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- MacDonald, Patrick, et al.
(författare)
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Impaired glucose-stimulated insulin secretion, enhanced IP insulin tolerance and increased {beta}-cell mass in mice lacking the p110{gamma} isoform of PI3-kinase.
- 2004
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 145:9, s. 4078-4083
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Tidskriftsartikel (refereegranskat)abstract
- Phosphoinositide 3-kinase (PI3 kinase) has been implicated in G protein-coupled receptor regulation of pancreatic ß-cell growth and glucose-stimulated insulin secretion. The G protein-activated p110{gamma} isoform of PI3 kinase was detected in insulinoma cells, mouse islets, and human islets. In 7- to 10-wk-old mice, knockout of p110{gamma} reduced the plasma insulin response to ip glucose injection and impaired first and second phase glucose-stimulated insulin secretion from pancreata perfused ex vivo. The p110{gamma} –/– mice responded to preinjection with the glucagon-like peptide-1 receptor agonist exendin 4, such that plasma glucose and insulin responses to ip glucose injection were not different from wild types. Mice lacking p110{gamma} were not diabetic and were only slightly glucose intolerant (ip glucose injection) compared with wild types, in part due to enhanced responsiveness to insulin as determined by an ip insulin tolerance test. Despite severely reduced insulin secretion in these animals, the p110{gamma} –/– mice had greater pancreatic insulin content, and an increased ß-cell mass due to ß-cell hypertrophy. These surprising results suggest that the G protein-coupled p110{gamma} isoform of PI3 kinase is not central to the development or maintenance of sufficient ß-cell mass but positively regulates glucose-stimulated insulin secretion.
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- Bastviken, David, 1971-
(författare)
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Anoxic degradation of organic matter in lakes : implications for carbon cycling and aquatic food webs
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Considerable evidence from laboratory studies and marine environments suggests that degradation of organic matter (OM) is restricted under anoxic conditions compared to when molecular oxygen (O2) is present. However, other studies contradict this view since they found similar OM degradation rates and bacterial growth rates under both oxic and anoxic conditions in aquatic environments. Studies from freshwater environments are rare, and have been primarily based on bacterial production estimates. Anoxic degradation of OM in lakes is commonly considered to be slow and of little importance for overall lake food webs compared to oxic degradation. The present thesis and the work it is based on challenge this view. First, the performance of a commonly used method to measure bacterial production was tested in both oxic and anoxic lake water. Then, the oxic and anoxic potentials of bacterial growth and OM mineralization were compared in lake water and sediment. In addition, I assessed the potential of carbon transfer from methane (CH4; i.e. an end-product of anoxic degradation) to pelagic food webs. Three methods for measuring water column methane oxidation were evaluated. Then, the potential transport of methane carbon into the microbial community via methane oxidation, and further -up the food web- into the zooplankton community was estimated. Results indicate 1) that OM degradation and bacterial growth may be similar in oxic and anoxic lake environments, 2) that OM characteristics may be more important for the mineralization than the O2 regime per se in the short term (daysweeks), and 3) that methane can be a significant source of carbon and energy for pelagic food webs. This suggests that the anoxic carbon metabolism may be extensive and potentially important for pelagic organisms in many lakes.
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- Bruton, Joseph D., et al.
(författare)
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Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent signal for insulin secretion
- 2003
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 17:2, s. 301-303
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Tidskriftsartikel (refereegranskat)abstract
- The ryanodine (RY) receptors in beta-cells amplify signals by Ca2+-induced Ca2+ release (CICR). The role of CICR in insulin secretion remains unclear in spite of the fact that caffeine is known to stimulate secretion. This effect of caffeine is attributed solely to the inhibition of cAMP-phosphodiesterases (cAMP-PDEs). We demonstrate that stimulation of insulin secretion by caffeine is due to a sensitization of the RY receptors. The dose-response relationship of caffeine-induced inhibition of cAMP-PDEs was not correlated with the stimulation of insulin secretion. Sensitization of the RY receptors stimulated insulin secretion in a context-dependent manner, that is, only in the presence of a high concentration of glucose. This effect of caffeine depended on an increase in [Ca2+]i. Confocal images of beta-cells demonstrated an increase in [Ca2+]i induced by caffeine but not by forskolin. 9-Methyl-7-bromoeudistomin D (MBED), which sensitizes RY receptors, did not inhibit cAMP-PDEs, but it stimulated secretion in a glucose-dependent manner. The stimulation of secretion by caffeine and MBED involved both the first and the second phases of secretion. We conclude that the RY receptors of beta-cells mediate a distinct glucose-dependent signal for insulin secretion and may be a target for developing drugs that will stimulate insulin secretion only in a glucose-dependent manner.
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- Ell, Alida H., et al.
(författare)
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Dehydrogenation of aromatic amines to imines via ruthenium-catalyzed hydrogen transfer.
- 2002
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Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345 .- 1364-548X. ; :10, s. 1144-1145
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Tidskriftsartikel (refereegranskat)abstract
- An efficient ruthenium-catalyzed transfer dehydrogenation of amines to imines was achieved under mild conditions using 2,6-dimethoxybenzoquinone (I) or a catalytic amt. of I with MnO2 as oxidant. [on SciFinder(R)]
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- Hua, Jianyi, et al.
(författare)
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Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate.
- 2003
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Ingår i: Anticancer research. - 1791-7530. ; 23:2B, s. 1433-1440
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Tidskriftsartikel (refereegranskat)abstract
- Oxi4503, which is the diphosphate prodrug of combretastatin A1, is a novel vascular targeting agent from the combretastatin family. Another member of this family, Combretastatin A-4 phosphate (CA4P), is a well-characterized vascular targeting agent already being evaluated in clinical trials. The potential for tumor vascular targeting by Oxi4503 was assessed in a mouse system. This approach aims to shut down the established tumor vasculature, leading to the development of extensive tumor cell necrosis. The vascular effects of Oxi4503 were assessed in the s.c. implanted MDA-MB-231 adenocarcinoma and the MHEC5-T hemangio-endothelioma in SCID mice and in a range of normal tissues. Blood flow was measured by i.v. injection of fluorescence beads, while quantitative fluorescence microscopy was used to measure the spatial heterogeneity of blood flow in tumor sections. Oxi4503 induced the shutdown of tumor blood vessels in a dose-dependent pattern with an ED50 at 3 mg/kg in contrast to 43 mg/kg of CA4P. Quantitative fluorescence microscopy showed that Oxi4503 increased the spatial heterogeneity in tumor blood flow. Oxi4503 affected peripheral tumor regions less than central regions, although this was not as pronounced as seen with CA4P, where only central regions were affected. The vascular shutdown induced by administration of Oxi4503 at a dose of 6 mg/kg resulted in extensive cell loss 24 hours following treatment, which translated into a significant effect on tumor growth. Tumor growth was completely repressed at doses above 12.5 mg/kg of Oxi4503, while doses above 25 mg/kg showed tumor regression and even complete regression in some animals. These results are promising for the use of Oxi4503 as a tumor vascular targeting agent. Moreover the potent antitumor effect when administered as a single agent suggests a different activity profile than CA4P.
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- Magnuson, Martin, et al.
(författare)
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Electronic-structure investigation of CeB6 by means of soft-x-ray scattering
- 2001
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 63:7, s. 075101-
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Tidskriftsartikel (refereegranskat)abstract
- The electronic structure of the heavy fermion compound CeB6 is probed by resonant inelastic soft-x-ray scattering using photon energies across the Ce 3d and 4d absorption edges. The hybridization between the localized 4f orbitals and the delocalized valence-band states is studied by identifying the different spectral contributions from inelastic Raman scattering and normal fluorescence. Pronounced energy-loss structures are observed below the elastic peak at both the 3d and 4d thresholds. The origin and character of the inelastic scattering structures are discussed in terms of charge-transfer excitations in connection to the dipole allowed transitions with 4f character. Calculations within the single-impurity Anderson model with full multiplet effects are found to yield consistent spectral functions to the experimental data.
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| 27. |
- Pamies, Oscar, et al.
(författare)
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An efficient and mild ruthenium-catalyzed racemization of amines : application to the synthesis of enantiomerically pure amines.
- 2002
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Ingår i: Tetrahedron Letters. - 0040-4039 .- 1359-8562. ; 43:26, s. 4699-4702
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Tidskriftsartikel (refereegranskat)abstract
- An efficient and mild Ru-catalyzed racemization of amines under transfer hydrogenation conditions is reported. A significant advantage of this new procedure is that the ruthenium hydrogen transfer catalysts allow high functional group tolerance. Interestingly, both primary and secondary amines were efficiently racemized under these conditions. We also report on the combination of this new amine racemization with an enzymic kinetic resoln. of primary amines. [on SciFinder(R)]
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| 28. |
- Routh, Joyanto, 1968-, et al.
(författare)
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Volatile organic acids and microbial processes in the Yegua formation, east-central Texas
- 2001
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Ingår i: Applied Geochemistry. - : Elsevier. - 0883-2927 .- 1872-9134. ; 16:2, s. 183-195
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Tidskriftsartikel (refereegranskat)abstract
- Geochemical and microbiological evidence indicates that viable microorganisms produce and consume volatile organic acids (VOA) in the Yegua formation. Acetic and propionic acid concentrations in mudstones range from 200 to 1270 and 20 to 38 nmol·gdw−1 respectively, whereas concentrations in sands are 50–200 and less than 20 nmol·gdw−1. VOA concentrations in sediments and in laboratory incubations suggest net production of VOAs by microorganisms in mudstones, and net consumption of VOAs by SO4 reducing bacteria (SRB) in sands. Notably, SRB activity is mostly confined to aquifer sands. Vertical diffusion and advection were modeled to estimate acetic acid transport from aquitard to aquifer. Assuming that SRB completely respire the acetic acid transported into the aquifer (3.2 μmol·l−1·m·a−1), the CO2 production rate in the aquifer sands is 5.3 μmol·l−1·a−1. This slow mineralization rate of in situ organic matter is within the range for deep aquifers, and probably accounts for the long-term survival of microorganisms in oligotrophic environments. Finally, the microbial communities in Yegua sediments appear to exhibit a loose commensalism, with microorganisms in aquitards providing VOAs for respiratory processes (i.e., SO4 reduction) in aquifers.
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| 32. |
- Samec, Joseph S. M., et al.
(författare)
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Ruthenium-catalyzed transfer hydrogenation of imines by propan-2-ol in benzene.
- 2002
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Ingår i: Chemistry - A European Journal. - 0947-6539 .- 1521-3765. ; 8:13, s. 2955-2961
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Tidskriftsartikel (refereegranskat)abstract
- Transfer hydrogenation of a variety of different imines to the corresponding amines by propan-2-ol in benzene catalyzed by [Ru2(CO)4(Ό-H)(C4Ph4COHOCC4Ph4)] (1) has been studied. The reaction is highly efficient with turnover frequencies of over 800 per h, and the product amines were obtained in excellent yields. A remarkable concn. dependence of propan-2-ol was obsd. when the reaction was run in benzene as cosolvent. An optimum was obtained at 24 equiv of propan-2-ol to imine, and further increase of the propan-2-ol led to a dramatic decrease in rate. Also the use of polar cosolvents with 24 equiv of propan-2-ol gave a low rate. It was found that ketimines react faster than aldimines and that electron-donating substituents on the imine increase the rate of the catalytic transfer hydrogenation. Electron-withdrawing substituents decreased the rate. An isomerization was obsd. with imines having an α-hydrogen at the N-alkyl substituent, which is in accordance with a mechanism involving a ruthenium-amine intermediate. It was demonstrated that the ruthenium-amine complex from α-methylbenzylamine, corresponding to the postulated intermediate, can replace 1 as catalyst in the transfer hydrogenation of imines. A primary deuterium isotope effect of kCH/CD = 2.7 ± 0.25 was obsd. when 2-deuterio-propan-2-ol was used in place of propan-2-ol in the transfer hydrogenation of N-phenyl-(1-phenylethylidene)amine. [on SciFinder(R)]
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| 35. |
- Schreiber, Martin A, et al.
(författare)
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The effect of recombinant factor VIIa on coagulopathic pigs with grade V liver injuries.
- 2002
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Ingår i: Journal of Trauma. - 0022-5282. ; 53:2, s. 252-257
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recombinant factor VIIa (rFVIIa) has been used to decrease bleeding in a number of settings including hemophilia, liver transplantation, intractable bleeding, and cirrhosis. Experience in the trauma setting is limited. This study was performed to determine whether rFVIIa would reduce bleeding after a grade V liver injury in hypothermic, dilutionally coagulopathic pigs when used as an adjunct to abdominal packing and to determine whether increasing the dose of the drug increased its hemostatic efficacy. METHODS: Thirty animals were randomized to receive 180 microg/kg of rFVIIa, 720 microg/kg of rFVIIa, or vehicle buffer control. After laparotomy and splenectomy, animals underwent a 60% blood volume isovolemic exchange transfusion with 5% human albumin. The animals' temperature was maintained at 33 degrees C and a standardized grade V liver injury was made with a liver clamp. Thirty seconds after injury, the abdomen was packed with laparotomy sponges, resuscitation was initiated, and blinded therapy was given. Animals were resuscitated to their baseline mean arterial pressure and the study was continued for 2 hours. Serial coagulation parameters were measured at the temperature they were drawn. After the study period, surviving animals were killed, posttreatment blood loss was measured, and an autopsy was performed. RESULTS: Ten animals were randomized to each group. After administration of study drug, factor VII clotting activity (FVII:C) was higher in the 720 microg/kg group than in the 180 microg/kg group (p < 0.01). FVII:C was higher in both treatment groups than in the control group (p < 0.01). The mean prothrombin time was shorter in the treatment groups than in the control group (p < 0.05). Mean arterial pressure was lower in the control group than in the treatment groups throughout the study (p < 0.01). Mean blood loss was less in the treatment groups than in the control group (p = 0.03). Mortality was not different between groups. There were no differences between the groups that received rFVIIa in any measured parameters except for FVII:C. Liver injuries were similar between groups and there was no evidence of microthrombosis on lung histology. CONCLUSION: rFVIIa reduces blood loss in hypothermic, dilutionally coagulopathic pigs with grade V injuries when used as an adjunct to packing. Increasing the dose does not enhance the hemostatic effect.
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- Weinstein, M.C., et al.
(författare)
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Principles of Good Practice for Decision Analytic Modeling in Health-Care Evaluation: Report of the ISPOR Task Force on Good Research Practices—Modeling Studies
- 2003
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Ingår i: Value in health. - : Elsevier Inc. - 1524-4733 .- 1098-3015. ; 6:1, s. 9-17
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Tidskriftsartikel (refereegranskat)abstract
- Mathematical modeling is used widely in economic evaluations of pharmaceuticals and other health-care technologies. Users of models in government and the private sector need to be able to evaluate the quality of models according to scientific criteria of good practice. This report describes the consensus of a task force convened to provide modelers with guidelines for conducting and reporting modeling studies. The task force was appointed with the advice and consent of the Board of Directors of ISPOR. Members were experienced developers or users of models, worked in academia and industry, and came from several countries in North America and Europe. The task force met on three occasions, conducted frequent correspondence and exchanges of drafts by electronic mail, and solicited comments on three drafts from a core group of external reviewers and more broadly from the membership of ISPOR. Criteria for assessing the quality of models fell into three areas: model structure, data used as inputs to models, and model validation. Several major themes cut across these areas. Models and their results should be represented as aids to decision making, not as statements of scientific fact; therefore, it is inappropriate to demand that models be validated prospectively before use. However, model assumptions regarding causal structure and parameter estimates should be continually assessed against data, and models should be revised accordingly. Structural assumptions and parameter estimates should be reported clearly and explicitly, and opportunities for users to appreciate the conditional relationship between inputs and outputs should be provided through sensitivity analyses. Model-based evaluations are a valuable resource for health-care decision makers. It is the responsibility of model developers to conduct modeling studies according to the best practicable standards of quality and to communicate results with adequate disclosure of assumptions and with the caveat that conclusions are conditional upon the assumptions and data on which the model is built.
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