Dopamine Sulfoconjugation in the Rat Brain: Regulation by Monoamine Oxidase

An increase of free 3,4-dihydroxyphenylethylamine (DA, dopamine) in the rat brain such as is found following 3,4-dihydroxyphenylalanine (L-DOPA) administration or an intraventricular injection of free dopamine did not result in DA sulfate formation, despite the presence of phenolsulfotransferase activity in various regions of the brain and the high affinity of DA for this enzyme. However, when rats were pretreated with pargyline, a monoamine oxidase inhibitor, the same treatment with L-DOPA or free DA led to active synthesis of DA sulfate. The increase in DA sulfate was significantly correlated with the degree of monoamine oxidase inhibition and directly proportional to free DA concentrations in the hypothalamus (r = 0.86), striatum (r = 0.54), and brainstem (r = 0.89). The highest ratio of DA sulfate to free DA was found in the hypothalamus, suggesting that sulfoconjugation is most active in this region. Prior treatment of rats with 6-hydroxydopamine did not decrease DA sulfate concentrations, indicating that sulfoconjugation occurs most likely in extraneuronal tissues not destroyed by the neurotoxin. The results are compatible with the notion that phenolsulfotransferase may be highly compartmentalized and that inhibition of monoamine oxidase allows the newly generated free DA to become accessible to the sulfoconjugating enzyme, resulting in increase in DA sulfation.     

Cycling of soil carbon in a Japanese red pine forest II. Changes occurring in the first year after a clear-felling

Cycling of soil carbon in the first year after a clear-felling was compared with that before the felling in a Japanese red pine forest in Hiroshima Prefecture, west Japan. The daily mean temperature at the soil surface in summer was increased after the felling in comparison to that before felling, and the water content of both the A₀ layer and the surface mineral soil was decreased due to the loss of the forest canopy. The rate of weight loss of the A₀ layer was reduced after felling. However, accumulation of the A₀ layer rapidly decreased because of the lack of litter supply to the forest floor. Low soil respiration after felling was mainly caused by the cessation of root respiration. Analysis of annual soil carbon cycling was then conducted using a compartment model. The relative decomposition rate of the A₀ layer decreased whereas that of humus and dead roots in mineral soil increased to some extent after felling. The accumulation of carbon in mineral soil, however, increased slightly due to the supply of humus from roots killed by the felling.     

The structural simplification of an epidemiological compartment model

It is shown how a multicompartmental infectious disease model can be systematically examined for reduction of structural complexity. For steadystate situations, four basic rules are proposed for eliminating components of flow-lines, whole flow-lines, and compartments, plus combining compartments. An application to a typhoid fever model allows calculations to be done on a pocket calculator. The approach could be particularly important in developing countries.     

Development,characterization, and application of a 2‐Compartment system to investigate the impact of pH inhomogeneities in large‐scale CHO‐based processes

Large‐scale bioreactors for the production of monoclonal antibodies reach volumes of up to 25 000 L. With increasing bioreactor size, mixing is however affected negatively, resulting in the formation of gradients throughout the reactor. These gradients can adversely affect process performance at large scale. Since mammalian cells are sensitive to changes in pH, this study investigated the effects of pH gradients on process performance. A 2‐Compartment System was established for this purpose to expose only a fraction of the cell population to pH excursions and thereby mimicking a large‐scale bioreactor. Cells were exposed to repeated pH amplitudes of 0.4 units (pH 7.3), which resulted in decreased viable cell counts, as well as the inhibition of the lactate metabolic shift. These effects were furthermore accompanied by increased absolute lactate levels. Continuous assessment of molecular attributes of the expressed target protein revealed that subunit assembly or N‐glycosylation patterns were only slightly influenced by the pH excursions. The exposure of more cells to the same pH amplitudes further impaired process performance, indicating this is an important factor, which influences the impact of pH inhomogeneity. This knowledge can aid in the design of pH control strategies to minimize the effects of pH inhomogeneity in large‐scale bioreactors.     

Capillaries within compartments: microvascular interpretation of dynamic positron emission tomography data

Measurement of exchange of substances between blood and tissue has been a long-lasting challenge to physiologists, and considerable theoretical and experimental accomplishments were achieved before the development of the positron emission tomography (PET). Today, when modeling data from modern PET scanners, little use is made of earlier microvascular research in the compartmental models, which have become the standard model by which the vast majority of dynamic PET data are analysed. However, modern PET scanners provide data with a sufficient temporal resolution and good counting statistics to allow estimation of parameters in models with more physiological realism. We explore the standard compartmental model and find that incorporation of blood flow leads to paradoxes, such as kinetic rate constants being time-dependent, and tracers being cleared from a capillary faster than they can be supplied by blood flow. The inability of the standard model to incorporate blood flow consequently raises a need for models that include more physiology, and we develop microvascular models which remove the inconsistencies. The microvascular models can be regarded as a revision of the input function. Whereas the standard model uses the organ inlet concentration as the concentration throughout the vascular compartment, we consider models that make use of spatial averaging of the concentrations in the capillary volume, which is what the PET scanner actually registers. The microvascular models are developed for both single- and multi-capillary systems and include effects of non-exchanging vessels. They are suitable for analysing dynamic PET data from any capillary bed using either intravascular or diffusible tracers, in terms of physiological parameters which include regional blood flow.     

阿奇霉素治疗支原体肺炎的序贯疗法定量分析

利用室分析方法,建立了药物动力学模型,给出了静脉、口服多次用药后血药浓度,并绘制出药时曲线,分析了所给的阿奇霉素治疗支原体肺炎的序贯疗法用药方案可行性,提高了用药的依从性。     

黄土高原刺槐细根生长模型

通过室分析方法建立了细根表面积密度随土层深度变化的房室模型,并根据黄土高原人工刺槐林细根的调查数据,从数值上验证了模型S=Ah~B（C＋Dh＋Eh~2＋Fh~3）是房室模型的简化形式,还进一步建立了黄土高原刺槐细根生长关于土层深度和时间的动态生长模型.经验证,该模型能准确地计算黄土高原不同水分生态区及不同时间和土层的刺槐细根表面积密度,具有很高的应用价值.     

Modelling Human Granulopoiesis under Poly-chemotherapy with G-CSF Support

Cytotoxic drugs administered in polychemotherapy cause a characteristic neutropenic period depending on the schedule of the drugs, which can partly be prevented by G-CSF growth factor support. To quantify these effects and to gain a deeper insight into the dynamics of bone marrow recovery after such suppressing and stimulating disturbances, we construct a biomathematical compartment model of human granulopoiesis under polychemotherapy with G-CSF support. The underlying assumptions and mathematical techniques used to obtain the model are explained in detail. A large variety of biological and clinical data as well as knowledge from a model of murine haematopoiesis are evaluated to construct a physiological model for humans.Particular emphasis is placed on estimating the influence of chemotherapeutic drugs on the granulopoietic system. As a result, we present an innovative method to estimate the bone marrow damage caused by cytotoxic drugs with respect to single identifiable cell stages only on the basis of measured peripheral blood leukocyte dynamics. Conversely, our model can be used in a planning phase of a clinical trial to estimate the haematotoxicity of regimens based on new combinations of drugs already considered and with or without growth factor support.Acknowledgement This paper was supported by the DFG (Deutsche Forschungsgemeinschaft) in the framework of the project Aufbau von Simulationsmodellen der h{\a}matopoetischen Dynamik nach konventioneller und hochdosierter Chemotherapie und Zytokingabe beim Menschen (Nr. LO 342/8-2). We would like to thank the German High Grade Non-Hodgkins-Lymphoma Study Group and the German Hodgkins Lymphoma Study Group for the kind provision of data.     

The egghead gene is required for compartmentalization in Drosophila optic lobe development

The correct targeting of photoreceptor neurons (R-cells) in the developing Drosophila visual system requires multiple guidance systems in the eye-brain complex as well as the precise organization of the target area. Here, we report that the egghead (egh) gene, encoding a glycosyltransferase, is required for a compartment boundary between lamina glia and lobula cortex, which is necessary for appropriate R1-R6 innervation of the lamina. In the absence of egh, R1-R6 axons form a disorganized lamina plexus and some R1-R6 axons project abnormally to the medulla instead of the lamina. Mosaic analysis demonstrates that this is not due to a loss of egh function in the eye or in the neurons and glia of the lamina. Rather, as indicated by clonal analysis and cell-specific genetic rescue experiments, egh is required in cells of the lobula complex primordium which transiently abuts the lamina and medulla in the developing larval brain. In the absence of egh, perturbation of sheath-like glial processes occurs at the boundary region delimiting lamina glia and lobula cortex, and inappropriate invasion of lobula cortex cells across this boundary region disrupts the pattern of lamina glia resulting in inappropriate R1-R6 innervation. This finding underscores the importance of the lamina/lobula compartment boundary in R1-R6 axon targeting.     

Models-of-data and models-of-processes in the post-genomic era

As we are entering the post-genomic era, models-of-data, such as mining and filtering methods for gene sequences and microarrays and the clustering of co-expressed genes, must be complemented with models-of-processes that explain relationships between genomic information and phenomena at biochemical and physiological levels. Many of these models will have the structure of compartment models, whose conceptualization, identification and analysis will fundamentally benefit from the seminal work of John Jacquez. The article indicates with three vignettes that non-linear compartment models in the formulation of biochemical systems theory are viable candidates for post-genomic models-of-processes.