Role of Mechanistic Transport Studies in Lead Optimization

2007 ◽  
pp. 25-47 ◽  
Author(s):  
Jerome Hochman ◽  
Qin Mei ◽  
Masayo Yamazaki ◽  
Cuyue Tang ◽  
Thomayant Prueksaritanont ◽  
...  
Keyword(s):  
Lead Optimization ◽  
Transport Studies

Synchronization of transport and supply in beach-dune interaction

2009 ◽  
Vol 33 (6) ◽  
pp. 733-746 ◽  
Author(s):  
Chris Houser
Keyword(s):  
Sediment Supply ◽  
Limited Capacity ◽  
Storm Events ◽  
Nearshore Processes ◽  
Transport Studies ◽  
Lack Of Information ◽  
Dynamic Constraint ◽  
Explicit Recognition ◽  
Process Scale

This review considers the role of nearshore processes and morphological change as a flexible and dynamic constraint on the supply and transport of sediment between beach and dune. It is argued that the lack of information in this regard remains a central barrier to the development of a theory of beach-dune interaction that can be translated across scales and between field sites. Existing beach-dune models do not consider how and when sediment gets transferred to the backshore where it becomes available for transport by wind. Rather, existing models largely ascribe regional variations in dune morphology to fixed constraints on beach slope and sediment budget, without explicit recognition of processes involved. Recent (process-scale) transport studies have shown that the transfer of sediment is both spatially variable and temporally intermittent as a result of transport limitations across the beachface. While these studies have identified varied controls on sediment transport and exchange, there remains a limited capacity to predict the evolution of beach-dune systems, largely because the beachface tends to be viewed as a static transport surface without regard to supply or to the changing limits to transport. Following storm erosion, dune recovery first requires that the beach recovers through the onshore migration and welding of nearshore bars, followed by accretion in the backshore to create a supply of sediment for transport by the wind. The dependence of dune recovery on the synchronization of transport events with the recovery of sediment supply in the backshore creates a strong asymmetry in dune recovery that makes barrier island susceptible to widespread erosion and breaching if a change in the frequency or grouping of storm events is capable of resetting the bar system (offshore) before the next extreme storm.

NMR spectroscopy in drug design

2001 ◽  
Vol 73 (9) ◽  
pp. 1429-1436 ◽  
Author(s):  
Markus Heller ◽  
Horst Kessler
Keyword(s):  
Small Molecules ◽  
Lead Optimization ◽  
Drug Candidate ◽  
Resonance Spectroscopy ◽  
Ligand Complex ◽  
New Techniques ◽  
Lead Finding ◽  
Efficient Screening ◽  
Insight Into

The process of preclinical drug discovery consists of two steps: finding of initial hits (binding ligands to a medicinal relevant target, usually a protein) and lead optimization. Nuclear magnetic resonance spectroscopy is a powerful tool that can provide valuable information to every step of drug development. NMR is commonly used for characterizing the structure and molecular dynamics of target or ligand molecules. During the structure-based lead optimization, NMR provides insight into the structural and dynamical properties of the target-ligand complex. Recently, the use of NMR in the lead finding process by screening technologies has been shown. For the latter use, new techniques have also been developed. Those techniques, in combination with high throughput, have lead to an efficient screening of libraries composed of small molecules. In this article, the role of NMR during the discovery of a drug candidate is described.

Parathyroid hormone mediates changes in calcium transport in uremic rat brain synaptosomes

1988 ◽  
Vol 254 (6) ◽  
pp. F837-F844 ◽  
Author(s):  
C. L. Fraser ◽  
P. Sarnacki
Keyword(s):  
Parathyroid Hormone ◽  
Rat Brain ◽  
Calcium Transport ◽  
Base Line ◽  
Transport Mechanisms ◽  
Rat Brain Synaptosomes ◽  
Transport Studies ◽  
Brain Synaptosomes ◽  
Uptake Studies

In previous studies, we showed that Ca2+ transport by both Na+ gradient-stimulated Ca2+ uptake and ATP-stimulated Ca2+ uptake was increased in synaptosomes from uremic rat brain. The possible role of parathyroid hormone (PTH) in this observation was investigated by performing Ca2+ transport studies in synaptosomes by these two mechanisms. Studies were performed in vesicles from rats that were either normal, uremic, uremic parathyroidectomized (PTX-U), or uremic parathyroidectomized but treated with PTH. In uremic rats, transport by both Na+ gradient-stimulated Ca2+ uptake and ATP-stimulated Ca2+ uptake was increased by 30 and 47%, respectively, whereas uptake was returned to base line in synaptosomes from PTX-U rats. Additionally, the administration of PTH to PTX-U rats resulted in a significant increase (P less than 0.001) of 36 and 41%, respectively, above the values observed in PTX-U rats. To determine whether the increased accumulation of Ca2+ in synaptosomes in uremia was a result of PTH alone and/or to the uremic environment, we next performed uptake studies in synaptosomes that were isolated from nonuremic rats that were either normal, parathyroidectomized (PTX) or PTX but treated with 2.8–100 micrograms PTH. By both transport mechanisms, uptake was significantly (P less than 0.01) decreased from normal by 27% in the PTX group, and either 2.8 or 110 micrograms PTH resulted in a significant increase in transport to base line by Na+-gradient stimulated Ca2+ uptake. However, Ca2+ accumulation by ATP-stimulated Ca2+ uptake was significantly increased to base line only with 100 micrograms PTH.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of mitochondrial glutamine/glutamate metabolism by glutamate transport: studies with 15N

2001 ◽  
Vol 280 (5) ◽  
pp. C1151-C1159 ◽  
Author(s):  
Tomas Welbourne ◽  
Itzhak Nissim
Keyword(s):  
Glutamate Uptake ◽  
Glutamate Transport ◽  
Glutamate Metabolism ◽  
Glutamine Concentration ◽  
Metabolic Fate ◽  
Glutamate Concentration ◽  
Transport Studies ◽  
The Media ◽  
Transport Inhibitors

We focused on the role of plasma membrane glutamate uptake in modulating the intracellular glutaminase (GA) and glutamate dehydrogenase (GDH) flux and in determining the fate of the intracellular glutamate in the proximal tubule-like LLC-PK1-F+ cell line. We used high-affinity glutamate transport inhibitors d-aspartate (d-Asp) and dl-threo-β-hydroxyaspartate (THA) to block extracellular uptake and then used [15N]glutamate or [2-15N]glutamine to follow the metabolic fate and distribution of glutamine and glutamate. In monolayers incubated with [2-15N]glutamine (99 atom %excess), glutamine and glutamate equilibrated throughout the intra- and extracellular compartments. In the presence of 5 mMd-Asp and 0.5 mM THA, glutamine distribution remained unchanged, but the intracellular glutamate enrichment decreased by 33% ( P < 0.05) as the extracellular enrichment increased by 39% ( P < 0.005). With glutamate uptake blocked, intracellular glutamate concentration decreased by 37% ( P < 0.0001), in contrast to intracellular glutamine concentration, which remained unchanged. Both glutamine disappearance from the media and the estimated intracellular GA flux increased with the fall in the intracellular glutamate concentration. The labeled glutamate and NH[Formula: see text] formed from [2-15N]glutamine and recovered in the media increased 12- and 3-fold, respectively, consistent with accelerated GA and GDH flux. However, labeled alanine formation was reduced by 37%, indicating inhibition of transamination. Although both d-Asp and THA alone accelerated the GA and GDH flux, only THA inhibited transamination. These results are consistent with glutamate transport both regulating and being regulated by glutamine and glutamate metabolism in epithelial cells.

THE ROLE OF RADIOTRACER TECHNIQUES IN OFF-SHORE CONTAMINANT TRANSPORT STUDIES

2000 ◽  
Author(s):  
PETER AIREY ◽  
MYINT ZAW ◽  
JIYUAN TU ◽  
TOM KLUSS ◽  
RON SZYMCZAK ◽  
...  
Keyword(s):  
Contaminant Transport ◽  
Transport Studies ◽  
Radiotracer Techniques

scholarly journals Disruption of the NF-H Gene Increases Axonal Microtubule Content and Velocity of Neurofilament Transport: Relief of Axonopathy Resulting from the Toxin β,β′-Iminodipropionitrile

1998 ◽  
Vol 143 (1) ◽  
pp. 183-193 ◽  
Author(s):  
Qinzhang Zhu ◽  
Michael Lindenbaum ◽  
Françoise Levavasseur ◽  
Hélène Jacomy ◽  
Jean-Pierre Julien
Keyword(s):  
Motor Neurons ◽  
Knockout Mice ◽  
Fold Increase ◽  
Neuronal Function ◽  
Neurofilament Light ◽  
Transport Studies ◽  
Gene Coding ◽  
M Proteins ◽  
Neurofilament Transport

To investigate the role of the neurofilament heavy (NF-H) subunit in neuronal function, we generated mice bearing a targeted disruption of the gene coding for the NF-H subunit. Surprisingly, the lack of NF-H subunits had little effect on axonal calibers and electron microscopy revealed no significant changes in the number and packing density of neurofilaments made up of only the neurofilament light (NF-L) and neurofilament medium (NF-M) subunits. However, our analysis of NF-H knockout mice revealed an ∼2.4-fold increase of microtubule density in their large ventral root axons. This finding was further corroborated by a corresponding increase in the ratio of assembled tubulin to NF-L protein in insoluble cytoskeletal preparations from the sciatic nerve. Axonal transport studies carried out by the injection of [35S]methionine into spinal cord revealed an increased transport velocity of newly synthesized NF-L and NF-M proteins in motor axons of NF-H knockout mice. When treated with β,β′-iminodipropionitrile (IDPN), a neurotoxin that segregates microtubules and retards neurofilament transport, mice heterozygous or homozygous for the NF-H null mutation did not develop neurofilamentous swellings in motor neurons, unlike normal mouse littermates. These results indicate that the NF-H subunit is a key mediator of IDPN-induced axonopathy.

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