase over the wild type in tolerance to paraquat. Tests on callus from sexual progeny showed that the paraquat-tolerant phenotypes of clones PQT4, PQT6, and probably also PQT13 resulted from dominant nuclear mutations, but the number of loci involved is not yet known. Paraquat spray experiments indicated that slight paraquat-tolerance was expressed at the plant level in PQT13, but not in any of the other clones tested.

Embryo callus was produced in up to 12% of the undeveloped seeds of the interspecific cross L. esculentum cv. VFNT cherry x L. peruvianum LA1283-4, a cross which does not produce viable seeds. Plants were produced from 90% of those callus clones by regeneration and rooting. Evidence that these plants were hybrid includes morphology, isoenzyme patterns and fertility relations. Both diploid and tetraploid plants were produced, 40% of the regenerated callus clones producing at least one diploid plant. Thus, up to 4% of the undeveloped seeds plated for callus production eventually yielded diploid hybrid plants. In contrast, among 401 undeveloped seeds dissected, no embryos suitable for embryo culture were found. A backcross of the embryo callus hybrids to the L. esculentum parent has succeeded — producing, as expected, only undeveloped seeds; these undeveloped seeds have produced callus.

The ideal conservative treatment for lower limb oedema would be one that provided intermittent compression whilst allowing the patient to remain mobile. In this article we describe the development of a pneumatic ambulatory compression device that utilizes the patient's weight applied, during walking, to air cells under the foot to provide compression to the ankle and calf. In volunteer studies this device typically produced a cycle of interface pressure changes from 20 to 45-50 mmHg on the lower calf and 20 to 35-40 mmHg on the upper calf.

Paradoxically, the attitude of infertility patients towards multiple births has never been investigated. We therefore generated a survey by questionnaire, which was sent to 3800 consecutive unselected couples with infertility problems: 582 responses were received (15% response rate) and analysed. The percentage distribution of the responses to 21 questions, addressing attitudes towards and knowledge about the risk of multiple gestations, was the main outcome. Worry about multiple births was expressed, independent of the number of multiples, although fear about multiple conceptions was rejected by a large majority (64%). The risk of a twin birth was not strongly perceived, but the perception of risk increased with increasing numbers of multiples: triplets (50-62%), quadruplets or more (71-72%). A desire for the conception of twins was expressed by 67-90% of couples, a desire for the conception of triplets was equally expressed and rejected, and for a multiple gestation beyond triplets was rejected by 73-82% of couples. Patients were educated about the risks of selective embryo reduction and responded in a bimodal fashion to the option of utilizing this procedure, with equal numbers being willing to consider or reject it. Age, parity and length of infertility did not affect the couples' worry or fear about multiples. The desire for twins and triples, however, was correlated significantly with age (twins, P = 0.032; triplets, P = 0.03); there was no such correlation for larger multiples. The length of infertility was correlated with a positive attitude towards multiples beyond triplets (P = 0.029) but was not correlated with a desire for twins or triplets. Prior parity did not affect the attitude towards multiples at all.(ABSTRACT TRUNCATED AT 250 WORDS)

A hallmark of the mammalian brain cholecystokinin (CCK) receptor, CCK-B/gastrin (CCK-BR), is its high affinity for two structurally related peptides, CCK and gastrin. Previous radioligand binding experiments suggested that the predominant CCK receptor from Xenopus laevis brain shares high affinity for sulfated cholecystokinin octapeptide but has > or = 1000-fold lower affinity for gastrin. To determine the molecular basis for this pharmacological divergence between mammalian and lower vertebrate receptors, we isolated a cDNA encoding the X. laevis brain CCK receptor (CCK-XLR). CCK-XLR shares approximately 50% homology at the amino acid level with both the human CCK-BR and the peripheral CCK-A receptor subtypes. The recombinant X. laevis receptor has a distinct pharmacological profile of agonist and antagonist affinities and as such offers a useful tool for structure-function studies. We used CCK-XLR to map the human CCK-BR domains that confer high affinity for gastrin. A series of chimeric CCK-BR/CCK-XLR constructs was generated and pharmacologically characterized. While maintaining wild-type affinity for sulfated cholecystokinin octapeptide, receptors with increasing amino-terminal contributions from CCK-BR demonstrated a stepwise increase in gastrin affinity. Further dissection of the amino-terminal third of the human receptor, a domain that confers a > 250-fold increase in gastrin affinity, revealed the importance of interactions among at least three subdomains. Additional structural requirements for gastrin affinity mapped to a segment spanning transmembrane domains IV and V.

Modern casting materials are becoming available in an increasing and bewildering variety. A series of tests has been devised to investigate the properties of these materials. They have been tested for strength, flexibility, lamination, fatigue life and radiolucency. Their properties have been compared with those of plaster of Paris in order that the role of the newer materials can be defined. It is suggested that the tests described might form the basis of a standard from which user trials could be designed to appraise the value of these materials in clinical practice.