Changes In Transport System Research Articles

Cation movements at alkaline pH in bacteria growing without respiration.

The respiratory chain has a central role in energy metabolism as a generator of a proton motive force in aerobic bacteria. In contrast, Enterococcus hirae (formerly Streptococcus faecalis), which lacks the respiratory chain, generates this proton gradient via a F-type H+ ATPase, but it works only at a pH below 8; no significant proton motive force is generated at a pH above 8. An Escherichia coli mutant deficient in both the respiratory chain and the H+ ATPase grew with a negligible proton motive force within the wide range of medium pH. It has been suggested that both E. hirae and E. coli are able to grow even when the cytoplasm is alkalinized beyond pH 8. These observations lead to the conclusion that bacteria can survive without operating cation transport systems driven by a proton motive force at alkaline pH. The activity of any transport system with optimum pH around neutrality should decline when both the outside and inside of cells are alkalinized. Thus, changes in transport systems as well as cellular metabolism may be essential for bacterial adaptation to changes in environmental pH.

Aer on the inside looking out: paradigm for a PAS–HAMP role in sensing oxygen, redox and energy

Aer, the Escherichia coli aerotaxis (oxygen-sensing) receptor, is representative of a small class of receptors that face the cytoplasm in bacteria. Instead of sensing oxygen directly, Aer detects redox changes in the electron transport system or cytoplasm when the bacteria enter or leave a hypoxic microniche. As a result, Aer sensing also enables bacteria to avoid environments where carbon deficiency, unfavourable reduction potential or other insults would limit energy production. An FAD-binding PAS domain is the sensor for Aer and a HAMP domain interacts with the PAS domain to form an input-output module for signal transduction. By analogy to the first solution structure of an isolated HAMP domain from Archaeoglobus, Aer HAMP is proposed to fold into a four-helix bundle that rotates between a signal-on and signal-off conformation. Aer is the first protein in which a PAS-HAMP input-output module has been investigated. The structure and signal transduction mechanism of Aer is providing important insights into signalling by PAS and HAMP domains.

Chronic influence of demanding physical exercise on venous blood-gas status

Although there is comprehensive information on several parameters related to acute changes of the oxygen transport system in athletes, little information is available on chronic adaptations of the respiratory system at rest, as reflected by the out-of-competition venous blood-gas status. Such changes may represent markers of a more efficient oxygen metabolism at rest, associated with a superior physical recovery. Venous blood-gas status was investigated in two subpopulations of competitive athletes (47 male professional road cyclists, 72 male elite road cyclists) who had observed an 18-24-h resting period from the last training session, and 58 male sedentary blood donors. Significant differences were observed for the p50 values (the oxygen tension at which the haemoglobin is 50% saturated) between sedentary controls (25+/-1 mmHg) and either elite (26+/-1 mmHg; p<0.01) or professional athletes (27+/-0.8; p<0.01), whereas other conventional parameters of the venous blood-gas status (pH, P(O2), P(CO2) and saturation) did not differ significantly between the three study populations. Results of the present investigation suggest that intensive training may be associated with a right-shift of the standard oxygen dissociation curve, as attested by the increased p50. This rightward shift is usually considered a helpful adaptation, enabling a relatively more efficiently mechanism of oxygen delivery to the peripheral tissues, enabling physiological advantages during exercise and improved recovery.

A Study on the Temporal Transferability of Transport Modal Choice Models

Understanding individual modal choice decisions is fundamental when developing and planning transportation systems. Developing precise travel behavior models and testing their forecasting capabilities also have an important role. This study provides empirical analysis of the temporal transferability of Multinomial Logit and Neuro-Fuzzy Multinomial Logit models. In the estimation context, the results of the models are compared with the actual modal choices to investigate their accuracy. In the application context, the evaluation of the models is based on predictive performances, where models re-calibrated from a small data sample and models transferred from the estimation context are evaluated. Accordingly, a sensitivity analysis that aims to examine travelers' behavior under the transportation system changes is presented. Overall, the Neuro-Fuzzy Multinomial Logit model performs better than the Multinomial Logit model. However, both models do not show satisfactory forecasting behavior when directly transferred to the application context. The classical Logit model is not able to correctly represent the influence of Parking Cost on modal choices, although this attribute is identified as statistically important for modeling modal choices. However, the neuro-fuzz model has shown that travelers are very sensitive to variations on parking fees, which was implemented as a strategic policy action so as to motivate changes in travelers' behavior towards sustainable transport modes. The results of this study suggest that travelers' behavior could be better explained by incorporating the neuro-fuzzy utility functions into the Multinomial Logit model rather than using the classical Multinomial Logit structure.JEL Classification: R4 Transportation Studies R41 Transportation: Demand, Supply and Congestion Safety and Accidents, Transportation Noise

Incorporating land use in metropolitan transportation planning

In current practice, very few Metropolitan Planning Agencies attempt to capture the effects of transportation system changes on land use, and the consequent feedback effects on transportation system performance, despite substantial evidence that these effects may be significant. In this paper, we present a case study on the application of UrbanSim, a detailed land use simulation model system, and its integration with a regional travel demand model in the Greater Wasatch Front area of Utah. Like several other metropolitan areas, this region has recently been confronted with legal challenges to proposed highway projects, drawing substantial scrutiny to the land use-transportation connection. We describe the UrbanSim model specification, results from model estimation, and sensitivity analyses conducted with the combined land use and travel model system. The results of the sensitivity analysis suggest that accounting for the land use effects of a regional transportation plan may produce significant shifts in key transportation evaluation measures such as vehicle miles traveled, vehicle hours traveled, and hours of congestion delay.

Differentiation between electron transport sensing and proton motive force sensing by the Aer and Tsr receptors for aerotaxis

Aerotaxis (oxygen-seeking) behaviour in Escherichia coli is a response to changes in the electron transport system and not oxygen per se. Because changes in proton motive force (PMF) are coupled to respiratory electron transport, it is difficult to differentiate between PMF, electron transport or redox, all primary candidates for the signal sensed by the aerotaxis receptors, Aer and Tsr. We constructed electron transport mutants that produced different respiratory H+/e- stoichiometries. These strains expressed binary combinations of one NADH dehydrogenase and one quinol oxidase. We then introduced either an aer or tsr mutation into each mutant to create two sets of electron transport mutants. In vivo H+/e- ratios for strains grown in glycerol medium ranged from 1.46+/-0.18-3.04+/-0.47, but rates of respiration and growth were similar. The PMF jump in response to oxygen was proportional to the H+/e- ratio in each set of mutants (r2=0.986-0.996). The length of Tsr-mediated aerotaxis responses increased with the PMF jump (r2=0.988), but Aer-mediated responses did not correlate with either PMF changes (r2=0.297) or the rate of electron transport (r2=0.066). Aer-mediated responses were linked to NADH dehydrogenase I, although there was no absolute requirement. The data indicate that Tsr responds to changes in PMF, but strong Aer responses to oxygen are associated with redox changes in NADH dehydrogenase I.

Change in Hydraulic Resistance and Shoot Morphology of Napiergrass (Pennisetum purpureum Schumach.) under Shaded Condition

Acclimation to light condition is associated with change in water transport system in napiergrass. In this study, the effects of shading on shoot hydraulic resistance and morphology of napiergrass (Pennisetum purpureum Schumach.) were investigated. In the plants under shading (to 30% of full sunlight) for 30 days (S plants), total hydraulic resistance of a shoot (Rshoot) increased from that of full sunlight (control). In the plants grown under shade condition for 24 d followed by full sunlight conditions for 6 d (SF), the Rshoot value was intermediate between that of control and S plants. A similar response to shading was found in total hydraulic resistance of a stem (Rstem), which accounted for more than 60% of Rshoot, but the total hydraulic resistance of the leaves was not significantly affected by shading. Leaf length, leaf area and stem length were larger, but the stem cross-sectional area (SA) was smaller in S and SF plants than in the control plants. SF plants showed similar leaf length, leaf area and stem length to those in S plants, but the SA in SF plants was slightly larger. Normalization of Rstem by SA and stem length decreased the difference among the treatments, indicating the increase of Rshoot and Rstem under shading resulted from the decrease of SA and the increase of stem length.

Adult and in utero exposure to cocaine alters sensitivity to the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Cocaine abuse is a significant problem in the United States, including its use by approximately 1% of pregnant women. Cocaine acts as an indirect agonist of dopamine at the dopamine transporter, resulting in the presence of excess dopamine in the synapse. Since synaptic dopamine can rapidly oxidize to form free radicals, it was hypothesized that exposure to this drug might produce damage in dopaminergic systems such as the substantia nigra pars compacta, damage to which is a hallmark of Parkinson’s disease. To test this hypothesis we exposed mice both in utero and as adults to cocaine and examined its effects on the nigrostriatal system. We found that exposure to cocaine both in utero or as adults did not affect substantia nigra cell number, but did make these neurons more susceptible to the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We also found long-lasting changes in D2 receptor mRNA levels as well as changes in the monoamine transport system and several growth factors. This work suggests that use of cocaine might be a predisposing factor for development of Parkinson’s disease in both adults exposed chronically as well as in individuals exposed prenatally.

Perspectives on noise in the menu of environmental issues, and the role of technical solutions relative to policy approaches

Over the last thirty years, the number of people affected by aircraft noise has decreased while air travel has grown dramatically. Despite this success, environmental issues, both noise and emissions, may become the key constraint on future air transportation expansion. As part of the Next Generation Air Transportation System Plan, the goal is for environmental protection that allows for sustained aviation growth. This includes reductions, in absolute terms, of community noise and local air quality emissions from aviation that significantly impact human health and welfare. Achieving these goals will require a multi‐pronged approach that combines source reduction technology, operational abatement procedures, intelligent land use planning, and airport and aircraft operating restrictions. Given the interdependencies of impacts, there is a need to move from stand‐alone models to an integrated tool set that allows understanding of the interactions between noise, air quality, economic costs and benefits. Such models would enable more effective evaluation of proposed air transportation system changes and allow communities and decision‐makers better information to reach decisions on the proposed changes. FAA has initiated a multi‐year, multi‐million dollar effort to develop these models and improved capabilities and decision‐making that will aid in tackling the enviornnmental challenges of aviation growth.

Effects of Nutrient and Pest Management on Soil Microorganism in Hybrid Rice Double‐Annual Cropping System*

Combined effects on soil microbial activity of nutrient and pest management in hybrid rice double‐annual cropping system were studied. The results of a field experiment demonstrated significant changes in soil phospholipid content, heterotrophic bacteria, proteolytic bacteria, and electron transport system (ETS)/dehydrogenase activity studied with different management practices and at different growth stages. Marked depletions in the soil microbial biomass phospholipid contents were found with the advancement of crop growth stages, while the incorporation of fertilizers and/or pesticides also produced slight changes, lowest microbial biomass phospholipid content was found with pesticides‐alone application. A decline in the bacterial abundance of heterotrophic bacteria and proteolytic bacteria was observed with the continuance of crop growth, while lowest abundance of heterotrophic bacteria and proteolytic bacteria were found with pesticides‐alone application, which coincided with the similar decline of soil microbial biomass. A consistent increase in ETS activity was measured during the different crop growth stages of rice. The use of fertilizers (NPK) alone or fertilizers and pesticides increased it, while a decline was noticed with pesticides‐alone application as compared with the control. *Sino‐Germany Cooperation Project on Agricultural Science and Technology, No. 2001‐47.

Growth Hormone and Epidermal Growth Factor Upregulate Specific Sodium-Dependent Glutamine Uptake Systems in Human Intestinal C2BBe1 Cells ,

Glutamine (Gln) is one of the major oxidative fuels of the enterocyte and enters from the lumen via Na(+)-dependent transport mechanisms. When given parenterally, growth hormone (GH) + epidermal growth factor (EGF) increase apical Gln uptake after massive enterectomy in rabbits. Although both receptors are basolateral, GH and EGF are present in luminal contents. We hypothesized that short-term luminal growth factor exposure to enterocytes increases apical Gln uptake by selective upregulation of systems A, B(0,+), or ASC+B(0). A monolayer of C2(BBe)1 cells was exposed for 10 or 60 min to GH (500 microg/L), EGF (100 microg/L), both, or neither. Initial uptake of [(3)H]Gln (50 micromol/L) was measured in the presence of Na(+) or choline. The contributions of systems A, B(0,+), and ASC+B(0) were determined by competitive inhibition with arginine and/or alpha-(methylamino)butyric acid. Gln uptake was linear for up to 8 min. Na(+)-independent transport was negligible. Under control conditions the relative contributions of systems A, B(0,+), and ASC+B(0) were 0, 19 +/- 6, and 80 +/- 4%, respectively. GH alone had no effect on Gln transport. After 10 min of EGF exposure, Na(+)-dependent Gln uptake increased by 50% (P < 0.001) with no change in individual transport systems. Combined EGF and GH for 60 min increased Gln transport by system B(0,+) nearly 250% (P < 0.001) and system A from undetectable levels to 16% of total transport (P < 0.01). Thus, short-term luminal exposure to EGF+GH increases Na(+)-dependent Gln transport mainly by upregulating system B(0+).

Influence of Accessibility on Residential Location Choice

There has been substantial discussion among planners about the influence of transport in residential location choices. The purpose of this paper is to analyze the importance of accessibility in explaining residential location choices. The paper addresses this issue by presenting and analyzing findings from the literature and results of a housing market estimation study in the Netherlands. The research findings for the Netherlands illustrate that the transport system influences residential moves at three stages: in move-stay choice, estimation results show that households are less likely to move away from a more accessible location; travel time variables are significant for all household types, and therefore changes in the transport system will affect the size of the housing market and search area of the households; the model estimation results suggest that accessibility of a specific location for many household types is not a significant variable in their location choice. Overall, the empirical results suggest that the role of accessibility is significant but small compared with the effect of demographic factors, neighborhood amenities, and dwelling attributes in explaining residential location choices. The empirical findings are confirmed by findings in the literature; the present results are located at the lower end of findings reported in the literature. An important factor contributing to this result is that accessibility changes among regions in the Netherlands are rather small.

Developmental decrease in rat small intestinal creatine uptake

Phosphocreatine is an energy buffer and transducer in the heart, the brain and the skeletal muscle. Recently, we have demonstrated the presence of the Na +/Cl −/creatine transporter at the apical membrane of the small intestinal epithelium. Herein the ontogeny and segmental distribution of rat intestinal creatine transport activity are investigated. [ 14C]-Creatine uptake was measured in the jejunum and ileum of 16 day gestation foetuses, newborn, suckling, weaning, 1-, 2-, 7- and 12-month-old (adult) rats. Creatine content in amniotic fluid, in rat and commercial milk and in rat chow, was measured by HPLC. NaCl-dependent creatine uptake was maximal in newborn rats and, in all the ages tested, higher in the ileum than in the jejunum. In the latter, NaCl-dependent creatine uptake was undetectable after weaning. Kinetic studies revealed that the jejunum and ileum have the same creatine uptake system, and that maturation decreases its V max but not the apparent K m. Maintenance of the pups on a commercial milk diet supplemented with creatine prevented the ileal periweaning decline in creatine uptake activity, but not that in the jejunum. In 1-month-old rats, supplementation with creatine increased ileal, but not jejunal, creatine uptake. The results demonstrate for the first time that: (i) creatine uptake along the length of the small intestine is mediated by the same transport system, (ii) the activity of this transport system changes in a specific manner with maturation and (iii) these changes appear to be genetically programmed and controlled by the intestinal creatine content.

An energy taxis transducer promotes root colonization by Azospirillum brasilense.

Motility responses triggered by changes in the electron transport system are collectively known as energy taxis. In Azospirillum brasilense, energy taxis was shown to be the principal form of locomotor control. In the present study, we have identified a novel chemoreceptor-like protein, named Tlp1, which serves as an energy taxis transducer. The Tlp1 protein is predicted to have an N-terminal periplasmic region and a cytoplasmic C-terminal signaling module homologous to those of other chemoreceptors. The predicted periplasmic region of Tlp1 comprises a conserved domain that is found in two types of microbial sensory receptors: chemotaxis transducers and histidine kinases. However, the function of this domain is currently unknown. We characterized the behavior of a tlp1 mutant by a series of spatial and temporal gradient assays. The tlp1 mutant is deficient in (i) chemotaxis to several rapidly oxidizable substrates, (ii) taxis to terminal electron acceptors (oxygen and nitrate), and (iii) redox taxis. Taken together, the data strongly suggest that Tlp1 mediates energy taxis in A. brasilense. Using qualitative and quantitative assays, we have also demonstrated that the tlp1 mutant is impaired in colonization of plant roots. This finding supports the hypothesis that energy taxis and therefore bacterial metabolism might be key factors in determining host specificity in Azospirillum-grass associations.

Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice.

Clearance rates for serotonin (5-HT) in heterozygote (+/-) and homozygote (-/-) serotonin transporter (5-HTT) knockout (KO) mice have not been determined in vivo. Moreover, the effect of selective serotonin reuptake inhibitors (SSRIs) on 5-HT clearance in these mice has not been examined. In this study, the rate of clearance of exogenously applied 5-HT was measured in the CA3 region of the hippocampus of anesthetized mice using high-speed chronoamperometry. Compared with wild-type mice, the maximal rate of 5-HT clearance from extracellular fluid (ECF) was decreased in heterozygotes and more markedly so in KO mice. Heterozygote mice were more sensitive to the 5-HT uptake inhibitor, fluvoxamine, resulting in longer clearance times for 5-HT than in wild-type mice; as expected, the KO mice were completely unresponsive to fluvoxamine. There were no associated changes in norepinephrine transporter density, nor was there an effect of the norepinephrine uptake inhibitor, desipramine, on 5-HT clearance in any genotype. Thus, adaptive changes in the norepinephrine transport system do not occur in the CA3 region of hippocampus as a consequence of 5-HTT KO. These data highlight the potential of the heterozygote 5-HTT mutant mice to model the dynamic in vivo consequences of the human 5-HTT polymorphism.

Hypoxia alters expression and function of syncytin and its receptor during trophoblast cell fusion of human placental BeWo cells: implications for impaired trophoblast syncytialisation in pre-eclampsia

The fundamental process of placental trophoblast cell fusion (syncytiotrophoblast formation or syncytialisation) which is a characteristic of this tissue is poorly understood. Pre-eclampsia is associated with placental hypoxia and suppressed syncytiotrophoblast formation. We therefore have studied the effect of low-oxygen tensions on the rate of cell fusion, relative abundance of mRNAs encoding syncytin and its receptor, amino acid transport system B 0, which are thought to be involved in trophoblast cell fusion (as well as the activity of amino acid transport through this system) in a cell model of syncytialisation (BeWo cells following forskolin treatment). Forskolin-induced cell fusion (determined by a quantitative flow cytometry assay) was reversibly suppressed in 2% oxygen compared to 20% oxygen. This was associated with suppressed secretion of human chorionic gonadotropin. Forskolin stimulated relatively less syncytin mRNA (determined by reverse transcription–polymerase chain reaction) in 2% than in 20% oxygen and there was no stimulation after 48 h in 2% oxygen. There was a spontaneous, time-dependent increase of amino acid transporter B 0 mRNA in vehicle, which was suppressed by 2% oxygen and by forskolin treatment in 20% oxygen. Forskolin-induced changes in amino acid transport system B 0 function were not seen in cells cultured for 48 h in 2% oxygen. These observations suggest that under conditions of low ambient oxygen, dysregulation of expression of syncytin and of its receptor may suppress the normal process of cell fusion necessary for syncytiotrophoblast formation and contributes to syncytiotrophoblast abnormalities characteristic of pre-eclampsia.

A mixed spatially correlated logit model: formulation and application to residential choice modeling

In recent years, there have been important developments in the simulation analysis of the mixed multinomial logit model as well as in the formulation of increasingly flexible closed-form models belonging to the generalized extreme value class. In this paper, we bring these developments together to propose a mixed spatially correlated logit (MSCL) model for location-related choices. The MSCL model represents a powerful approach to capture both random taste variations as well as spatial correlation in location choice analysis. The MSCL model is applied to an analysis of residential location choice using data drawn from the 1996 Dallas–Fort Worth household survey. The empirical results underscore the need to capture unobserved taste variations and spatial correlation, both for improved data fit and the realistic assessment of the effect of sociodemographic, transportation system, and land-use changes on residential location choice.

Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats

Exposure to methamphetamine causes behavioral sensitization in experimental animals. However, the precise mechanism of this behavioral sensitization has not yet been fully elucidated. Accordingly, we evaluated the pharmacokinetic properties of methamphetamine in rats behaviorally sensitized to methamphetamine following its repeated administration (6 mg/kg, i.p., once a day for 5 days followed by a 21-day drug abstinence period). In the sensitized rats, methamphetamine (0.8 mg/kg)-induced locomotor activity was significantly enhanced, suggesting the successful establishment of behavioral sensitization to methamphetamine. Significant increases in the concentrations of methamphetamine in plasma and brain dialysate, as well as the delayed disappearance of methamphetamine from plasma, were observed in the sensitized rats after intravenous injection of methamphetamine (5 mg/kg). The tissue to plasma concentration ratio (K p) of methamphetamine in lung and heart decreased in the sensitized rats. The renal excretion of methamphetamine, which is sensitive to several cations, was also decreased in the sensitized rats. Moreover, in the sensitized rats, the expression of organic cation transporter 3 (OCT3) mRNA was decreased in kidney, brain and heart as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Taken together, these results suggest that the behavioral outcome of sensitization to methamphetamine might, in part, be due to the increased levels of methamphetamine in plasma and brain extracellular areas, as well as an altered tissue distribution of methamphetamine associated with changes in the cation transport system.

Exposure of brown trout Salmo trutta to a sublethal concentration of copper in soft acidic water: effects upon gas exchange and ammonia accumulation.

The present study was undertaken to answer two questions relating to the exposure of brown trout Salmo trutta to sublethal concentrations of copper and low pH (CLP) for 96 h. (1) What is the effect of these pollutants on the rate of oxygen consumption (M(O(2))) at different levels of exercise and (2) why does ammonia accumulate within these fish, when the low external pH should favour the diffusion of NH(3) across the gills? Mean M(O(2)) of fish in CLP and control (normal pH and no added copper) conditions were not significantly different from each other at any level of exercise. This suggests that exposure to CLP was not a 'loading' factor at any level of activity. However, both maximum M(O(2)) and critical swimming speed (U(crit)) were significantly lower in the CLP trout (5.5+/-1.6 mmol O(2) kg(-1) h(-1) and 1.12+/-0.06 BL s(-1), respectively) than in control fish (18.5+/-2.3 mmol O(2) kg(-1) h(-1) and 2.04+/-0.11 BL s(-1), respectively). There was no evidence from cardiovascular variables, such as heart rate and cardiac output, to suggest any changes in the oxygen transport system to compensate for any possible reduction in branchial gas exchange. Thus, it is suggested that oxygen exchange and transport do not limit the swimming performance of CLP trout, but that exposure to CLP reduces the maximum demand for O(2), i.e. it is a limiting factor. The accumulation of ammonia in the plasma and white muscles during exposure to CLP has already been implicated in reducing the swimming performance of brown trout. Inhibition of cortisol synthesis abolished a large proportion of the increases in both the accumulation and excretion of ammonia that occurred during the second 48 h of the exposure to CLP, but did not inhibit ammonia accumulation completely. It is suggested that CLP not only causes an increase in the rate of production of ammonia, which is enhanced when the level of cortisol starts to increase after 48 h, but that it also inhibits an excretory mechanism (most probably Na(+)/NH(4)(+) exchange) that is non-obligatory under 'normal' conditions (when passive diffusion is sufficient), but is required in order to respond to unusually high ammonia loads.

Effect of dihydrokainate on the antitumor activity of doxorubicin

For biochemical modulation, components of green tea have been shown to be useful modulators in combination with doxorubicin (DOX). We have confirmed that theanine enhances the antitumor activity of DOX due to inhibition of DOX efflux from tumor cells. Because theanine is a glutamate analogue, we found that it is associated with a change in the drug transport system on the tumor cell membrane, in particular glutamate transporters. We examined the effect of dihydrokainate (DHK), one of the useful glutamate transporter inhibitors. DHK also inhibits DOX efflux significantly and reduces the glutamate uptake by Ehrlich ascites carcinoma cells. The potential contribution of glutamate transporters not only to glutamate uptake but also to cell membrane export of DOX has been shown. In addition, the combination of DHK with DOX significantly enhances the antitumor activity of DOX, by 1.8-fold ( P<0.001). The DOX concentration in tumors significantly increases on combination with DHK and is correlated with the reduced tumor weight. On the other hand, DHK tends to reduce the DOX concentration in normal tissues. We expect that DHK has different actions in tumor and normal tissues because different isoforms of glutamate transporters are expressed in the two tissues. Thus, the results suggest that DHK is a novel and useful modulator for inducing enhancement of antitumor activity.