Showing papers by "Heidelberg University published in 2000"

Review of Particle Physics

Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions., plus 2778 new measurements from 645 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors., probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, top quark, muon anomalous magnetic moment, extra dimensions, particle detectors, cosmic background radiation, dark matter, cosmological parameters, and big bang cosmology.

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.

Abstract: The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.

PhosphinooxazolinesA New Class of Versatile, Modular P,N-Ligands for Asymmetric Catalysis

Abstract: Chiral phosphinooxazolines (PHOX ligands), which coordinate to a metal center with a N- and a P-atom, allow effective enantiocontrol in a variety of metal-catalyzed reactions. They are readily synthesized, and because of their modular structure, the steric and electronic properties can be tailored for a specific application by variation of the oxazoline ring, the backbone, and the phosphine moiety.

Multiple Actions of Steroid Hormones—A Focus on Rapid, Nongenomic Effects

Abstract: According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. Based upon similarities in molecular structure, specific receptors for steroids, vitamin D3 derivatives, thyroid hormone, retinoids, and a variety of orphan receptors are considered to represent a superfamily of steroid receptors. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized that are clearly incompatible with the genomic model. These rapid, nongenomic steroid actions are likely to be transmitted via specific membrane receptors. Evidence for nongenomic steroid effects and distinct receptors involved is presented for all steroid groups including related compounds like vitamin D3 and thyroid hormones. The physiological and clinical relevance of these rapid effects is still largely unclear, but their existence in vivo has been clearly shown in various settings including human studies. Drugs that specifically affect nongenomic steroid action may find applications in various clinical areas such as cardiovascular and central nervous disorders, electrolyte homeostasis, and infertility. In addition to a short description of genomic steroid action, this review pays particular attention to the current knowledge and important results on the mechanisms of nongenomic steroid action. The modes of action are discussed in relation to their potential physiological or pathophysiological relevance and with regard to a cross-talk between genomic and nongenomic responses.

Primary sclerosing cholangitis.

Abstract: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibrosing inflammation and obliteration of intra- and/or extrahepatic bile ducts. The disease is one of the most common cholestatic diseases in adults and is diagnosed with increasing frequency. It is very often associated with ulcerative colitis. Patients with PSC have an increased incidence of bile duct carcinomas, and those with ulcerative colitis also have an increased incidence of colonic carcinomas. In end-stage disease, liver transplantation is the treatment of choice. Immunosuppressive treatment has little effect. Ursodeoxycholic acid (UDCA), which has been shown to improve liver histology and survival in patients with primary biliary cirrhosis, has a beneficial effect in PSC, provided that patients who develop major duct stenoses are treated endoscopically. The aim is to treat patients as early as possible to prevent progression to the advanced stages of the disease. During treatment with UDCA, stenoses of major ducts may develop, and early endoscopic dilation is highly effective. Because UDCA treatment improves but does not cure cholestatic liver diseases, permanent treatment seems to be necessary. Such prolonged treatment with UDCA may be recommended because, until now, no side effects have been reported. In patients with end-stage disease, UDCA is not effective and liver transplantation is indicated.

Consumer health informatics

Abstract: Medical informatics has expanded rapidly over the past couple of years. After decades of development of information systems designed primarily for physicians and other healthcare managers and professionals, there is an increasing interest in reaching consumers and patients directly through computers and telecommunications systems. Consumer health informatics is the branch of medical informatics that analyses consumers' needs for information; studies and implements methods of making information accessible to consumers; and models and integrates consumers' preferences into medical information systems. Consumer informatics stands at the crossroads of other disciplines, such as nursing informatics, public health, health promotion, health education, library science, and communication science, and is perhaps the most challenging and rapidly expanding field in medical informatics; it is paving the way for health care in the information age. This non-exhaustive review focuses on topics from the field of consumer health informatics because there has been a markedly increased interest in this field (additional information is available on the BMJ 's website). Medline was searched using the terms “consumer” and “informatics.” The proceedings of the American Medical Informatics Association's symposiums (1998 and 1999) and the proceedings of the ninth World Congress on Medical Informatics (Medinfo 1998) were hand searched. The AltaVista search engine was used to retrieve information from the internet, using the search string “+definition + consumer health informatics” to find unpublished reports.1–3 Medical informatics is “the field that concerns itself with the cognitive, information processing, and communication tasks of medical practice, education, and research.” 4 Until recently medical informatics focused on developing applications for health professionals: medical informaticians looked at medical practice mainly through the eyes of health professionals rather than through the eyes of patients. Ten years ago Greenes and Shortliffe wrote: “After many years of development of information systems to support the infrastructure of …

Local control of the immune response in the liver.

Abstract: The physiological function of the liver--such as removal of pathogens and antigens from the blood, protein synthesis and metabolism--requires an immune response that is adapted to these tasks and is locally regulated. Pathogenic microorganisms must be efficiently eliminated while the large number of antigens derived from the gastrointestinal tract must be tolerized. From experimental observations it is evident that the liver favours the induction of tolerance rather than the induction of immunity. The liver probably not only is involved in transplantation tolerance but contributes as well to tolerance to orally ingested antigens (entering the liver with portal-venous blood) and to containment of systemic immune responses (antigen from the systemic circulation entering the liver with arterial blood). This review summarizes the experimental data that shed light on the molecular mechanisms and the cell populations of the liver involved in local immune regulation in the liver. Although hepatocytes constitute the major cell population of the liver, direct interaction of hepatocytes with leukocytes in the blood is unlikely. Sinusoidal endothelial cells, which line the hepatic sinusoids and separate hepatocytes from leukocytes in the sinusoidal lumen, and Kupffer cells, the resident macrophage population of the liver, can directly interact with passenger leukocytes. In the liver, clearance of antigen from the blood occurs mainly by sinusoidal endothelial cells through very efficient receptor-mediated endocytosis. Liver sinusoidal endothelial cells constitutively express all molecules necessary for antigen presentation (CD54, CD80, CD86, MHC class I and class II and CD40) and can function as antigen-presenting cells for CD4+ and CD8+ T cells. Thus, these cells probably contribute to hepatic immune surveillance by activation of effector T cells. Antigen-specific T-cell activation is influenced by the local microenvironment. This microenvironment is characterized by the physiological presence of bacterial constituents such as endotoxin and by the local release of immunosuppressive mediators such as interleukin-10, prostaglandin E2 and transforming growth factor-beta. Different hepatic cell populations may contribute in different ways to tolerance induction in the liver. In vitro experiments revealed that naive T cells are activated by resident sinusoidal endothelial cells but do not differentiate into effector T cells. These T cells show a cytokine profile and a functional phenotype that is compatible with the induction of tolerance. Besides sinusoidal endothelial cells, other cell populations of the liver, such as dendritic cells, Kupffer cells and perhaps also hepatocytes, may contribute to tolerance induction by deletion of T cells through induction of apoptosis.

Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles

Abstract: Here, to study lipid-protein interactions that contribute to the biogenesis of regulated secretory vesicles, we have developed new approaches by which to label proteins in vivo, using photoactivatable cholesterol and glycerophospholipids. We identify synaptophysin as a major specifically cholesterol-binding protein in PC12 cells and brain synaptic vesicles. Limited cholesterol depletion, which has little effect on total endocytic activity, blocks the biogenesis of synaptic-like microvesicles (SLMVs) from the plasma membrane. We propose that specific interactions between cholesterol and SLMV membrane proteins, such as synaptophysin, contribute to both the segregation of SLMV membrane constituents from plasma-membrane constituents, and the induction of synaptic-vesicle curvature.

Retention of prominin in microvilli reveals distinct cholesterol-based lipid micro-domains in the apical plasma membrane.

Abstract: Membrane cholesterol-sphingolipid 'rafts', which are characterized by their insolubility in the non-ionic detergent Triton X-100 in the cold, have been implicated in the sorting of certain membrane proteins, such as placental alkaline phosphatase (PLAP), to the apical plasma membrane domain of epithelial cells. Here we show that prominin, an apically sorted pentaspan membrane protein, becomes associated in the trans-Golgi network with a lipid raft that is soluble in Triton X-100 but insoluble in another non-ionic detergent, Lubrol WX. At the cell surface, prominin remains insoluble in Lubrol WX and is selectively associated with microvilli, being largely segregated from the membrane subdomains containing PLAP. Cholesterol depletion results in the loss of prominin's microvillus-specific localization but does not lead to its complete intermixing with PLAP. We propose the coexistence within a membrane domain, such as the apical plasma membrane, of different cholesterol-based lipid rafts, which underlie the generation and maintenance of membrane subdomains.

Development of WHO guidelines on generalized cost-effectiveness analysis.

Abstract: The growing use of cost-effectiveness analysis (CEA) to evaluate specific interventions is dominated by studies of prospective new interventions compared with current practice. This type of analysis does not explicitly take a sectoral perspective in which the costs and effectiveness of all possible interventions are compared, in order to select the mix that maximizes health for a given set of resource constraints. WHO guidelines on generalized CEA propose the application of CEA to a wide range of interventions to provide general information on the relative costs and health benefits of different interventions in the absence of various highly local decision constraints. This general approach will contribute to judgements on whether interventions are highly cost-effective, highly cost-ineffective, or something in between. Generalized CEAs require the evaluation of a set of interventions with respect to the counterfactual of the null set of the related interventions, i.e. the natural history of disease. Such general perceptions of relative cost-effectiveness, which do not pertain to any specific decision-maker, can be a useful reference point for evaluating the directions for enhancing allocative efficiency in a variety of settings. The proposed framework allows the identification of current allocative inefficiencies as well as opportunities presented by new interventions.

Geochemical background - can we calculate it?

Abstract: The term "background" is discussed and a definition is suggested to put an end to the currently unsatisfying (non-)definition of geochemical or natural background. Based on the requirements stated in the definition, several simple and robust statistical methods are applied to different data sets (n>50) from the atmosphere, pedosphere, and biosphere in order to explore their potential for the evaluation of a useful and robust background. Compared with the original data set both the calculated distribution, based upon the lower 50% of the values, as well as a 2σ-approximation of the normalised data set lead to promising and realistic results. Both methods seem appropriate for a fast and reliable evaluation of likely upper limits of background values. Nevertheless, even this robust method is not able to present absolute and doubtlessly correct background values. True quantification of any natural or geochemical background still requires a thorough investigation and is impossible without costly expert knowledge.

The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans

Abstract: In metazoans, most pre-messenger RNAs contain introns that are removed by splicing. The spliced mRNAs are then exported to the cytoplasm. Recent studies showed that splicing promotes efficient mRNA export, but the mechanism for coupling these two processes is not known. Here we show that Aly, the metazoan homologue of the yeast mRNA export factor Yralp (ref. 2), is recruited to messenger ribonucleoprotein (mRNP) complexes generated by splicing. In contrast, Aly does not associate with mRNPs assembled on identical mRNAs that already have no introns or with heterogenous nuclear RNP (hnRNP) complexes. Aly is recruited during spliceosome assembly, and then becomes tightly associated with the spliced mRNP. Aly shuttles between the nucleus and cytoplasm, and excess recombinant Aly increases both the rate and efficiency of mRNA export in vivo. Consistent with its splicing-dependent recruitment, Aly co-localizes with splicing factors in the nucleus. We conclude that splicing is required for efficient mRNA export as a result of coupling between the splicing and the mRNA export machineries.

Phosphoprotein Associated with Glycosphingolipid-Enriched Microdomains (Pag), a Novel Ubiquitously Expressed Transmembrane Adaptor Protein, Binds the Protein Tyrosine Kinase Csk and Is Involved in Regulation of T Cell Activation

Abstract: According to a recently proposed hypothesis, initiation of signal transduction via immunoreceptors depends on interactions of the engaged immunoreceptor with glycosphingolipid-enriched membrane microdomains (GEMs). In this study, we describe a novel GEM-associated transmembrane adaptor protein, termed phosphoprotein associated with GEMs (PAG). PAG comprises a short extracellular domain of 16 amino acids and a 397-amino acid cytoplasmic tail containing ten tyrosine residues that are likely phosphorylated by Src family kinases. In lymphoid cell lines and in resting peripheral blood α/β T cells, PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood α/β T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates. Moreover, overexpression of PAG in Jurkat cells downregulates T cell receptor–mediated activation of the transcription factor nuclear factor of activated T cells. These findings collectively suggest that in the absence of external stimuli, the PAG–Csk complex transmits negative regulatory signals and thus may help to keep resting T cells in a quiescent state.

The Glomerular Slit Diaphragm Is a Modified Adherens Junction

Abstract: The glomerular slit diaphragm between podocyte foot processes shares typical morphologic features with an adherens junction. Differentiated cultured podocytes form cellular structures comparable to filtration slits in vivo. At those sites, zonula occludens-1 (ZO-1) was coexpressed with P-cadherin as well as with alpha-, beta-, and gamma-catenin. In situ, P-cadherin was detected at the slit diaphragm in association with ZO-1 as shown by confocal microscopy and immunogold double labeling electron microscopy. P-cadherin expression in vivo and in vitro was confirmed by reverse transcription-PCR. These findings led to the concept that the slit diaphragm represents an adherens junction composed of P-cadherin, alpha-, beta-, and gamma-catenin, and ZO-1. In contrast to an adherens junction of a similar composition recently described in cultured fibroblasts, the slit diaphragm complex does not contain vinculin, which was found in nearby focal contacts. A P-cadherin-based adherens junction is well-suited to explain the zipper-like structure of the slit diaphragm. The present study should allow new avenues leading to the identification of additional slit diaphragm-associated proteins conferring specificity to this unique cell junction.

Learning and memory in pain pathways

Abstract: The neurons of the central nervous system not only have the capacity to transmit, inhibit and weigh information, but they may also store information for prolonged periods of time (e.g. by use-dependent change in synaptic strength). Synaptic plasticity in hippocampus is an extensively studied cellular model of learning and memory and recent studies suggest that similar mechanisms also apply to pain pathways and may account for some forms of hyperalgesia, allodynia and analgesia. The discovery of synaptic longterm plasticity in nociceptive systems provides a relatively simple and straight forward concept for a number of clinically relevant phenomena. Here, I will brie y summarize key aspects of synaptic plasticity in general. Then I will describe related changes at nociceptive synapses and discuss the potential relevance of these mechanisms for the development, the prevention and the treatment of chronic pain.

(Non)Thermal Aspects of Charmonium Production and a New Look at J/$\psi$ Suppression

Abstract: To investigate a recent proposal that J/$\psi$ production in ultra-relativistic nuclear collisions is of thermal origin we have reanalyzed the data from the NA38/50 collaboration within a thermal model including charm. Comparison of the calculated with measured yields demonstrates the non-thermal origin of hidden charm production at SPS energy. However, the ratio $\psi^{'}$/(J/$\psi)$ exhibits, in central nucleus-nucleus collisions, thermal features which lead us to a new interpretation of open charm and charmonium production at SPS energy. Implications for RHIC and LHC energy measurements will be discussed.

Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells.

Abstract: Intrathymic expression of tissue-specific self antigens may be involved in immunological tolerance and protection from autoimmune disease We have analyzed the role of T-cell tolerance to proteolipid protein (PLP), the main protein of the myelin sheath, in susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis Intrathymic expression of PLP was largely restricted to the shorter splice variant, DM20 Expression of DM20 by thymic epithelium was sufficient to confer T-cell tolerance to all epitopes of PLP in EAE-resistant C57BL/6 mice In contrast, the major T-cell epitope in SJL/J mice was only encoded by the central nervous system-specific exon of PLP, but not by thymic DM20 Thus, lack of tolerance to this epitope offers an explanation for the exquisite susceptibility of SJL/J mice to EAE As PLP expression in the human thymus is also restricted to the DM20 isoform, these findings have implications for selection of the autoimmune T-cell repertoire in multiple sclerosis

Thioredoxin reductase as a pathophysiological factor and drug target

Abstract: Human cytosolic thioredoxin reductase (TrxR), a homodimeric protein containing 1 selenocysteine and 1 FAD per subunit of 55 kDa, catalyses the NADPH-dependent reduction of thioredoxin disulfide and of numerous other oxidized cell constituents. As a general reducing enzyme with little substrate specificity, it also contributes to redox homeostasis and is involved in prevention, intervention and repair of damage caused by H2O2-based oxidative stress. Being a selenite-reducing enzyme as well as a selenol-containing enzyme, human TrxR plays a central role in selenium (patho)physiology. Both dietary selenium deficiency and selenium oversupplementation, a lifestyle phenomenon of our time, appear to interfere with the activity of TrxR. Selenocysteine 496 of human TrxR is a major target of the anti-rheumatic gold-containing drug auranofin, the formal Ki for the stoichiometric inhibition being 4 nM. The hypothesis that TrxR and extracellular thioredoxin play a pathophysiologic role in chronic diseases such as rheumatoid arthritis, Sjogren's syndrom, AIDS, and certain malignancies, is substantiated by biochemical, virological, and clinical evidence. Reduced thioredoxin acts as an autocrine growth factor in various tumour diseases, as a chemoattractant, and it synergises with interleukins 1 and 2. The effects of anti-tumour drugs such as carmustine and cisplatin can be explained in part by the inhibition of TrxR. Consistently, high levels of the enzyme can support drug resistance. TrxRs from different organisms such as Escherichia coli, Mycobacterium leprae, Plasmodium falciparum, Drosophila melanogaster, and man show a surprising diversity in their chemical mechanism of thioredoxin reduction. This is the basis for attempts to develop specific TrxR inhibitors as drugs against bacterial infections like leprosy and parasitic diseases like amebiasis and malaria.

Graphical interaction models for multivariate time series 1

Abstract: In this paper we extend the concept of graphical models for multivariate data to multivariate time series. We define a partial correlation graph for time series and use the partial spectral coherence between two components given the remaining components to identify the edges of the graph. As an example we consider multivariate autoregressive processes. The method is applied to air pollution data.

Tet repressor-based system for regulated gene expression in eukaryotic cells: principles and advances.

Abstract: Publisher Summary The tetracycline (Tc) responsive regulatory systems have been applied to control gene activities in eukaryotes. They are shown to function in cultured cells from mammals, plants, amphibians, and insects as well as in whole organisms including yeast, Drosophila, plants, mice, and rats. The basic regulatory circuits of the Tet systems and the elements constituting these circuits are based on simple principles. A number of parameters must be reconciled when setting up one of the systems for a particular purpose. When considering properties of the Tet system, such as degree (tightness) of control, expression levels, and regulation factors, it is crucial to distinguish among experimental situations in which the systems are stably inserted in the genome of cells in culture or of transgenic organisms and situations in which the respective regulatory elements are in a nonintegrated state, as in transient expression experiments or when contained in episomes.

Osteoporosis Due to Cancer Treatment: Pathogenesis and Management

Abstract: Many therapeutic regimens in cancer treatment carry the risk of causing or favoring the development of osteoporosis. Therapies in which hypogonadism may occur are most relevant in this respect. Prompt hormone replacement therapy is indicated in these patients. In patients in whom this is undesirable because of a hormone-dependent tumor, the risk of osteoporosis should be assessed by means of osteodensitometry, and prophylactic or therapeutic measures should be instituted if necessary. Early intervention improves outcome because osteoporosis therapy is most effective in preventing deterioration of bone mass. There remains much uncertainty in assessing the risk of combination chemotherapy with regard to the development of osteoporosis. Negative effects on the skeleton have, however, been demonstrated for individual drugs, such as methotrexate and ifosfamide. Negative effects of the tumor itself on bone metabolism may aggravate the degree of osteoporosis. Detailed data and long-term experience to assess the risk are urgently needed in this area and constitute an important research topic for the coming years and decades. This review discusses the most prevalent mechanisms of osteoporosis caused by cancer treatment and outlines therapeutic strategies for the prevention and treatment of therapy-induced bone loss.