Showing papers by "Heidelberg University published in 1994"

Review of particle properties.

Abstract: This biennial Review summarizes much of Particle Physics. Using data from previous editions, plus 2205 new measurements from 667 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. This edition features expanded coverage of CP violation in B mesons and of neutrino oscillations. For the first time we cover searches for evidence of extra dimensions (both in the particle listings and in a new review). Another new review is on Grand Unified Theories. A booklet is available containing the Summary Tables and abbreviated versions of some of the other sections of this full Review. All tables, listings, and reviews (and errata) are also available on the Particle Data Group website: http://pdg.lbl.gov.

Objective measurement of wave aberrations of the human eye with the use of a Hartmann-Shack wave-front sensor

Abstract: A Hartmann-Shack wave-front sensor is used to measure the wave aberrations of the human eye by sensing the wave front emerging from the eye produced by the retinal reflection of a focused light spot on the fovea. Since the test involves the measurements of the local slopes of the wave front, the actual wave front is reconstructed by the use of wave-front estimation with Zernike polynomials. From the estimated Zernike coefficients of the tested wave front the aberrations of the eye are evaluated. It is shown that with this method, using a Hartmann-Shack wave-front sensor, one can obtain a fast, precise, and objective measurement of the aberrations of the eye.

Combined spatial and temporal imaging of brain activity during visual selective attention in humans.

Abstract: VISUAL–SPATIAL attention is an essential brain function that enables us to select and preferentially process high priority information in the visual fields1,2. Several brain areas have been shown to participate in the control of spatial attention in humans3–5, but little is known about the underlying selection mechanisms. Non-invasive scalp recordings of event-related potentials (e.r.ps) in humans have shown that attended visual stimuli are preferentially selected as early as 80–90 ms after stimulus onset6,7, but current e.r.p. methods do not permit a precise localization of the participating cortical areas. In this study we combined neuroimaging (positron emission tomography) with e.r.p. recording in order to describe both the cortical anatomy and time course of attentional selection processes. Together these methods showed that visual inputs from attended locations receive enhanced processing in the extrastriate cortex (fusiform gyrus) at 80–130 ms after stimulus onset. These findings reinforce early selection models of attention8–10.

The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth

Abstract: The formation of new blood vessels (angiogenesis) is critical for the growth of tumours and is a dominant feature in various angiogenic diseases such as diabetic retinopathy, arthritis, haemangiomas and psoriasis. Recognition of the potential therapeutic benefits of controlling pathological angiogenesis has led to a search for angiogenesis inhibitors. Here we report that 2-methoxyoestradiol, an endogenous oestrogen metabolite of previously unknown function, is a potent inhibitor of endothelial cell proliferation and migration as well as angiogenesis in vitro. Moreover, when administered orally in mice, it strongly inhibits the neovascularization of solid tumors and suppresses their growth. Unlike the angiostatic steroids of corticoid structure, it does not require the co-administration of heparin or sulphated cyclodextrins for activity. Thus, 2-methoxyoestradiol is the first steroid to have high antiangiogenic activity by itself. Our results suggest that this compound may have therapeutic potential in cancer and other angiogenic diseases.

The traveling salesman: computational solutions for TSP applications

Abstract: Basic Concepts.- Related Problems and Applications.- Geometric Concepts.- Candidate Sets.- Construction Heuristics.- Improving Solutions.- Heuristics for Large Geometric Problems.- Further Heuristic Approaches.- Lower Bounds.- A Case Study: TSPs in Printed Circuit Board Production.- Practical TSP Solving.

Control of kinetic properties of AMPA receptor channels by nuclear RNA editing

Abstract: AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor channels mediate the fast component of excitatory postsynaptic currents in the central nervous system. Site-selective nuclear RNA editing controls the calcium permeability of these channels, and RNA editing at a second site is shown here to affect the kinetic aspects of these channels in rat brain. In three of the four AMPA receptor subunits (GluR-B, -C, and -D), intronic elements determine a codon switch (AGA, arginine, to GGA, glycine) in the primary transcripts in a position termed the R/G site, which immediately precedes the alternatively spliced modules "flip" and "flop." The extent of editing at this site progresses with brain development in a manner specific for subunit and splice form, and edited channels possess faster recovery rates from desensitization.

Integrin cytoplasmic domains mediate inside-out signal transduction

Abstract: We analyzed the binding of fibronectin to integrin alpha 5 beta 1 in various cells; in some cells fibronectin bound with low affinity (e.g., K562 cells) whereas in others (e.g., CHO), it bound with high affinity (Kd approximately 100 nM) in an energy-dependent manner. We constructed chimeras of the extracellular and transmembrane domains of alpha IIb beta 3 joined to the cytoplasmic domains of alpha 5 beta 1. The affinity state of these chimeras was assessed by binding of fibrinogen or the monoclonal antibody, PAC1. The cytoplasmic domains of alpha 5 beta 1 conferred an energy-dependent high affinity state on alpha IIb beta 3 in CHO but not K562 cells. Three additional alpha cytoplasmic domains (alpha 2, alpha 6A, alpha 6B) conferred PAC1 binding in CHO cells, while three others (alpha M, alpha L, alpha v) did not. In the high affinity alpha chimeras, cotransfection with a truncated (beta 3 delta 724) or mutated (beta 3(S752-->P)) beta 3 subunit abolished high affinity binding. Thus, both cytoplasmic domains are required for energy-dependent, cell type-specific affinity modulation. In addition, mutations that disrupted a highly conserved alpha subunit GFFKR motif, resulted in high affinity binding of ligands to alpha IIb beta 3. In contrast to the chimeras, the high affinity state of these mutants was independent of cellular metabolism, cell type, and the bulk of the beta subunit cytoplasmic domain. Thus, integrin cytoplasmic domains mediate inside-out signaling. Furthermore, the highly conserved GFFKR motif of the alpha subunit cytoplasmic domain maintains the default low affinity state.

Convenient single-step, one tube purification of PCR products for direct sequencing.

Abstract: Structural alterations of the apolipoprotein E (apo E) are known to influence the lipid metabolism. The three most common isoproteins Arg 158) are encoded by three co-dominant alleles (e2, el, e4). Phenotyping is cumbersome and, therefore, several methods for apo E genotyping have been developed. Of these, PCR-RFLP (restriction fragment length polymorphism) is currently most rapid and cost-effective (1). To detect mutations not affecting restriction sites, direct PCR sequencing of apo E fragments is the method of choice. This, however, requires purification of PCR products, which is routinely accomplished by techniques like gel electrophoresis or chromatography. We have established a new purification method using exonuclease I (exo I) and shrimp alkaline phosphatase (sAP) to degrade excess primers and nucleotides, which are the main factors interfering with dideoxy PCR sequencing. This procedure simply requires the addition of the enzymes to the PCR product, avoiding frequent sample handling and DNA loss through technical manipulation. Human DNA was extracted from 50 iA EDTA blood with Tris-EDTA lysis and proteinase K digestion. The PCR reaction mix (50 ill) was optimized to contain 10 /tl of DNA extract, 30 pmol of the primers F4 and F6 (2), 5 pi of dimethyl sulfoxide (DMSO), 10 pmol of each dNTP, 2 U of Taq polymerase 5 ii\\ of 10 X PCR buffer (GeneAMP; Perkin-Elmer). After initial denaturation (95°C 5 min) 35 cycles (95°C 20 sec, 60°C 30 sec, 72 °C 30 sec) of amplification were performed, followed by a final extension (72°C 10 min; DNA Thermal Cycler 480, Perkin-Elmer). 2 jil of PCR product (244 bp) were mixed with 1 U exo I and 1 U sAP (USB, Cleveland, USA) and incubated for 1 h at 37°C. The enzymes were inactivated for 15 min at 72°C. The purified PCR product was diluted to a final volume of 10 /tl for cycle sequencing (3) with 0.5 pmol biotinylated primer F6 (A Taq™ Cycle Sequencing Kit; USB) under the same conditions as for PCR of genomic DNA. For chemiluminescence detection (4) we used the 'Sequenase® Images™ non-isotopic DNA sequence detection kit' (USB). Sequencing data obtained with sAP/exo I purified DNA are at least equal to those after column chromatography and superior to those using unpurified templates (Figure 1). Adjusting the purified DNA solutions for dilution we saw a slightly better efficiency of cycle sequencing in the enzymatically purified DNA.

A molecular determinant for submillisecond desensitization in glutamate receptors

Abstract: The decay of excitatory postsynaptic currents in central neurons mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors is likely to be shaped either by receptor desensitization or by offset after removal of glutamate from the synaptic cleft. Native AMPA receptors show desensitization time constants of 1 to about 10 milliseconds, but the underlying molecular determinants of these large differences are unknown. Cloned AMPA receptors carrying the "flop" splice variants of glutamate receptor subtype C (GluR-C) and GluR-D are shown to have desensitization time constants of around 1 millisecond, whereas those with the "flip" variants are about four times slower. Cerebellar granule cells switch their expression of GluR-D splice variants from mostly flip forms in early stages to predominantly flop forms in the adult rat brain. These findings suggest that rapid desensitization of AMPA receptors can be regulated by the expression and alternative splicing of GluR-D gene transcripts.

Sensitivity and prognostic value of early CT in occlusion of the middle cerebral artery trunk.

Abstract: PURPOSE To investigate the incidence and prognostic value of local brain swelling, the extent of parenchymal hypodensity, and the hyperdense middle cerebral artery sign as shown by CT within the first 5 hours after the onset of symptoms in patients with angiographically proved middle cerebral artery trunk occlusions. METHODS Fifty-three patients were studied prospectively with CT 46 to 292 minutes (median, 120; mean, 134 +/- 59) after symptom onset and scored clinically at admission and 4 weeks later. All patients were treated with recombinant tissue plasminogen activator (30 to 100 mg). RESULTS Early CT showed parenchymal hypodensity in 43 patients (81%), local brain swelling in 20 patients (38%), and hyperdensity of the middle cerebral artery trunk in 25 patients (47%). Hypodensity covering more than 50% of the middle cerebral artery territory had an 85%, local brain swelling a 70%, and the hyperdense middle cerebral artery sign a 32% positive predictive value for fatal clinical outcome. Specificity of these findings for fatal outcome was 94%, 83%, and 51%, respectively, and sensitivity was 61%, 78% and 44%, respectively. CONCLUSIONS Early CT in acute middle cerebral artery trunk occlusion is highly predictive for fatal clinical outcome if there is extended hypodensity or local brain swelling despite aggressive therapeutic attempts such as thrombolysis or decompressive surgery.

Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.

Abstract: Meth-A sarcoma cells were stable transfected to overexpress (sense construct) or underexpress (antisense construct) tissue factor. In vitro, there was no difference in plating efficiency or growth between these cell lines. In vivo, tumor cells transfected to overexpress tissue factor grew more rapidly, and established larger and more vascularized tumors than control transfectants. Antisense transfectants grew the slowest and were the least vascularized. Anticoagulation of mice with warfarin did not alter the difference between these tumor lines. Tumor cells over-expressing tissue factor released more (compared with control transfectants) mitogenic activity for endothelial cells in parallel with enhanced transcription of vascular permeability factor/vascular endothelial cell growth factor (VEGF/VPF), and diminished transcription of thrombospondin (TSP2), a molecule with anti-angiogenic properties. Antisense tissue factor transfectants, while releasing the lowest amount of mitogenic activity, had increased thrombospondin and decreased VEGF/VPF transcription compared with control transfectants or wild-type cells. Experiments with these sense, antisense, truncated sense, or vector tumor lines gave comparable results in complete medium, serum free medium or in the presence of hirudin, indicating that the activation of the coagulation mechanism was not likely to be responsible for changes in tumor cell properties. These results suggest that tissue factor regulates angiogenic properties of tumor cells by altering the production of growth regulatory molecules of endothelium by a mechanism distinct from tissue factor activation of the coagulation mechanism.

The ATP hydrolysis-dependent reaction cycle of the Escherichia coli Hsp70 system DnaK, DnaJ, and GrpE

Abstract: Molecular chaperones of the Hsp70 class bind unfolded polypeptide chains and are thought to be involved in the cellular folding pathway of many proteins. DnaK, the Hsp70 protein of Escherichia coli, is regulated by the chaperone protein DnaJ and the cofactor GrpE. To gain a biologically relevant understanding of the mechanism of Hsp70 action, we have analyzed a model reaction in which DnaK, DnaJ, and GrpE mediate the folding of denatured firefly luciferase. The binding and release of substrate protein for folding involves the following ATP hydrolysis-dependent cycle: (i) unfolded luciferase binds initially to DnaJ; (ii) upon interaction with luciferase-DnaJ, DnaK hydrolyzes its bound ATP, resulting in the formation of a stable luciferase-DnaK-DnaJ complex; (iii) GrpE releases ADP from DnaK; and (iv) ATP binding to DnaK triggers the release of substrate protein, thus completing the reaction cycle. A single cycle of binding and release leads to folding of only a fraction of luciferase molecules. Several rounds of ATP-dependent interaction with DnaK and DnaJ are required for fully efficient folding.

Flow-equations for Hamiltonians

Abstract: Flow-equations are introduced in order to bring Hamiltonians closer to diagonalization It is characteristic for these equations that matrix-elements between degenerate or almost degenerate states do not decay or decay very slowly In order to understand different types of physical systems in this framework it is probably necessary to classify various types of these degeneracies and to investigate the corresponding physical behavior In general these equations generate many-particle interactions However, for an n-orbital model the equations for the two-particle interaction are closed in the limit of large n Solutions of these equations for a one-dimensional model are considered There appear convergency problems, which are removed, if instead of diagonalization only a block-diagonalization into blocks with the same number of quasiparticles is performed

Standard Model CP-violation and Baryon asymmetry

Abstract: In CP arguments, we argue against a Standard Model explanation of the baryon asymmetry of the universe in the presence of a first order phase transition. A CP-asymmetry is found in the reflection coefficients of quarks hitting the phase boundary created during the electroweak transition. The problem is analyzed both in an academic zero temperature case and in the realistic finite temperature one. The building blocks are similar in both cases: Kobayashi-Maskawa CP-violation, CP-even phases in the reflection coefficients of quarks, and physical transitions due to fermion self-energies. In both cases an effect is present at order $\alpha_W^2 $ in rate. A regular GIM behavior is found as intuitively expected. In the finite temperature case, a crucial role is played by the damping rate of quasiparticles in a hot plasma, which is a relevant scale together with MW and the temperature. The effect is many orders of magnitude below what observation requires, and indicates that non-standard physics is indeed needed ...

Isolation and characterization of the intracellular MHC class II compartment

Abstract: An intracellular compartment has been isolated to which MHC class II molecules are transported on their way to the plasma membrane. They arrive with an associated invariant chain which is then proteolytically processed while MHC class II molecules acquire antigenic peptide. These loaded class II molecules then leave the compartment devoid of invariant chain and bound for the plasma membrane. This compartment represents a new stage in the endocytic/ lysosomal pathway.

Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA

Abstract: Developmental and regional alternative splicing of the NMDAR1 subunit gene transcript was examined by in situ hybridization in the developing and adult rat brain. NMDAR1 mRNA, barely detectable at embryonic day 14, increased gradually during development until the third postnatal week, after which it declined slightly to adult levels, when it was detected in every examined neuronal type. Each splice form of the primary NMDAR1 gene transcript was found to follow a parallel profile of abundance in the brain, but marked regional differences were observed in splicing at both 5′ and 3′ sequences. The individual regional distributions of splice forms appeared to be established around birth, with little change thereafter, except in the overall abundance. The NMDAR1-a and NMDAR1–2 splice forms occurred extensively and approximately homogeneously throughout brain gray matter. The NMDAR1-b variant was found primarily in the sensorimotor cortex, neonatal lateral caudate, thalamus, hippocampal CA3 field, and cerebellar granule cells, but was absent from adult caudate. The NMDAR1–1 and -4 splice forms were detected in almost complementary patterns; the former was concentrated in more rostral structures such as cortex, caudate, and hippocampus, while the latter was principally in more caudal regions such as thalamus, colliculi, and cerebellum. These two splice forms accounted for a greater proportion of the adult NMDAR1 mRNA than that of the neonate. The NMDAR1–3 mRNA variant was scarce, being detected only at very low levels in postnatal cortex and hippocampus. The different splice forms may generate regional differences in NMDA receptor properties during development and in the adult CNS.

Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice

Abstract: During hepatitis B virus (HBV) infection, distinct host-virus interactions may establish the patterns of viral clearance and persistence and the extent of virus-associated pathology. It is generally thought that HBV-specific class I-restricted cytotoxic T lymphocytes (CTLs) play a critical role in this process by destroying infected hepatocytes. This cytopathic mechanism, however, could be lethal if most of the hepatocytes are infected. In the current study, we demonstrate that class I-restricted HBV-specific CTLs profoundly suppress hepatocellular HBV gene expression in HBV transgenic mice by a noncytolytic process, the strength of which greatly exceeds the cytopathic effect of the CTLs in magnitude and duration. We also show that the regulatory effect of the CTLs is initially mediated by interferon gamma and tumor necrosis factor alpha, is delayed in onset, and becomes independent of these cytokines shortly after it begins. The data indicate that the anti-viral CTL response activates a complex regulatory cascade that inhibits hepatocellular HBV gene expression without killing the cell. The extent to which this mechanism contributes to viral clearance or viral persistence during HBV infection remains to be determined.

Multiplicative functions on the lattice of non-crossing partitions and free convolution.

Abstract: The lattice of non-crossing partitions was introduced by Kreweras [Kre] in 1972 and examined further by Poupard [Pou] and Edelman [Edel, Ede2]. In the last time there has been an increased interest in this lattice, on one hand from the purely combinatorial point of view [SiU, EdS, Sire, BSS] and on the other hand from a (quantum) probabilistic point of view [GSS, Spel, Spe2, Spe3]. We became interested in this lattice when we noticed that it is connected with some new form of convolution for probability measures, the 'free' convolution introduced by Voiculescu [Voil, Voi2, Voi3]. This connection between the free convolution and the lattice of non-crossing partitions is exactly analogous to the connection between the usual convolution and the lattice of all partitions. We shall work out this connection in the last part of this work. The intention of this article is to show that both the purely combinatorial and the probabilistic point of view can benefit from each other. Motivated by Voiculescu's formula for the R-series of free convolution we examine multiplicative functions on the lattice of non-crossing partitions and prove our main theorem, which is much in the spirit of Voiculescu's formula. We shall then use this main theorem for deriving some known results on non-crossing partitions in a unified way. This part of our work is purely combinatorial, the free convolution serves only as a motivation for our theorem. In the last section we shall switch to the probabilistie side and show how the lattice of non-crossing partitions determines the structure of the free convolution. Voiculescu's formula will then follow as an easy corollary of our main theorem. In this respect, we shall get a purely combinatorial proof of this formula without any operator algebraic or functional analytic tools.

Isolation of a neural chondroitin sulfate proteoglycan with neurite outgrowth promoting properties.

Abstract: Proteoglycans are expressed in various tissues on cell surfaces and in the extracellular matrix and display substantial heterogeneity of both protein and carbohydrate constituents. The functions of individual proteoglycans of the nervous system are not well characterized, partly because specific reagents which would permit their isolation are missing. We report here that the monoclonal antibody 473HD, which binds to the surface of early differentiation stages of murine astrocytes and oligodendrocytes, reacts with the chondroitin sulfate/dermatan sulfate hybrid epitope DSD-1 expressed on a central nervous system chondroitin sulfate proteoglycan designated DSD-1-PG. When purified from detergent-free postnatal days 7 to 14 mouse brain extracts, DSD-1-PG displays an apparent molecular mass between 800-1,000 kD with a prominent core glycoprotein of 350-400 kD. Polyclonal anti-DSD-1-PG antibodies and monoclonal antibody 473HD react with the same molecular species as shown by immunocytochemistry and sequential immunoprecipitation performed on postnatal mouse cerebellar cultures, suggesting that the DSD-1 epitope is restricted to one proteoglycan. DSD-1-PG promotes neurite outgrowth of embryonic day 14 mesencephalic and embryonic day 18 hippocampal neurons from rat, a process which can be blocked by monoclonal antibody 473HD and by enzymatic removal of the DSD-1-epitope. These results show that the hybrid glycosaminoglycan structure DSD-1 supports the morphological differentiation of central nervous system neurons.

Expression of APO-1 (CD95), a member of the NGF/TNF receptor superfamily, in normal and neoplastic colon epithelium.

Abstract: APO-I is a 48-kDa cell-membrane protein identical to the Fas antigen now designated CD95. It is a member of the NGF/TNF receptor superfamily. Anti-APO-I monoclonal antibody induces apoptosis in a variety of cell types expressing this antigen. We immunohistochemically investigated APO-I expression in normal colon mucosa, 20 adenomas, 258 colon carcinomas and 10 liver metastases and carried out in vitro studies using a panel of colon-carcinoma cell lines. Immunohistochemically, APO-I was regularly expressed at the basolateral membrane of normal colon epithelia. In a minor fraction of colon adenomas and in 39.1% of colon carcinomas APO-I expression was diminished and in 48.1% of carcinomas, predominantly of the non-mucinous type, APO-I expression was completely abrogated. The normal level of APO-I in carcinomas was correlated with the mucinous type. Reduced/lost APO-I expression was more frequent in rectal carcinomas. Complete loss of APO-I was more frequent in tumors that had already metastasized. APO-I expression in liver metastases essentially corresponded to that of the primary tumors. Comparative analysis with data from previous studies revealed that the mode of APO-I expression is correlated with that of HLA-A,B,C./β2m, HLA-DR, HLA-D-associated invariant chain and of the secretory component. Surface expression of APO-I was heterogeneous in colon-carcinoma cell lines; SW480 expressed considerable amounts of APO-I on all cells, while HT-29 constitutively did less so and only in a minority of cells. Surface density of APO-I and the fraction of positive cells in HT-29 was enhanced by interferon-gamma (IFN-γ) and, additively, by tumor necrosis factor-alpha (TNF-α), whereas in SW480 APO-I expression was not modulated by these cytokines. We conclude that neoplastic transformation of colon epithelium often leads to a loss of the physiologic, high level of surface APO-I by giving rise either to a stable lack of APO-I or to an IFN-γ/TNF-α-sensitive phenotype of inducible APO-I expression. © 1994 Wiley-Liss, Inc.

Interferon gamma stimulation modulates the proteolytic activity and cleavage site preference of 20S mouse proteasomes.

Abstract: The proteasome is a 700-kD multisubunit enzyme complex with several proteolytically active sites. The enzyme complex is involved in both ubiquitin-dependent and -independent protein degradation and may contribute to the processing of antigens presented by major histocompatibility complex (MHC) class I molecules. Here we demonstrate that treatment of mouse fibroblast cells with 20 U interferon gamma (IFN-gamma) for 3 d induces a change in the proteasome subunit composition and that the beta-type subunit LMP2, which is encoded in the MHC class II region, is incorporated into the enzyme complex. This is paralleled by reduction of the homologous delta-subunit. IFN-gamma stimulation results in a downregulation of the chymotrypsin-like Suc-LLVY-MCA peptide hydrolyzing activity of 20S proteasomes whereas the trypsin-like activity remains unaffected. When tested as a substrate a synthetic 25-mer polypeptide whose sequence covers the antigenic nonapeptide YPHFMPTNL of the MCMV pp89, 20S proteasomes of IFN-gamma-induced cells exhibit altered chymotrypsin-like cleavage site preferences. In the absence of IFN-gamma induction, the naturally processed nonamer peptide that is presented by MHC class I molecules appears as a minor cleavage product. IFN-gamma activation does not result in an increase of the final peptide but results in a different set of peptides. We hypothesize that these peptides represent precursor peptides that can be trimmed to final peptide size.