The discovery value of “Big Science”

The increasing complexity of biomedical research is leading to the exploration of new models for large-scale collaborative research. This Big Science approach, however, has created anxieties and potential tensions between investigator-driven research, and research guided by a more organized, collaborative effort. Another potential tension exists between research conducted purely in search of new knowledge and research aimed at finding solutions. We argue that big biomedicine—the work of coordinated multidisciplinary groups that use the latest technologies to solve complex problems—can be an important way to harness the creativity of individual investigators, stimulate innovation, and supply the infrastructure, experimental systems, and resources needed to solve the urgent health problems confronted by our global society. We discuss this using the example of the Global HIV Vaccine Enterprise

Regulation of CA II and H + , K + -ATPase Gene Expression in Canine Gastric Parietal Cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75197/1/j.1749-6632.1989.tb25154.x.pd

Rapid Sequestration and Degradation of Somatostatin Analogues by Isolated Brain Microvessels

Somatostatin (SRIF) is a putative peptide neurotransmitter that may interact with brain capillaries following neurosecretion of the peptide. The present studies investigate the binding and metabolism of SRIF analogues in isolated bovine brain microvessels. 125 I [Tyr 1 ]SRIF was rapidly degraded by capillary aminopeptidase with a half-time of approximately 3 min at 23°C. The microvessel aminopeptidase had a low affinity and high capacity for the peptide, K m = 76 Μ M and V max = 74 nmol min −1 . 125 I-[Tyr 11 ]SRIF was converted to free iodotyrosine at a much slower rate, presumably by a lower-activity endopeptidase. 125 I-[Tyr 11 ]SRIF was rapidly bound by microvessels, whereas another basic peptide, [Tyr 8 ]bradykinin, or an acidic peptide, CCK8, or a neutral peptide, leucine enkephalin, were bound to a considerably less extent. The binding of 125 I-[Tyr 11 ]SRIF to the capillaries was nonsaturable up to a concentration of 1 Μg/ml of unlabeled peptide, and the binding reaction was extremely rapid, reaching equilibrium within 5 s at either 0°C or 37°C. Approximately 20% of the SRIF bound by the microvessels was resistant to acid wash and presumably represented internalized peptide. In addition, the 125 I-[Tyr 11 ]SRIF bound rapidly to the endothelial cytoskeleton remaining after a 1% Triton X-100 extraction of the microvessels. The peptide-cytoskeletal binding reaction was nonsaturable up to 1 Μg/ml of unlabeled [Tyr 11 ]SRIF, but it was inhibited by 0.5% polylysine or 0.8 M KC1 and was stimulated by 1 m M dithiothreiotol. These studies suggest that brain microvessels rapidly sequester and degrade SRIF analogues and that this may represent one mechanism for rapid inactivation of the neuropeptides subsequent to neurosecretion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66285/1/j.1471-4159.1985.tb08741.x.pd

Mechanisms for the stimulatory and inhibitory effects of carbamoylcholine on canine gastric D-cells

We have previously reported that carbamoylcholine (carbachol), a recognized inhibitor of somatostatin release from D-cells, can act as stimulant following pretreatment of cells with pertussis toxin. In the present studies we have observed that pertussis toxin reverses the inhibitory effects of carbachol on D-cell stimulated with either cAMP or 12-0-tetradecanoyl-phorbol 13-acetate. Furthermore, the stimulatory effects of carbachol on D-cells pretreated with pertussis toxin potentiated the actions of pentagastrin without further enhancing the release of 3H-inositol trisphosphate from prelabeled cells. These studies suggest that carbachol exerts its inhibitory effects on D-cells via pertussis toxin sensitive guaninine nucleotide binding proteins at a point distal to the activation of different signal transduction mechanisms and that the stimulatory effects of carbachol are mediated by mechanisms that are independent of membrane phosphoinositide turnover.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26606/1/0000147.pd

Progastrin-like immunoreactivity in porcine antrum: Identification and characterization with region-specific antisera

In an effort to identify and characterize precursors of gastrin in tissues, we generated region-specific antisera against a synthetic progastrin peptide, Tyr-Gly-Trp-Met-Asp-Phe-Gly-Arg-Arg (GL9), as deduced from the nucleotide sequence of gastrin mRNA. This antisera did not cross-react with gastrin or progastrin peptides with shorter carboxyl-terminal extensions. Progastrin-like immunoreactivity (PGLI) was measured in porcine antrum at a concentration of 6.8 +/- 1.2 pmol/g wet weight (mean +/- SE, N = 5), or roughly 0.2% of that of gastrin. On Sephadex G50 chromatography, a major peak of PGLI was eluted as a slightly larger molecule than gastrin heptadecapeptide (G17) but possessed the same N-terminal immunoreactivity. These findings suggest that G17 may be formed by processing of a carboxyl-terminally extended precursor as an alternative to cleavage of big gastrin (G34).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25781/1/0000342.pd

Characterization of gastrin amidation in the rat and porcine antrum: comparison with the pituitary

The formation of biologically active gastrin from glycine-extended processing intermediates occurs via the action of a peptide [alpha]-amidating enzyme. The observation that gastrin exists primarily as unamidated precursors in the pituitary but as amidated gastrin in the antrum prompted these studies to examine whether the amidating enzymes in the two organs were different in their characteristics. Furthermore, the amidating enzyme in the stomach has not previously been characterized in extensive detail. Amidating activity was quantified by measuring the conversion of Tyr-Gly-Trp-Met-Asp-Phe-Gly (glycine-extended hexagastrin) to Tyr-Gly-Trp-Met-Asp-Phe-NH2 (amidated hexagastrin) by radioimmunoassay. The activity of the antral enzyme in both the rat and hog had a similar apparent molecular weight (45,000-60,000), cofactor requirements (copper, ascorbic acid, and catalase), pH optima (5.5-8.5), and Km (12 [mu]M) as the pituitary enzyme. These data suggest that antral and pituitary peptide [alpha]-amidating enzymes are the same enzyme, thus it is unlikely that differences in amidating enzymes can account for the observed differences in the tissue specific processing of gastrin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28614/1/0000426.pd

Mapping of the gene encoding the [alpha]-subunit of the human H+, K+-ATPase to chromosome 19q13.1 by fluorescent in Situ hybridization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29823/1/0000169.pd

Spin-orbit coupling inactivity of Co2+^{2+} ion in geometrically frustrated magnet GeCo2_2O4_4

We report single-crystal neutron diffraction studies on a spinel antiferromagnet GeCo$_2$O$_4$, which exhibits magnetic order with a trigonal propagation vector and tetragonal lattice expansion ($c/a\simeq1.001$) below $T_{\rm N}=21$ K. For this inconsistency between spin and lattice in symmetry, magnetic Bragg reflections with a tetragonal propagation vector were discovered below $T_{\rm N}$. We discuss spin and orbital states of Co$^{2+}$ ion underlying the new magnetic component.Comment: 3 pages 2 figures, submitted to ICFCM proceeding (Journal of Physics: Conference Series, 2011

Fourteen and six c/sec positive bursts in comatose patients

Of ten patients with Reye's syndrome, there were five with stage II or III coma where EEGs revealed 14 c/sec positive bursst in a background of diffuse delta waves. Positive bursts disappeared upon EEG improvement in two survivors and when the EEG became nearly isoelectric in two other patients.Although 14 and 6 c/sec positive bursts are seen commonly during sleep in normal young persons, their occurence in association with diffuse delta waves in acutely ill, comatose patients has been rarely reported.It is not certain whether the present findings should be regarded as selective preservation of a type of sleep pattern or whether there are special factors that enhance positive bursts in stage II or III coma of Reye's syndrome.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21766/1/0000160.pd