Innovation and Foreign Investment Behavior of the U.S. Pharmaceutical Industry

This paper deals with the links between the development of new drugs, and particularly of innovative new drugs, and the international activities of U.S. drug companies. While U.S. drug companies have developed new production processes - the most notable being the fermentation process for making penicillin - we concentrate in this paper on new products. Since production costs comprise less than 40 percent of the selling price of drugs and since the person choosing the drug rarely pays for it, growth in company sales and profits comes more from introducing new products than from cutting costs and prices of old products. The main novelty of our study is our examination of "innovative" as contrasted with "imitative" new drugs. Previous studies have generally focused on the total number of new drugs produced each year, but since our interest is in the causes and consequences of innovation, we have concentrated on the products we have rated as innovative. Section I explains our criteria for this distinction and presents our enumeration of the innovative new drugs for each of the 22 companies in our sample. In Section II we discuss trends in the rate of drug innovation and the factors influencing those trends. Section III describes our sample of drug companies and characterizes them with respect to their size, research investment, and innovativeness. Section IV examines the relation of innovativeness to the foreign activities of individual firms. In Section V we analyze, for a sample of 7 new drugs introduced by two companies, the rate at which use of the drugs was diffused among various countries arid the impact of the presence of manufacturing plants on the rate of diffusion.

The Sinorhizobium meliloti MsbA2 protein is essential for the legume symbiosis

Sinorhizobium meliloti is a beneficial legume symbiont, closely related to Brucella species, which are chronic mammalian pathogens. We discovered that the S. meliloti MsbA2 protein is essential to ensure the symbiotic interaction with the host plant, alfalfa. S. meliloti invades plant cells via plant-derived structures known as infection threads. However, in the absence of MsbA2, S. meliloti remains trapped within abnormally thickened infection threads and induces a heightened plant defence response, characterized by a substantial thickening of the nodule endodermis layer and the accumulation of polyphenolic compounds. The S. meliloti MsbA2 protein is homologous to the Escherichia coli lipopolysaccharide/phospholipid trafficking protein MsbA. However, MsbA2 was not essential for the membrane transport of either lipopolysaccharide or phospholipids in S. meliloti. We determined that the msbA2 gene is transcribed in free-living S. meliloti and that in the absence of MsbA2 the polysaccharide content of S. meliloti is altered. Consequently, we propose a model whereby the altered polysaccharide content of the S. meliloti msbA2 mutant could be responsible for its symbiotic defect by inducing an inappropriate host response. © 2008 SGM

PEER Testbed Study on a Laboratory Building: Exercising Seismic Performance Assessment

From 2002 to 2004 (years five and six of a ten-year funding cycle), the PEER Center organized the majority of its research around six testbeds. Two buildings and two bridges, a campus, and a transportation network were selected as case studies to “exercise” the PEER performance-based earthquake engineering methodology. All projects involved interdisciplinary teams of researchers, each producing data to be used by other colleagues in their research. The testbeds demonstrated that it is possible to create the data necessary to populate the PEER performancebased framing equation, linking the hazard analysis, the structural analysis, the development of damage measures, loss analysis, and decision variables. This report describes one of the building testbeds—the UC Science Building. The project was chosen to focus attention on the consequences of losses of laboratory contents, particularly downtime. The UC Science testbed evaluated the earthquake hazard and the structural performance of a well-designed recently built reinforced concrete laboratory building using the OpenSees platform. Researchers conducted shake table tests on samples of critical laboratory contents in order to develop fragility curves used to analyze the probability of losses based on equipment failure. The UC Science testbed undertook an extreme case in performance assessment—linking performance of contents to operational failure. The research shows the interdependence of building structure, systems, and contents in performance assessment, and highlights where further research is needed. The Executive Summary provides a short description of the overall testbed research program, while the main body of the report includes summary chapters from individual researchers. More extensive research reports are cited in the reference section of each chapter

Rapid exchange of mammalian topoisomerase IIα at kinetochores and chromosome arms in mitosis

Astable cell line (GT2-LPk) derived from LLC-Pk was created in which endogenous DNA topoisomerase IIα (topoIIα) protein was downregulated and replaced by the expression of topoIIα fused with enhanced green fluorescent protein (EGFP–topoIIα). The EGFP–topoIIα faithfully mimicked the distribution of the endogenous protein in both interphase and mitosis. In early stages of mitosis, EGFP–topoIIα accumulated at kinetochores and in axial lines extending along the chromosome arms. During anaphase, EGFP–topoIIα diminished at kinetochores and increased in the cytoplasm with a portion accumulating into large circular foci that were mobile and appeared to fuse with the reforming nuclei. These cytoplasmic foci appearing at anaphase were coincident with precursor organelles of the reforming nucleolus called nucleolus-derived foci (NDF). Photobleaching of EGFP–topoIIα associated with kinetochores and chromosome arms showed that the majority of the protein rapidly exchanges (t1/2 of 16 s). Catalytic activity of topoIIα was essential for rapid dynamics, as ICRF-187, an inhibitor of topoIIα, blocked recovery after photobleaching. Although some topoIIα may be stably associated with chromosomes, these studies indicate that the majority undergoes rapid dynamic exchange. Rapid mobility of topoIIα in chromosomes may be essential to resolve strain imparted during chromosome condensation and segregation

NMR structure of a fungal virulence factor reveals structural homology with mammalian saposin B

The fungal protein CBP (calcium binding protein) is a known virulence factor with an unknown virulence mechanism. The protein was identified based on its ability to bind calcium and its prevalence as Histoplasma capsulatum’s most abundant secreted protein. However, CBP has no sequence homology with other calcium binding proteins and contains no known calcium-binding motifs. Here, the NMR structure of CBP reveals a highly intertwined homodimer and represents the first atomic level NMR model of any fungal virulence factor. Each CBP monomer is comprised of four α-helices that adopt the saposin fold, characteristic of a protein family that binds to membranes and lipids. This structural homology suggests that CBP functions as a lipid-binding protein, potentially interacting with host glycolipids in the phagolysosome of host cells

Extragalactic magnetism with SOFIA (SALSA Legacy Program). VI. The magnetic fields in the multi-phase interstellar medium of the Antennae galaxies

Mergers are thought to be a fundamental channel for galaxy growth, perturbing the gas dynamics and the magnetic fields (B-fields) in the interstellar medium (ISM). However, the mechanisms that amplify and dissipate B-fields during a merger remain unclear. We characterize the morphology of the ordered B-fields in the multi-phase ISM of the closest merger of two spiral galaxies, the Antennae galaxies. We compare the inferred B-fields using $154~\mu$m thermal dust and $11$ cm radio synchrotron emission polarimetric observations. We find that the $154~\mu$m B-fields are more ordered across the Antennae galaxies than the $11$ cm B-fields. The turbulent-to-ordered $154~\mu$m B-field increases at the galaxy cores and star-forming regions. The relic spiral arm has an ordered spiral $154~\mu$m B-field, while the $11$ cm B-field is radial. The $154~\mu$m B-field may be dominated by turbulent dynamos with high $^{12}$CO(1-0) velocity dispersion driven by star-forming regions, while the $11$ cm B-field is cospatial with high HI velocity dispersion driven by galaxy interaction. This result shows the dissociation between the warm gas mainly disturbed by the merger, and the dense gas still following the dynamics of the relic spiral arm. We find a $\sim8.9$ kpc scale ordered B-field connecting the two galaxies. The base of the tidal tail is cospatial with the HI and $^{12}$CO(1-0) emission and has compressed and/or sheared $154~\mu$m and $11$ cm B-fields driven by the merger. We suggest that amplify B-fields, with respect to the rest of the system and other spiral galaxies, may be supporting the gas flow between both galaxies and the tidal tail.Comment: 11 pages, 5 figures, Accepted for publication in ApJ Letter

Delivery of Dark Material to Vesta via Carbonaceous Chondritic Impacts

NASA's Dawn spacecraft observations of asteroid (4) Vesta reveal a surface with the highest albedo and color variation of any asteroid we have observed so far. Terrains rich in low albedo dark material (DM) have been identified using Dawn Framing Camera (FC) 0.75 {\mu}m filter images in several geologic settings: associated with impact craters (in the ejecta blanket material and/or on the crater walls and rims); as flow-like deposits or rays commonly associated with topographic highs; and as dark spots (likely secondary impacts) nearby impact craters. This DM could be a relic of ancient volcanic activity or exogenic in origin. We report that the majority of the spectra of DM are similar to carbonaceous chondrite meteorites mixed with materials indigenous to Vesta. Using high-resolution seven color images we compared DM color properties (albedo, band depth) with laboratory measurements of possible analog materials. Band depth and albedo of DM are identical to those of carbonaceous chondrite xenolith-rich howardite Mt. Pratt (PRA) 04401. Laboratory mixtures of Murchison CM2 carbonaceous chondrite and basaltic eucrite Millbillillie also show band depth and albedo affinity to DM. Modeling of carbonaceous chondrite abundance in DM (1-6 vol%) is consistent with howardite meteorites. We find no evidence for large-scale volcanism (exposed dikes/pyroclastic falls) as the source of DM. Our modeling efforts using impact crater scaling laws and numerical models of ejecta reaccretion suggest the delivery and emplacement of this DM on Vesta during the formation of the ~400 km Veneneia basin by a low-velocity (<2 km/sec) carbonaceous impactor. This discovery is important because it strengthens the long-held idea that primitive bodies are the source of carbon and probably volatiles in the early Solar System.Comment: Icarus (Accepted) Pages: 58 Figures: 15 Tables:

Increased ventral striatal volume in college-aged binge drinkers

BACKGROUND Binge drinking is a serious public health issue associated with cognitive, physiological, and anatomical differences from healthy individuals. No studies, however, have reported subcortical grey matter differences in this population. To address this, we compared the grey matter volumes of college-age binge drinkers and healthy controls, focusing on the ventral striatum, hippocampus and amygdala. METHOD T1-weighted images of 19 binge drinkers and 19 healthy volunteers were analyzed using voxel-based morphometry. Structural data were also covaried with Alcohol Use Disorders Identification Test (AUDIT) scores. Cluster-extent threshold and small volume corrections were both used to analyze imaging data. RESULTS Binge drinkers had significantly larger ventral striatal grey matter volumes compared to controls. There were no between group differences in hippocampal or amygdalar volume. Ventral striatal, amygdalar, and hippocampal volumes were also negatively related to AUDIT scores across groups. CONCLUSIONS Our findings stand in contrast to the lower ventral striatal volume previously observed in more severe forms of alcohol use disorders, suggesting that college-age binge drinkers may represent a distinct population from those groups. These findings may instead represent early sequelae, compensatory effects of repeated binge and withdrawal, or an endophenotypic risk factor