ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts

Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through at least three different transduction routes: Gαs-mediated stimulation of adenylylcyclase (AC), Gαq-mediated activation of phospholipase Cβ (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative role of different pathways in human skin fibroblast prolifera-tion. Using chemical inhibitors and activators of signal transduction, we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two counteracting pathways – an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulate d by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time, their point of divergence in mediating PTHrP dual and opposite mitogenic effects. Received 2 August 2002; received after revision 10 September 2002; accepted 18 October 2002 RID="*" ID="*"Corresponding author.     

Central neural control of pineal melatonin synthesis in rat

Summary To investigate a possible central neural influence on nocturnal pineal metabolic activity, frontal transsections of the stria medullaris thalami were conducted. Enzymes involved in melatonin synthesis, i.e. N-acetyltransferase and hydroxyindole-O-methyl-transferase, exhibited reduced activities in operated animals when compared to controls. These results indicate a modulatory role of central structures on noctural pineal indole metabolism.This study was supported by the Deutsche Forschungsgemeischaft and the Stifung Volkswagenwerk. The technical assistance provided by M. Henschel, I. v. Graevenitz and G. Schlich is gratefuly acknowledged.     

Diurnal variations in thermoregulatory responses to intrahypothalamic and intravenous injections of noradrenaline in the pigeon

Summary The differences in responses of T_b, T_f and both to intrahypothalamic and i.v. administration of NA were measured both at noon and at midnight in the pigeon. Although the T_b and were at a higher level in the daytime, no differences in the magnitude of the fall in and T_b were obtained after either intrahypothalamic or i.v. injections of NA, whether it was measured during the day or at night. The only marked difference was the more prominent vasodilatation in the daytime after both routes of injection.     

Immunologic blood-brain barrier in the polyoma virus--Syrian hamster system]

The authors report premilinary results of an experiment on permeability of the blood-brain barrier (BBB) to anti-tumor virus-induced immunological factors in the polyoma virus/Syrian Hamster system. The animals were protected by subcutaneous or intracranial injections with virus before challenge with polyoma virus transformed cells by both routes. BBB seemed to be permeable to the efferent part of the subcutaneously induced immune reaction. On the contrary, antigenic information introduced in the central nervous system was trapped inside the BBB. Thus the BBB might offer a "one-way" permeability in this system.     

基于多特征的域间路由节点安全状态评估方法

域间路由节点安全状态评估能够实现对BGP节点安全状态的直观、实时描述,可为制定合理的安全策略,及时定位、抑制异常路由事件提供数据参考.然而由于完整的异常域间路由集难以获取,使得传统基于数据融合的状态评估方法不再适用.分析BGP节点间交互路由过程中存在的统计特征以及这些特征与域间路由节点安全状态的关系,进而提出一种基于多特征的安全状态评估方法.以平均路径长度和路由事件发生频率等属性为安全特征,并借鉴云模型理论转换定量特征为定性概念的思想,构建域间路由安全特征云,将正常态下的多属性综合安全特征转换为安全正常态,然后通过度量安全特征偏离正常态的程度来计算节点偏离正常态的程度,由此得到域间路由节点面临安全威胁的概率.实验结果表明,该方法能够实现对域间路由节点安全状态的评估,准确性高、实时性强,可为域间路由系统的安全稳定运行提供有力支撑.     

Nanocarriers’ entry into the cell: relevance to drug delivery

Nanocarriers offer unique possibilities to overcome cellular barriers in order to improve the delivery of various drugs and drug candidates, including the promising therapeutic biomacromolecules (i.e., nucleic acids, proteins). There are various mechanisms of nanocarrier cell internalization that are dramatically influenced by nanoparticles’ physicochemical properties. Depending on the cellular uptake and intracellular trafficking, different pharmacological applications may be considered. This review will discuss these opportunities, starting with the phagocytosis pathway, which, being increasingly well characterized and understood, has allowed several successes in the treatment of certain cancers and infectious diseases. On the other hand, the non-phagocytic pathways encompass various complicated mechanisms, such as clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis, which are more challenging to control for pharmaceutical drug delivery applications. Nevertheless, various strategies are being actively investigated in order to tailor nanocarriers able to deliver anticancer agents, nucleic acids, proteins and peptides for therapeutic applications by these non-phagocytic routes.     

Oxygen consumption and the evolution of order: negentropy criteria applied to the evolution of ants

Optimization of energy use by evolving organisms, predicted by theoretical extensions of the neo-Darwinian theory, i. contrasted with that of irreversible thermodynamics, which predicts an increase in orderliness and thus an increase in energy consumption per unit of biomass. We compared this index with estimates of social complexity among ant genera and species. Our results show that simple optimization models cannot explain experimental data, and that social complexity correlates differently with negentropy at different levels of analysis. Comparing the genera among Formicidae, workers (not colonies) from genera with highly social species are less negentropic than those of socially primitive ones. At the sub-generic level, social complexity correlated positively with negentropy among species, for major workers inAcromyrmex and for minor workers inAtta. The results illustrate the complexity of thermodynamic criteria in the study of evolution but also hint at their usefulness. In this case, they show that two different evolutionary routes to the complex Attini ant societies may exist.     

带转向约束的城市垃圾收集车辆弧路径问题研究

考虑部分街道单行及转向限制等状况，采用带有转向禁忌条件的垃圾收集车辆弧路径问题模型对城市垃圾收运路线进行优化。建立将其转换为对应的点路径问题的求解模型，以减少问题规模；并使用聚类蚁群算法对该问题进行求解。成都市双楠辖区的实例优化结果表明，有/无转向约束的路线优化后，总路程分别减少了89984．96m和92330．04m，节约了31．1％和31．9％。效果明显。此外，优化后减少了需求车辆数，减少了车辆使用成本和人员雇佣成本。     

Fenretinide induces mitochondrial ROS and inhibits the mitochondrial respiratory chain in neuroblastoma

Fenretinide induces apoptosis in neuroblastoma by induction of reactive oxygen species (ROS). In this study, we investigated the role of mitochondria in fenretinide-induced cytotoxicity and ROS production in six neuroblastoma cell lines. ROS induction by fenretinide was of mitochondrial origin, demonstrated by detection of superoxide with MitoSOX, the scavenging effect of the mitochondrial antioxidant MitoQ and reduced ROS production in cells without a functional mitochondrial respiratory chain (Rho zero cells). In digitonin-permeabilized cells, a fenretinide concentration-dependent decrease in ATP synthesis and substrate oxidation was observed, reflecting inhibition of the mitochondrial respiratory chain. However, inhibition of the mitochondrial respiratory chain was not required for ROS production. Co-incubation of fenretinide with inhibitors of different complexes of the respiratory chain suggested that fenretinide-induced ROS production occurred via complex II. The cytotoxicity of fenretinide was exerted through the generation of mitochondrial ROS and, at higher concentrations, also through inhibition of the mitochondrial respiratory chain.     

Central neural control of pineal melatonin synthesis in the rat

To investigate a possible central neural influence on nocturnal pineal metabolic activity in rats, frontal transsections of the stria medullaris thalami were conducted. Enzymes involved in melatonin synthesis, i.e. N-acetyltransferase and hydroxyindole-O-methyl-transferase, exhibited reduced activities in operated animals when compared to controls. These results indicate a modulatory role of central structures on nocturnal pineal indole metabolism.     

Protective effects of hsp70 in inflammation

Inflammation results from the recruitement to a given tissue or organ and the activation of leucocytes, among which the monocytes-macrophages play a major role. These phagocytic cells produce high levels of reactive oxygen species (ROS) as well as cytokines. Whereas both ROS and cytokines have the potential to regulate the expression of heat shock (HS)/stress proteins (HSP), it appears that these proteins in turn have the ability to protect cells and tissues from the deleterious effects of inflammation. The mechanisms by which such protection occurs include prevention of ROS-induced DNA strand breaks and lipid peroxidation as well as protection from mitochondrial structure and function. In vivo, HS protects organs against a number of lesions associated with the increased production of ROS and/or cytokines. In an animal model for adult respiratory distress syndrome, an acute pulmonary inflammatory condition, HS completely prevented mortality. HSP (hsp70 in particular) may also exert protective effects in the immune system by contributing to the processing and presentation of bacterial and tumoral antigens. The analysis of the expression of hsp70 may prove of diagnostic and prognostic value in inflammatory conditions and therapeutical applications are being considered.     

Arterial and mixed venous blood gases following DNP infusions in rabbits

Summary Hypocapnia and respiratory alkalosis was found in arterial and mixed venous blood after i.v. administration of DNP. Stimulation of ventilation resulted in steady PO₂, when PvO₂ decreased, and seemed to be independent on CO₂.     

The ATP synthase (F0-F1) complex in oxidative phosphorylation.

The transmembrane electrochemical proton gradient generated by the redox systems of the respiratory chain in mitochondria and aerobic bacteria is utilized by proton translocating ATP synthases to catalyze the synthesis of ATP from ADP and P(i). The bacterial and mitochondrial H(+)-ATP synthases both consist of a membranous sector, F0, which forms a H(+)-channel, and an extramembranous sector, F1, which is responsible for catalysis. When detached from the membrane, the purified F1 sector functions mainly as an ATPase. In chloroplasts, the synthesis of ATP is also driven by a proton motive force, and the enzyme complex responsible for this synthesis is similar to the mitochondrial and bacterial ATP synthases. The synthesis of ATP by H(+)-ATP synthases proceeds without the formation of a phosphorylated enzyme intermediate, and involves co-operative interactions between the catalytic subunits.     

Evaluating community science

Community science—scientific investigation conducted partly or entirely by non-professional scientists—has many advantages. For example, community science mobilizes large numbers of volunteers who can, at low cost, collect more data than traditional teams of professional scientists. Participation in research can also increase volunteers’ knowledge about and appreciation of science. At the same time, there are worries about the quality of data that community science projects produce. Can the work of non-professionals really deliver trustworthy results? Attempts to answer this question generally compare data collected by volunteers to data collected by professional scientists. When volunteer data is more variable or less accurate than professionally collected data, then the community science project is judged to be inferior to traditional science. I argue that this is not the right standard to use when evaluating community science, because it relies on a false assumption about the aims of science. I show that if we adopt the view that science has diverse aims which are often in tension with one another, then we cannot justify holding community science data to an expert accuracy standard. Instead, we should evaluate the quality of community science data based on its adequacy-for-purpose.     

Lack of pyrogenic tolerance transmission between brain and periphery in the rabbit

Summary Successive injections of lipopolysaccharide (LPS) either intravenously (i.v.) or intracerebroventricularly (i.c.v.) induced pyrogenic tolerance to LPS in rabbits. Tolerance was shown by a decrease of the magnitude of the fever response to repeated doses of LPS, irrespective of the route of pyrogen administration. A significantly greater and more dramatic decrease of the fever index, however, was observed in rabbits made tolerant to pyrogen given i.v. than when the pyrogen was given i.c.v. Transmission of the pyrogenic toleraance between brain and peripheral tissues, however, has not been ascertained.     

Lack of pyrogenic tolerance transmission between brain and periphery in the rabbit

Successive injections of lipopolysaccharide (LPS) either intravenously (i.v.) or intracerebroventricularly (i.c.v.) induced pyrogenic tolerance to LPS in rabbits. Tolerance was shown by a decrease of the magnitude of the fever response to repeated doses of LPS, irrespective of the route of pyrogen administration. A significantly greater and more dramatic decrease of the fever index, however, was observed in rabbits made tolerant to pyrogen given i.v. than when the pyrogen was given i.c.v. Transmission of the pyrogenic tolerance between brain and peripheral tissues, however, has not been ascertained.     

Interaction of BW755C, a potent inhibitor of lipoxygenase and cyclo-oxygenase, with mitochondrial cytochrome oxidase

The interaction between BW755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline), a potent inhibitor of both lipoxygenase and cyclo-oxygenase, and respiratory chain in mitochondria and electron transport particles (ETP) from rat livers was examined. BW755C accelerated the oxygen uptake by mitochondria without the addition of substrate for the respiratory chain. Spectrophotometric study revealed that BW755C was quickly oxidized by cytochrome oxidase in mitochondria to a compound possessing an absorption maximum at 524 nm. p-Phenylenediamine (p-diaminobenzene, PPDA), which, like BW755C, serves as an electron donor to cytochrome oxidase, was shown to inhibit the generation of active oxygen in macrophages; the inhibition was stronger than that of BW755C. These results strongly suggest that the oxidative conversion of BW755C by mitochondrial cytochrome oxidase is associated with its potentially inhibitory action on the active oxygen-generating system in phagocytes.     

Ecological causes and consequences of bird orientation

Summary An advanced orientation capability offers possibilities for birds to optimize movement patterns in a wide variety of ecological situations. The adaptive significance of different patterns of angular dispersion and of orientation responses to topography and sociality are elucidated. The orientation capacity is characterized by flexibility, exemplified by reorientation promoting safety and restoration of fat reserves during migration. There are also limitations to the orientation process, leading to costs of migration through mis- or disorientation, and to constraints on the evolution of routes and timing of migratory flights. Young migrants may acquire an erroneous compass sense, and misorient several thousands of kilometers off their normal course. Widespread and dense fog of long duration causes disorientation and mortality among land birds migrating over the sea. Orientational constraints in the evolution of migration routes may be most easily disclosed at high geographic and magnetic latitudes. Here the birds are faced with special difficulties in using their celestial as well as their magnetic compasses. The sun compass could be used for great circle orientation, but observed spring flight trajectories of high arctic shorebirds and geese seem to conform with rhumbline routes.     

生态水利工程设计若干问题的探讨

通过分析水利工程与生态水利工程的差异,提出生态水利工程的开发应有明确的生态服务目标与功能以及工程选址、布局、施工过程的环境友好性与经济性。同时提出生态水利工程设计主要面临4个方面的问题：①缺乏基于不同区域的生态水利工程设计方法与评价标准;②水利工程设计人员与生态科技工作者往往缺少合作的机会与机制;③生态水利工程与原有水利工程设施难以协调运行;④生态水利工程设计缺少生态水文测验资料。研究结果认为生态水利工程设计应基于以下技术路线：①以生态水文学与工程水文学作为工程设计的基础,进行水文过程的分析与计算;②识别工程可能影响的关键生态敏感目标;③生态水利工程的设计要与环境工程设计进行有机结合。     

Stereochemistry of enzymic processes in the biosynthesis of pyrrolizidine alkaloids.

The harmonization of biosynthetic pathways with organic reaction mechanisms has relied heavily on stereochemical studies. The field of biosynthesis of pyrrolizidine alkaloids exemplifies these connections through a wide range of common organic reactions including oxidation condensation, and decarboxylation. Further, the applications of biogenetic concepts and enzyme-catalysed reactions to synthesis are illustrated. The results are exciting, not only for their intrinsic scientific interest, but because they point the way to using plant enzymes to recognise structurally modified biosynthetic intermediates and hence open routes to the synthesis of new compounds that would otherwise be difficult to obtain.