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R Henderson

Publications and source records attributed to R Henderson.

At least 73 records · Page 4Linked to original sources
PubMed1996

Public-private interaction in pharmaceutical research.

We empirically examine interaction between the public and private sectors in pharmaceutical research using qualitative data on the drug discovery process and quantitative data on the incidence of coauthorship between public and private institutions. We find evidence of significant reciprocal interaction, and reject a simple "linear" dichotomous model in which the public sector performs basic research and the private sector exploits it. Linkages to the public sector differ across firms, reflecting variation in internal incentives and policy choices, and the nature of these linkages correlates with their research performance.

Academies and Institutes↗
PubMed1996

hprt mutation frequency among workers exposed to 1,3-butadiene in China.

Hypoxanthine-guanine phosphoribosyl transferase (hprt) mutation frequency (M(f)) was studied in workers at a polybutadiene rubber production facility in Yanshan, China. Exposed workers included for study were active either as process analysts, who sampled butadiene production process lines and analyzed product by gas chromatography, or as process operators, who did routine process control, minor maintenance and, as needed, major repair operations. For process analysts at the polymer and dimethyl formamide (DMF) facilities, the median air levels of BD were 1.0 and 3.5 ppm, respectively. Among process operators, air levels of 1.1 ppm were found during routine activities, while the median air level during pump repair and related operations was 45 ppm (6-h time-weighted average). Overall, M(f) was similar in unexposed (mean M(f) = 20.2 x 10(-6)) and butadiene-exposed (mean M(f) = 21.6 x 10(-6)) workers (P = 0.68). M(f) decreased with cloning efficiency, increased with age, and was moderately greater in women than in men. After adjustment by multiple regression analysis for mean age, sex, and cloning efficiency, the adjusted mean M(f)(Xadj) was 13.6 x 10(-6) in unexposed and 18.0 x 10(-6) in butadiene-exposed. This 32% difference was, however, not statistically significant (P = 0.13). Butadiene exposure was associated with a modest, if any, increase in hprt M(f) in this population of Chinese workers.

Adult↗
PubMed1996

Electron-crystallographic refinement of the structure of bacteriorhodopsin.

Using electron diffraction data corrected for diffuse scattering together with additional phase information from 30 new images of tilted specimens, an improved experimental density map has been calculated for bacteriorhodopsin. The atomic model has then been rebuilt into this new map with particular attention to the surface loops. All the residues from 7 to 227 as well as ten lipid molecules are now included, although a few amino acid residues in three of the six surface loops, about half of the lipid hydrophobic chains and all of the lipid head groups are disordered. The model has then been refined against the experimental diffraction amplitudes to an R-factor of 28% at 3.5 angstrom resolution with strict geometry (0.005 angstrom) bond length deviation) using the improvement of the "free" phase residual between calculated and experimental phases from images as an objective criterion of accuracy. For the refinement some new programs were developed to restrain the number of parameters, to be compatible with the limited resolution of our data. In the final refined model of the protein (2BRD), compared with earlier co-ordinates (1BRD), helix D has been moved towards the cytoplasm by almost 4 angstrom, and the overall accuracy of the co-ordinates of residues in the other six helices has been improved. As a result the positions of nearly all the important residues in bacteriorhodopsin are now well determined. In particular, the buried, protonated Asp115 is 7 angstrom from, and so not in contact with, the retinal and Met118 forms a cap on the pocket occupied by the beta-ionone ring. No clear density exists for the side-chain of Arg82, which forms a central part of the extracellular half-channel. The only arginine side-chain built into good density is that of Arg134 at the extracellular end of helix E, the others being disordered near one of the two surfaces. The interpretation of the end of helix F on the extracellular surface is now clearer; an extra loose helical turn has been built bringing the side-chain of Glu194 close to Arg134 to form a probable salt bridge. The model provides an improved framework for understanding the mechanism of the light-driven proton pumping. A number of cavities that could contain water molecules were found by searching the refined model, most of them above or below the Schiff base in the half-channels leading to the two surfaces. The ordered and disordered regions of the structure are described by the temperature factor distribution.

Amino Acid Sequence↗
PubMed1996

Hemodynamic correlates of spontaneous echo contrast in the descending aorta.

To identify the hemodynamic association of spontaneous echo contrast (SEC) in the descending aorta (DA), we measured aortic flow parameters in 102 consecutive patients studied with transesophageal echocardiography. SEC in the DA was identified in 19 of 102 patients (19%). Patients with SEC in the DA were older (67 +/- 9 vs 57 +/- 17 years; p = 0.001), had a higher proportion of chronic atrial arrhythmia (13 of 19 vs 11 of 83; p = 0.000001), and had a higher frequency of decreased left ventricular performance (10 of 19 vs 19 of 83; p = 0.01). Patients with SEC in the DA had larger aortic diameters (2.9 +/- 0.5 vs 2.3 +/- 0.4 cm; p = 0.0001), lower maximal velocity in the DA (42.6 +/- 12.8 vs 75.6 +/- 34.4 cm/s; p = 0.0001), and lower maximal shear rate (61.6 +/- 20.3 vs 139.9 +/- 78.8 s-1; p = 0.0001). There was no difference in volumetric flow in the DA between groups. In multivariate analysis, only arrhythmia (p = 0.008) and maximal shear rate (p = 0.002) were identified as significant independent predictors of SEC in the DA. We conclude that SEC in the DA is related to chronic atrial arrhythmia and shear rate but not to volumetric flow.

Adult↗
PubMed1996

Modelling conditional distributions in bivariate survival.

Conditional distributions for bivariate survival can be obtained via a model for the joint distribution, or, as has sometimes been suggested, by modelling the conditioned variable directly, with the conditioning variable included as a covariate. A quantitative comparison of estimated covariate effects and predictive distributions under the two approaches is given. The results are illustrated in a novel frailty application.

Humans↗
PubMed1996

Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis.

Epithelial-mesenchymal interactions are critical for the branching and differentiation of the lung, but the mechanisms involved are still unclear. To investigate this problem in mouse embryonic lung, we have studied the temporal and spatial expression of genes implicated in the morphogenesis of other organs. At 11.5 days p.c., hepatocyte nuclear factor-3beta (Hnf-3beta) is expressed uniformly throughout the epithelium, while Wnt-2 expression is confined to the distal mesenchyme. Sonic hedgehog (Shh) transcripts are found throughout the epithelium, with high levels in the distal tips of the terminal buds, while bone morphogenetic protein-4 (Bmp-4) transcripts are localized at high levels in the distal tips of the epithelium, with lower levels in the adjacent mesenchyme. Epithelial expression is also seen for Bmp-7, but transcripts are less dramatically upregulated at the distal tips. The Type I Bone morphogenetic protein receptor gene (Bmpr/Tfr-11/Brk-1) is expressed at low levels in the epithelium and in the distal mesenchyme. To investigate the role of Bmp-4 in lung development, we have misexpressed the gene throughout the distal epithelium of transgenic lungs using a surfactant protein C enhancer/promoter. From 15.5 days p.c., transgenic lungs are smaller than normal, with grossly distended terminal buds and, at birth, contain large air-filled sacs which do not support normal lung function. Labeling with BrdU reveals an inhibition of epithelia] proliferation in 15.5 days p.c. transgenic lungs. A small but significant stimulation of proliferation of mesenchymal cells is also observed, but this is accompanied by an increase in cell death. In situ hybridization with riboprobes for the proximal airway marker, CC10, and the distal airway marker, SP-C, shows normal differentiation of bronchiolar Clara cells but a reduction in the number of differentiated Type II cells in transgenic lungs. A model is proposed for the role of BMP4 and other signalling molecules in embryonic lung morphogenesis.

Animals↗
PubMed1996

Scale, scope, and spillovers: the determinants of research productivity in drug discovery.

We examine the relationship between firm size and research productivity in the pharmaceutical industry. Using detailed internal firm data, we find that larger research efforts are more productive, not only because they enjoy economies of scale, but also because they realize economies of scope by sustaining diverse portfolios of research projects that capture internal and external knowledge spillovers. In pharmaceuticals, economies of scope in research are important in shaping the boundaries of the firm, and it may be worth tolerating the static efficiency loss attributable to the market power of large firms in exchange for their superior innovative performance.

Drug Industry↗
PubMed1995

Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation.

In mice, retrovirus-associated breast cancers are promoted by immune mechanisms, and immunosuppression during the premalignant phase reduces the incidence of breast cancer and prolongs life. If some women likewise have immune promotion of breast cancer, the incidence of breast cancer in patients receiving therapeutic immunosuppression should be lower than that in a comparable cohort of non-immunosuppressed women. We examined the incidence of de-novo breast cancer arising in women receiving immunosuppressive therapy after kidney or heart transplantation, comparing the figures with published rates. In 25,914 immunosuppressed women followed for 1-11 years there were 86 cases of breast cancer compared with 113.8 expected (p = 0.009). Incidence was particularly low in the first transplant year with relative risk 0.49, rising to 0.84 in subsequent years. For all other major cancers the incidence was higher in the immunosuppressed women. If, as in mice, the reduced incidence of breast cancer is a direct effect of immunosuppression, these observations raise the possibility of therapeutic manipulation of specific immune mechanisms that promote tumour growth.

Adult↗
PubMed1995

Three-dimensional structure of halorhodopsin at 7 A resolution.

Two-dimensional crystalline patches containing the light-driven chloride pump, halorhodopsin, appear to form spontaneously in the cell membrane of an overproducing strain of Halobacterium. The three-dimensional structure (space group p42(1)2, a = 102 A) has been analysed by electron cryo-microscopy of tilted specimens. The map shows that halorhodopsin (HR) has an arrangement of seven transmembrane helices similar to that found in the related proton pump bacteriohodopsin (BR). The orientation of the polypeptide framework of HR in the membrane is rotated by 3 degrees relative to BR about an axis in the plane and the intramolecular space between the helices BC FG, which line the cytoplasmic half channel, appears slightly larger in HR than in BR, as would be expected for a chloride channel. The crystals of HR were too small for electron diffraction analysis of tilted specimens, so both the amplitudes and the phases of the Fourier components were obtained from images. This required anisotropic scaling of the image amplitudes in addition to correction for the defocus phase contrast transfer function. The procedure of rescaling the data (in this case roughly equivalent to sharpening with a temperature factor of-490) to compensate for a variety of image and crystal defects may also prove useful in the analysis of other structures for which no prior knowledge of a homologous structure exists and for which only small crystals can be obtained.

Amino Acid Sequence↗
PubMed1995

Problems and prediction in survival-data analysis.

Twenty-one years after its appearance, Cox's 1972 paper on 'Regression models and life tables' continues to be one of the most frequently cited publications in the scientific and medical literature. The proportional-hazards model and partial-likelihood technique have been applied to thousands of data sets, not always appropriately, and have motivated hundreds of theoretical studies, not always relevant. Recent developments are reviewed and continuing problems discussed, especially with respect to predictive inference. The accuracy of model-based predictions, and how they compare with consultants' judgements are investigated by means of an example.

Humans↗
PubMed1995

Freeze trapping of reaction intermediates.

Structural intermediates in a biological reaction may be monitored by rapid spectroscopic or somewhat slower structural techniques. Intermediates may evolve in real time (no trapping), be stabilized by chemical manipulation of the reactants, the macromolecule or the solvent (chemical trapping), or be stabilized by lowering the temperature (freeze trapping). The last is beginning to be coupled with X-ray diffraction, electron cryomicroscopy and solid-state NMR approaches to characterize the trapped intermediates. Care in conducting such experiments, together with an awareness of possible artefacts, is essential if reliable structural results are to be obtained.

Cryopreservation↗
PubMed1995

The potential and limitations of neutrons, electrons and X-rays for atomic resolution microscopy of unstained biological molecules.

Radiation damage is the main problem which prevents the determination of the structure of a single biological macromolecule at atomic resolution using any kind of microscopy. This is true whether neutrons, electrons or X-rays are used as the illumination. For neutrons, the cross-section for nuclear capture and the associated energy deposition and radiation damage could be reduced by using samples that are fully deuterated and 15N-labelled and by using fast neutrons, but single molecule biological microscopy is still not feasible. For naturally occurring biological material, electrons at present provide the most information for a given amount of radiation damage. Using phase contrast electron microscopy on biological molecules and macromolecular assemblies of approximately 10(5) molecular weight and above, there is in theory enough information present in the image to allow determination of the position and orientation of individual particles: the application of averaging methods can then be used to provide an atomic resolution structure. The images of approximately 10,000 particles are required. Below 10(5) molecular weight, some kind of crystal or other geometrically ordered aggregate is necessary to provide a sufficiently high combined molecular weight to allow for the alignment. In practice, the present quality of the best images still falls short of that attainable in theory and this means that a greater number of particles must be averaged and that the molecular weight limitation is somewhat larger than the predicted limit. For X-rays, the amount of damage per useful elastic scattering event is several hundred times greater than for electrons at all wavelengths and energies and therefore the requirements on specimen size and number of particles are correspondingly larger. Because of the lack of sufficiently bright neutron sources in the foreseeable future, electron microscopy in practice provides the greatest potential for immediate progress.

Biophysical Phenomena↗