Application of Rat In Situ Single-pass Intestinal Perfusion in the Evaluation of Presystemic Extraction of Indinavir Under Different Perfusion Rates

Background/PurposeFirst-pass effect has been an important concern for oral pharmaceuticals. An in vivo system was developed for measuring different concentrations of pharmaceuticals in the portal vein and hepatic vein (via the inferior vena cava) for delineating presystemic metabolism under different perfusion rates by using indinavir as an exemplary agent.MethodsAn in situ single-pass intestinal perfusion technique was modified from previous studies to concomitantly obtain portal and hepatic venous bloods. Portal and hepatic venous samples were simultaneously taken from rats at appropriate time points using the perfusion model of 1 mg/mL indinavir at flow rates of 0.05, 0.1, 0.5 and 1.0 mL/min. The indinavir concentrations were assayed by binary-gradient high-pressure liquid chromatography with UV detection.ResultsThe mean indinavir concentrations in portal vein concentration−time profiles at different perfusion times under various flow rates were all higher than those obtained for hepatic veins. At flow rates of 0.5 and 1.0 mL/min, in particular, the area under the curve (AUC) and maximal concentration (C max) of indinavir absorption were significantly different between portal veins and hepatic veins (p < 0.05), indicating considerable hepatic involvement in the presystemic extraction of indinavir. The system also has potential for use when estimating the hepatic extraction ratio (E H) and hepatic clearance (Cl H).ConclusionThis in vivo approach could provide another useful tool for improving our basic understanding of the absorption kinetics and hepatic metabolism of pharmaceuticals under development and facilitating the clinical application of such

Electromagnetic Wave Theory and Remote Sensing

Contains reports on eight research projects.Joint Services Electronics Program (Contract DAAG29-83-K-0003)National Science Foundation (Grant ECS82-03390)Schlumberger-Doll Research CenterNational Aeronautics and Space Administration (Contract NAG5-141)National Aeronautics and Space Administration (Contract NAS5-26861)National Aeronautics and Space Administration (Contract NAG5-270)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0258)International Business Machines, Inc

<i>Schizosaccharomyces pombe</i> Pol II transcription elongation factor ELL functions as part of a rudimentary super elongation complex

ELL family transcription factors activate the overall rate of RNA polymerase II (Pol II) transcription elongation by binding directly to Pol II and suppressing its tendency to pause. In metazoa, ELL regulates Pol II transcription elongation as part of a large multisubunit complex referred to as the Super Elongation Complex (SEC), which includes P-TEFb and EAF, AF9 or ENL, and an AFF family protein. Although orthologs of ELL and EAF have been identified in lower eukaryotes including Schizosaccharomyces pombe, it has been unclear whether SEClike complexes function in lower eukaryotes. In this report, we describe isolation from S. pombe of an ELL-containing complex with features of a rudimentary SEC. This complex includes S. pombe Ell1, Eaf1, and a previously uncharacterized protein we designate Ell1 binding protein 1 (Ebp1), which is distantly related to metazoan AFF family members. Like the metazoan SEC, this S. pombe ELL complex appears to function broadly in Pol II transcription. Interestingly, it appears to have a particularly important role in regulating genes involved in cell separation

Electromagnetic Wave Theory and Applications

Contains reports on eleven research projects.Joint Services Electronics Program (Contract DAAG29-83-K-0003)Joint Services Electronics Program (Contract DAAL03-86-K-0002)National Science Foundation (Grant ECS82-03390)National Science Foundation (Grant ECS85-04381)Schlumberger-Doll Research CenterNational Aeronautics and Space Administration (Contract NAG 5-141)National Aeronautics and Space Administration (Contract NAS 5-26861)National Aeronautics and Space Administration (Contract NAG 5-270)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0258)National Aeronautics and Space Administration (Contract NAG 5-725)International Business Machines, Inc.Lincoln Laborator

Electromagnetic Wave Theory and Applications

Contains reports on twelve research projects.Joint Services Electronics Program (Contract DAALO3-86-K-0002)National Science Foundation (Grant ECS 85-04381)National Aeronautics and Space Administration/Goddard Space Flight Center (Contract NAG5-270)National Aeronautics and Space Administration/Goddard Space Flight Center (Contract NAG5-725)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0258)U.S. Navy - Office of Naval Research (Contract N00014-86-K-0533)U.S. Army - Research Office Durham (Contract DAAG29-85-K-0079)International Business Machines, Inc.National Aeronautics and Space Administration/Goddard Space Flight Center (Contract NAG5-269)Simulation TechnologiesSchlumberger-Doll Researc

DMS triggers apoptosis associated with the inhibition of SPHK1/NF-κB activation and increase in intracellular Ca2+ concentration in human cancer cells

N,N-Dimethyl-D-erythro-sphingosine (DMS) is known to induce cell apoptosis by specifically inhibiting sphingosine kinase 1 (SPHK1) and modulating the activity of cellular ceramide levels. The present study investigated the effects and the mechanism(s) of action of DMS in human lung cancer cells. We found that DMS dose-dependently suppressed cell proliferation and induced cell apoptosis in the human lung cancer cell line, A549. Mechanistically, treatment with DMS suppressed the activation of SPHK1 and nuclear factor-B (NF-B) p65, but increased intracellular [Ca2+]i in A549 cells. This study demonstrates that DMS triggers the apoptosis of human lung cancer cells through the modulation of SPHK1, NF-B and calcium signaling. These molecules may represent targets for anticancer drug design

Electromagnetic Wave Theory and Applications

Contains table of contents for Section 3, research summary and reports on six research projects.Joint Services Electronics Program (Contract DAAL 03-86-K-0002)Joint Services Electronics Program (Contract DAAL 03-89-C-0001)U.S. Navy - Office of Naval Research (Contract N00014-86-K-0533)National Science Foundation (Contract ECS 86-20029)U.S. Army Research Office (Contract DAAL03 88-K-0057)International Business Machine CorporationSchlumberger-Doll ResearchNational Aeronautics and Space Administration (Contract NAG 5-270)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0258)National Aeronautics and Space Administration (Contract NAG 5-769)U.S. Army Corps of Engineers - Waterways Experimental Station (Contract DACA39-87-K-0022)Simulation TechnologiesU.S. Air Force - Rome Air Development Center (Contract F19628-88-K-0013)U.S. Navy - Office of Naval Research (Contract N00014-89-J-1107)Digital Equipment Corporatio

Preservation of citrus fruit, and dissipation by diffusion and degradation of postharvest pesticides during storage

We investigated the effects of residues of the postharvest pesticides 2,4-dichlorophenol, carbendazim, iprodione and prochloraz in citrus fruits, where they were encountered in average contents of 0.765 ± 0.060, 0.367 ± 0.030, 0.739 ± 0.055, and 0.929 ± 0.074 mg kg−1, respectively, and exhibited half-lives of 6.47–77.00 d upon storage at 3 °C for 45 d. The contents in 2,4-dichlorophenol and carbendazim did not exceed the maximum residue levels (MRLs) set by the European Union (1.0 mg kg−1) and China (5.0 mg kg−1). Preservatives added to Valencia citrus fruit (Citrus sinensis L. Osbeck) were degraded slowly at 3 °C. More than 50 % of their amounts remained on the fruit peel and never reached the pulp —by exception, the content in carbendazim of the pulp of oranges stored at 21 °C for 7 d was as high as 0.52 mg kg−1, which testifies to the need for storage at lower temperatures. Residue degradation exhibited strong, negative correlation with temperature, the relationship between the degradation rate constant (k) and temperature being of the Arrhenius type. Carbendazim proved an effective preservative for citrus fruit. Fruits should be carefully controlled for residual pesticide levels in order to ensure that they are safe for human consumption.Universidade de Vigo/CISU

Intrarenal resistance index for the assessment of acute renal injury in a rat liver transplantation model

Abstract Background Acute kidney injury (AKI) is a common complication after liver transplantation (LT) and associated with a high mortality. The renal resistive index (RI) is used to assess early renal function impairment in critical care patients. However, limited data are available concerning changes of renal RI and the development of AKI early after reperfusion. We approached to investigate the changes of renal RI and AKI after reperfusion in a rat liver transplantation model. Methods Rats were randomly divided into sham group or LT group. Ten rats in each group were used for the hemodynamic study and twenty for Doppler measurements during the procedure. Ten rats were sacrificed 30 min or 2 h after the reperfusion. We harvested kidneys, serum and urine for further analysis of the renal function. Results The intrarenal RI increased significantly in the anhepatic stage and decreased significantly after the reperfusion in the LT group compared with sham group (P &lt; 0.05). AKI was seen after the reperfusion in the LT group. No correlation was noted between the RI and renal function parameters 30 min after reperfusion. Conclusions The intrarenal RI increased significantly during the anhepatic stage, and decreased significantly early after the reperfusion. Intrarenal RI was unable to assess renal function in a rat liver transplantation model. </jats:sec

Dual-Space Optimization: Improved Molecule Sequence Design by Latent Prompt Transformer

Designing molecules with desirable properties, such as drug-likeliness and high binding affinities towards protein targets, is a challenging problem. In this paper, we propose the Dual-Space Optimization (DSO) method that integrates latent space sampling and data space selection to solve this problem. DSO iteratively updates a latent space generative model and a synthetic dataset in an optimization process that gradually shifts the generative model and the synthetic data towards regions of desired property values. Our generative model takes the form of a Latent Prompt Transformer (LPT) where the latent vector serves as the prompt of a causal transformer. Our extensive experiments demonstrate effectiveness of the proposed method, which sets new performance benchmarks across single-objective, multi-objective and constrained molecule design tasks