Platelet-derived chemokines: pathophysiology and therapeutic aspects

The identification of chemokines in blood platelets has strengthened our view of these cells as participants in immune host defense. Platelet chemokines representing prestored and rapidly releasable proteins may play a major role as first-line inflammatory mediators. This is evident from their capability to recruit early inflammatory cells such as neutrophil granulocytes and monocytes and even to exhibit direct antimicrobial activity. However, insight is growing that platelet chemokines may be also long-term regulators, e.g., by activating T lymphocytes, by modulating the formation of endothelium and even thrombocytopoiesis itself. This review deals with the individual and cooperative functionality of platelet chemokines, as well as their potential as a basis for therapeutic intervention in the pathology of inflammation, infection, allergy and tumors. Within this context, therapeutic strategies based on the use of antibodies, modified chemokines, chemokine-binding proteins and chemokine receptor antagonists as well as first clinical studies will be addressed.     

Developmental and pathological angiogenesis in the central nervous system

Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood–brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases.     

Modeling and forecasting commodity market volatility with long-term economic and financial variables

This paper investigates the time-varying volatility patterns of some major commodities as well as the potential factors that drive their long-term volatility component. For this purpose, we make use of a recently proposed generalized autoregressive conditional heteroskedasticity–mixed data sampling approach, which typically allows us to examine the role of economic and financial variables of different frequencies. Using commodity futures for Crude Oil (WTI and Brent), Gold, Silver and Platinum, as well as a commodity index, our results show the necessity for disentangling the short-term and long-term components in modeling and forecasting commodity volatility. They also indicate that the long-term volatility of most commodity futures is significantly driven by the level of global real economic activity as well as changes in consumer sentiment, industrial production, and economic policy uncertainty. However, the forecasting results are not alike across commodity futures as no single model fits all commodities.     

Cardiomyokines from the heart

The heart is regarded as an endocrine organ as well as a pump for circulation, since atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were discovered in cardiomyocytes to be secreted as hormones. Both ANP and BNP bind to their receptors expressed on remote organs, such as kidneys and blood vessels; therefore, the heart controls the circulation by pumping blood and by secreting endocrine peptides. Cardiomyocytes secrete other peptides besides natriuretic peptides. Although most of such cardiomyocyte-derived peptides act on the heart in autocrine/paracrine fashions, several peptides target remote organs. In this review, to overview current knowledge of endocrine properties of the heart, we focus on cardiomyocyte-derived peptides (cardiomyokines) that act on the remote organs as well as the heart. Cardiomyokines act on remote organs to regulate cardiovascular homeostasis, systemic metabolism, and inflammation. Therefore, through its endocrine function, the heart can maintain physiological conditions and prevent organ damage under pathological conditions.     

Molecular mechanisms of lymphatic vascular development

Lymphatic vasculature has recently emerged as a prominent area in biomedical research because of its essential role in the maintenance of normal fluid homeostasis and the involvement in pathogenesis of several human diseases, such as solid tumor metastasis, inflammation and lymphedema. Identification of lymphatic endothelial specific markers and regulators, such as VEGFR-3, VEGF-C/D, PROX1, podoplanin, LYVE-1, ephrinB2 and FOXC2, and the development of mouse models have laid a foundation for our understanding of the major steps controlling growth and remodeling of lymphatic vessels. In this review we summarize recent advances in the field and discuss how this knowledge as well as use of model organisms, such as zebrafish and Xenopus, should allow further in depth analysis of the lymphatic vascular system. Received 26 January 2007; received after revision 5 March 2007; accepted 29 March 2007     

A discoidin domain receptor 1 knock-out mouse as a novel model for osteoarthritis of the temporomandibular joint

Discoidin domain receptor 1 (DDR-1)-deficient mice exhibited a high incidence of osteoarthritis (OA) in the temporomandibular joint (TMJ) as early as 9 weeks of age. They showed typical histological signs of OA, including surface fissures, loss of proteoglycans, chondrocyte cluster formation, collagen type I upregulation, and atypical collagen fibril arrangements. Chondrocytes isolated from the TMJs of DDR-1-deficient mice maintained their osteoarthritic characteristics when placed in culture. They expressed high levels of runx-2 and collagen type I, as well as low levels of sox-9 and aggrecan. The expression of DDR-2, a key factor in OA, was increased. DDR-1-deficient chondrocytes from the TMJ were positively influenced towards chondrogenesis by a three-dimensional matrix combined with a runx-2 knockdown or stimulation with extracellular matrix components, such as nidogen-2. Therefore, the DDR-1 knock-out mouse can serve as a novel model for temporomandibular disorders, such as OA of the TMJ, and will help to develop new treatment options, particularly those involving tissue regeneration.     

Meteorotropy and medical-meteorological forecasts

The meteorotropic reaction of the human organism is a function of different factors, such as the type and intensity of the effects of the physical environment as well as individual conditions like adaptive capacity and state of health. Many medical-meteorological studies show causal correlations between conditions in the lower atmosphere and reactions of the human organism, but also combined or synergistic effects of different weather situations, which can only be proved stochastically. These effects are described and the methodology of the investigations, as well as the results, critically discussed. Furthermore, application of the results in the areas of medical-meteorological consultation, with the goal of improving living conditions, is considered.     

环境相容性农药发展的必然性和可能途径

农药是农业生产的重要物资,发展环境相容性农药是农药发展的必然趋势,这是环境保护和农业可持续发展以及农药自身发展的要求所决定的。对已经存在的农药品种进行制剂和改进施药器械以及围绕施药器械改进施药技术,使农药减少对环境、对施药者的危害,这是发展环境相容性农药的一条有效和简便的途径。更根本的途径在于作为农药的化合物本身。大力发展生物源农药,直接利用生物材料作为农药以及筛选生物中存在的活性物质作为先导化合物开发新型农药,是目前研究开发环境容性农药的有益途径。另辟蹊径,在研制的思路上创新,在研制方法上采用高新技术,是必须要走的道路。在生物源材料中筛选先导化合物,可采用“由源到果”之路,采用“由果到源”之路则更有效。新药筛选中的生物测定技术,随着农药的角色特征的转变而改变,也随着农药作用靶标的改变而改变。基因组学、生物信息学、组合化学、基因芯片、高通量筛选等现代技术的发展有利于促进新农药的发展。     

A structural view of microtubule dynamics

The essential microtubule property of dynamic instability is based on the binding, hydrolysis and exchange of GTP in each tubulin dimer. The recent high-resolution structures of tubulin and the microtubule have given us the first view at atomic level of properties such as nucleotide exchangeability, the linkage between polymerization and nucleotide hydrolysis. and the origin of microtubule destabilization, as well as the mode of action of antimitotic agents such as taxol.     

Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells

Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma.     

Ion channels in plant signaling

Plant ion channel activities are rapidly modulated in response to several environmental and endogenous stimuli such as light, pathogen attack and phytohormones. Electrophysiological as well as pharmacological studies provide strong evidence that ion channels are essential for the induction of specific cellular responses, implicating their tight linkage to signal transduction cascades. Ion channels propagate signals by modulating the membrane potential or by directly affecting cellular ion composition. In addition, they may also be effectors at the end of signaling cascades, as examplified by ion channels which determine the solute content of stomatal guard cells. Plant channels are themselves subject to regulation by a variety of cellular factors, including calcium, pH and cyclic nucleotides. In addition, they appear to be regulated by (de)-phosphorylation events as well as by direct interactions with cytoskeletal and other cellular proteins. This review summarizes current knowledge on the role of ion chan nels in plant signaling.     

Integrin antagonists

Integrins are a family of cell surface glycoproteins that mediate numerous cell-cell and cell-matrix interactions and are involved in biological processes such as tissue morphogenesis, leukocyte recirculation and migration, wound healing, blood clotting and immune response. Aberrant cell adhesion has been implicated in the pathogenesis of several diseases, including a number of inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease and asthma, as well as cancer and coronary heart disease. As such integrins are seen as excellent targets for the development of therapeutic agents. This report begins with an examination of the structure of integrin molecules and their ligands and then goes on to review the current state of development of antiintegrin antagonists. Received 13 April 1999; received after revision 28 May 1999; accepted 28 May 1999     

Memory

Our understanding of the cellular and molecular mechanisms underlying learning and memory formation derives from studies of species as diverse as worms, mollusks, insects, birds and mammals. Despite the quite different brain structures and neuronal networks, the studies support the current notion that neuronal activity leads to changes in synaptic connections as the neural substrate of behavioral plasticity. The analysis of the mechanisms underlying learning and memory formation reveals a surprisingly high conservation between invertebrates and mammals, both at the behavioral as well as the molecular level. This special issue provides an overview of the current knowledge on cellular and molecular processes underlying memory formation. The contributing reviews summarize the findings in different organisms, such as Aplysia, Drosophila, honeybees and mammals, and discuss new approaches, developments and hypotheses all aimed at understanding how the nervous system acquires, stores and retrieves information.     

Intracellular osmotic action

Water often acts as a critical reactant in cellular reactions. Its role can be detected by modulating water activity with osmotic agents. We describe the principles behind this 'osmotic stress' strategy, and survey the ubiquity of water effects on molecular structures that have aqueous, solute-excluding regions. These effects are seen with single-functioning molecules such as membrane channels and solution enzymes, as well as in the molecular assembly of actin, the organization of DNA and the specificity of protein/DNA interactions.     

Did Samuel Clarke really disavow action at a distance in his correspondence with Leibniz?: Newton,Clarke, and Bentley on gravitation and action at a distance

In this paper I ague against John Henry's claim that Newton embraced unmediated action at a distance as an explanation of gravity (Henry, 1994, 1999, 2011, 2014). In particular, I take issue with his apparent suggestion that the fact, as he sees it, that two of Newton's prominent followers, namely, Richard Bentley and Samuel Clarke, embraced unmediated action at a distance as an explanation of gravity provides significant supporting evidence that Newton did as well (see Henry, 1994 and 1999). Instead, I argue that while Bentley did ultimately defend the notion of unmediated action at a distance as an explanation of gravity, Newton himself accepted that notion neither in his correspondence with Bentley, as Henry has maintained, nor in any of his later works. I also provide evidence that suggests that Newton did, in fact, accept both the principle of local causation and the passivity of matter. Finally, I argue that whatever the case may be with respect to Newton on the matter, it is clear from his correspondence with Leibniz, as well as from his Boyle lectures, that contrary to what Henry has maintained, Clarke was a stalwart opponent of unmediated action at a distance due to his strong commitment to both the principle of local causation and the passivity of matter.     

Das allgemeine Bauprinzip des Lamellarsystems der Chloroplasten

Summary The lamellar system of chloroplasts consists of close double lamellae. In electronphotomicrographs, the walls of two adjacent double lamellae can be seen as one thick lamella. Because of this, the lamellae in the inner portion of a lamellar packet appear about twice as thick as those at the boundary of the packet and, in chloroplasts that contain grana, the granalamellae appear twice as thick as the stromalamellae.

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Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

The Dostoevsky Machine in Georgetown: scientific translation in the Cold War

SUMMARY

Machine Translation (MT) is now ubiquitous in discussions of translation. The roots of this phenomenon — first publicly unveiled in the so-called ‘Georgetown-IBM Experiment’ on 9 January 1954 — displayed not only the technological utopianism still associated with dreams of a universal computer translator, but was deeply enmeshed in the political pressures of the Cold War and a dominating conception of scientific writing as both the goal of machine translation as well as its method. Machine translation was created, in part, as a solution to a perceived crisis sparked by the massive expansion of Soviet science. Scientific prose was also perceived as linguistically simpler, and so served as the model for how to turn a language into a series of algorithms. This paper follows the rise of the Georgetown program — the largest single program in the world — from 1954 to the (as it turns out, temporary) collapse of MT in 1964.     

Galectins: matricellular glycan-binding proteins linking cell adhesion,migration, and survival

Galectins are a taxonomically widespread family of glycan-binding proteins, defined by at least one conserved carbohydrate-recognition domain with a canonical amino acid sequence and affinity for beta-galactosides. Because of their anti-adhesive as well as pro-adhesive extracellular functions, galectins appear to be a novel class of adhesion-modulating proteins collectively known as matricellular proteins (which include thrombospondin, SPARC, tenascin, hevin, and disintegrins). Accordingly, galectins can display de-adhesive effects when presented as soluble proteins to cells in a strong adhesive state. In this context, the de-adhesive properties of galectins should be considered as physiologically relevant as the proadhesive effects of these glycan-binding proteins. This article focuses on the roles of mammalian galectins in cell adhesion, spreading, and migration, and the crossregulation of these functions. Although careful attention should be paid when examining individual galectin functions due to overlapping distributions, these intriguing glycan-binding proteins offer promising possibilities for the treatment and intervention of a wide variety of pathological processes, including cancer, inflammation, and autoimmunity.