Showing papers by "University of Tübingen published in 1995"

Stereospecific Olefin Polymerization with Chiral Metallocene Catalysts

Abstract: Current studies on novel, metallocenebased catalysts for the polymerization of α-olefins have far-reaching implications for the development of new materials as well as for the understanding of basic reaction mechanisms responsible for the growth of a polymer chain at a catalyst center and the control of its stereoregularity. In contrast to heterogeneous Ziegler–Natta catalysts, polymerization by a homogeneous, metallocene-based catalyst occurs principally at a single type of metal center with a defined coordination environment. This makes it possible to correlate metallocene structures with polymer properties such as molecular weight, stereochemical microstructure, crystallization behavior, and mechanical properties. Homogeneous catalyst systems now afford efficient control of regio- and stereoregularities, molecular weights and molecular weight distributions, and comonomer incorporation. By providing a means for the homo- and copolymerization of cyclic olefins, the cyclopolymerization of dienes, and access even to functionalized polyolefins, these catalysts greatly expand the range and versatility of technically feasible types of polyolefin materials. For corrigendum see DOI:10.1002/anie.199513681

Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation

Abstract: Tie-1 and Tie-2 define a new class of receptor tyrosine kinases that are specifically expressed in developing vascular endothelial cells. To study the functions of Tie-1 and Tie-2 during vascular endothelial cell growth and differentiation in vivo, targeted mutations of the genes in mice were introduced by homologous recombination. Embryos deficient in Tie-1 failed to establish structural integrity of vascular endothelial cells, resulting in oedema and subsequently localized haemorrhage. However, analyses of embryos deficient in Tie-2 showed that it is important in angiogenesis, particularly for vascular network formation in endothelial cells. This result contrasts with previous reports on Tie-2 function in vasculogenesis and/or endothelial cell survival. Our in vivo analyses indicate that the structurally related receptor tyrosine kinases Tie-1 and Tie-2 have important but distinct roles in the formation of blood vessels.

Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation

Abstract: Although phantom-limb pain is a frequent consequence of the amputation of an extremity, little is known about its origin. On the basis of the demonstration of substantial plasticity of the somatosensory cortex after amputation or somatosensory deafferentation in adult monkeys, it has been suggested that cortical reorganization could account for some non-painful phantom-limb phenomena in amputees and that cortical reorganization has an adaptive (that is, pain-preventing) function. Theoretical and empirical work on chronic back pain has revealed a positive relationship between the amount of cortical alteration and the magnitude of pain, so we predicted that cortical reorganization and phantom-limb pain should be positively related. Using non-invasive neuromagnetic imaging techniques to determine cortical reorganization in humans, we report a very strong direct relationship (r = 0.93) between the amount of cortical reorganization and the magnitude of phantom limb pain (but not non-painful phantom phenomena) experienced after arm amputation. These data indicate that phantom-limb pain is related to, and may be a consequence of, plastic changes in primary somatosensory cortex.

SnO2 sensors: current status and future prospects☆

Abstract: A survey is given on the current status and future prospects in research and development of SnO2-based sensors. Atomistic models of molecular recognition are discussed first. They include physisorption, chemisorption, surface reaction, catalytic reaction, grain boundary reaction, bulk reaction and three-phase boundary reaction steps. The influence of contact geometry and crystallinity on the sensor response signal is outlined. A brief summary is given of the current status of sensor research and development with emphasis on ceramic, thick-film and thin-film sensors based on crystalline, polycrystalline and nanocrystalline SnO2. Three different aspects are mentioned in the outline which are expected to lead to significantly improved performances of future sensors: the improved selectivity through the modulation frequency in a.c. measurements, the improved stability through the better control of structures, and the improved selectivity and drift compensation through pattern recognition.

Fibroblasts, epithelial-cells, endothelial-cells and smooth-muscle cells are major targets of human cytomegalovirus-infection in lung and gastrointestinal tissues

Abstract: High titre replication of human cytomegalovirus (HCMV) in cell culture is restricted to primary human fibroblasts. During acute infection in vivo, HCMV nucleic acids and antigens have been found in various organs. Using only morphological criteria, inconsistent data have been reported about the cell types that can be infected by HCMV. In particular, the role of fibroblasts in organ infections has remained unclear. To define accurately the target cells of HCMV in vivo, tissue sections from lung and gastrointestinal tract of patients suffering from acute HCMV infection were investigated using immunohistochemical double-labelling analyses. Monoclonal antibodies with defined specificity against immediate early (IE), early (E) and late (L) viral antigens and antibodies directed against cell marker proteins were employed to identify infected cells. The results demonstrated that a broad spectrum of cells was infected by HCMV in vivo. Consistent with their susceptibility in culture, fibroblasts formed a major population of HCMV-infected cells. In contrast, haemopoietic cells were only infrequently stained with virus-specific antibodies. Fibroblasts, epithelial cells, endothelial cells, smooth muscle cells and macrophages appeared to be permissive for HCMV replication. Contrary to this, polymorphonuclear cells showed only IE gene expression, indicating that these cells were abortively infected. The analysis of the distribution of infected cells in tissue supported the hypothesis that endothelial cells and monocytes/macrophages may play a crucial role in the haematogenous spread of HCMV; in contrast, fibroblasts, smooth muscle cells and epithelial cells may form the cell populations important for the multiplication and spread of the virus in infected tissues.

The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis

Abstract: In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) the cytokines tumour necrosis factor-α (TNF), lymphotoxin-α (LT), and interferon-gamma (IFN-γ) are of central pathogenetic importance. A therapy capable of stopping neurological deterioration in MS patients is not yet available. Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-γ in human and rat auto-reactive T cells. Moreover, we show that rolipram is an effective treatment for EAE. Rolipram has extensively been studied in humans for the treatment of depression, but has not yet been marketed. The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials.

Energy-coupled transport and signal transduction through the Gram-negative outer membrane via TonB-ExbB-ExbD-dependent receptor proteins

Abstract: Iron in the form of ferric siderophore complexes and vitamin B12 are transported through the outer membrane of Gram-negative bacteria by a mechanism which consumes energy. There is no known energy source in the outer membrane or in the adjacent periplasmic space so that energy is provided by the electrochemical potential across the cytoplasmic membrane. Energy flows from the cytoplasmic into the outer membrane via a complex consisting of the TonB, ExbB and ExbD proteins which are anchored in the cytoplasmic membrane. It is proposed that the TonB--ExbB--ExbD complex opens--via an energized conformation of the TonB protein--channels in the outer membrane, formed by proteins which serves as highly specific binding sites for the various ferric siderophores and vitamin B12. In addition, outer membrane receptors together with the TonB--ExbB--ExbD complex are directly involved in induction of the transcription of ferric citrate and pseudobactin transport genes of Escherichia coli and Pseudomonas putida, respectively.

A structured epidemic model incorporating geographic mobility among regions.

Abstract: A model for the spread of infectious diseases among discrete geographic regions is presented that incorporates a mobility process that describes how contact occurs between individuals from different regions. The general formulation of the mobility process is described, and it is shown that the formulation encapsulates a range of mobility behavior from complete isolation of all regions (no mobility) to permanent migration between regions. It is then shown how this mobility process fits into an SIR epidemic model, and two examples are given extending its use. The examples include a model for disease transmission in a population with two distinct mobility patterns operating and a model developed to describe a 1984 measles epidemic on the Caribbean island of Dominica.

Tetrahedral grid refinement

Abstract: We present a refinement algorithm for unstructured tetrahedral grids which generates possibly highly non-uniform but nevertheless consistent (closed) and stable triangulations. Therefore we first define somelocal regular and irregular refinement rules that are applied to single elements. Theglobal refinement algorithm then describes how these local rules can be combined and rearranged in order to ensure consistency as well as stability. It is given in a rather general form and includes also grid coarsening.

Derepression of the activity of genetically engineered heat shock factor causes constitutive synthesis of heat shock proteins and increased thermotolerance in transgenic Arabidopsis

Abstract: ATHSF1 is a heat shock transcription factor (HSF) of Arabidopsis that is constitutively expressed but its activity for DNA binding, trimer formation and transcriptional activation of heat shock (hs) genes is repressed at normal temperatures. In this study the functional properties of chimeric HSF-glucuronidase (GUS) fusion proteins were tested. Ectopic expression of HSF-GUS or GUS-HSF in transgenic Arabidopsis plants resulted in a derepression of HSF functions as shown by trimer formation, specific DNA binding, and the constitutive expression of heat shock proteins (HSPs) at normal temperature. A novel GUS activity-staining protocol was used to show the specific binding of trimeric HSF fusion proteins to DNA and following hs, an interaction between chimeric HSF-GUS and authentic HSF proteins. The chimeric HSFs were insensitive to the negative regulation that counteracts activation of the authentic HSF at normal temperature. Heterotrimer complexes were reconstituted in vitro from recombinant ATHSF1 and HSF-GUS proteins expressed in Escherichia coli and using this protocol, the temperature-dependent activation of wt HSF was monitored in vivo and in vitro. Transgenic plants expressing constitutively active HSF-GUS fusion proteins are also constitutive for HSPs. Approximately 20% of the maximum heat-inducible levels of HSP18 were already present at normal temperature. The level of basic thermotolerance was significantly enhanced in these plants. The results indicate that genetic engineering using protein fusion is a very effective means to derepress the activity of an important regulatory protein in plants, that consequently activates a constitutive hs response in the absence of heat stress and eventually alters the thermotolerance phenotype.

Topographic organization of spinal and trigeminal somatosensory pathways to the rat parabrachial and Kölliker-Fuse nuclei

Abstract: We examined the organization of somatosensory projections to the parabrachial (PB) and Kolliker-Fuse (KF) nuclei by employing the retrograde and anterograde axonal transport of Fluorogold and Phaseolus vulgaris-leucoagglutinin (PHA-L), respectively. Small PHA-L injections were made into different parts of the spinal trigeminal complex, including the paratrigeminal nucleus, and into different segments and laminae of the spinal dorsal horn. The subnuclear distribution of axonal labeling in the PB and KF was mapped with a camera lucida. Our results show that the somatosensory input to the PB and KF is highly organized. Neurons in the spinal trigeminal nuclei project predominantly to the KF and to the ventral portion of the external lateral PB. Neurons in the paratrigeminal nucleus project to the ventral lateral PB, the external medial PB, and to caudal aspects of the medial PB. These findings were supported by retrograde tracing experiments with Fluorogold. Spinal cord neurons located in the superficial dorsal horn (laminae I-II) of upper cervical segments project specifically to the ventral portion of the external lateral PB and, although more sparsely, to various other lateral PB nuclei. In contrast, neurons in the superficial dorsal horn of thoracic and lumbar spinal segments project mainly to the dorsal lateral and the central lateral PB. Finally, neurons in the lateral reticulated area and the lateral spinal nucleus of all spinal segments project almost exclusively to the internal lateral PB, whereas neurons in the respective nuclei of upper cervical segments also project to the KF. From our data we conclude that the somatosensory projections to the PB and KF are topographically organized. It is assumed that these pathways, which run from trigeminal and spinal neurons through the PB and KF to various forebrain, medullary, and spinal nuclei, form functionally different neural circuits that are involved in somatoautonomic processing.

Development of glycinergic and glutamatergic synaptic transmission in the auditory brainstem of perinatal rats

Abstract: In contrast to our knowledge about the anatomical development of the mammalian central auditory system, the development of its physiological properties is still poorly understood. In order to better understand the physiological properties of the developing mammalian auditory brainstem, we made intracellular recordings in brainstem slices from perinatal rats to examine synaptic transmission in the superior olivary complex, the first binaural station in the ascending auditory pathway. We concentrated on neurons in the lateral superior olive (LSO), which in adults, are excited from the ipsilateral side and inhibited from the contralateral side. Already at embryonic day (E) 18, when axon collaterals begin to invade the LSO anlage, synaptic potentials could be evoked from ipsilateral, as well as from contralateral inputs. Ipsilaterally elicited PSPs were always depolarizing, regardless of age. They had a positive reversal potential and could be completely blocked by the non-NMDA glutamate receptor antagonist CNQX. In contrast, contralaterally elicited PSPs were depolarizing from E18-P4, yet they turned into “adult-like,#x201D; hyperpolarizing PSPs after P8. Their reversal potential shifted dramatically from -21.6 +/- 17.7 mV (E18-P0) to -73.0 +/- 7.1 mV (P10). Regardless of their polarity, contralaterally elicited PSPs were reversibly blocked by the glycine receptor antagonist strychnine. Bath application of glycine and its agonist beta-alanine further confirmed the transitory depolarizing action of glycine in the auditory brainstem. Since the transient excitatory behavior of glycine occurs during a period during which glycinergic synaptic connections in the LSO are refined by activity- dependent mechanisms, glycinergic excitation might be a mechanism by which synaptic rearrangement in the contralateral inhibitory pathway is accomplished.

A core group model for disease transmission

Abstract: Models for sexually transmitted diseases generally assume that the size of the core group is fixed. Publicly available information on disease prevalence may influence the recruitment of new susceptibles into highly sexually active populations. It is assumed that the recruitment rate into the core population is low while disease prevalence is high, core group members mix only with each other, disease levels outside the core are negligible, and some core group members reduce their risk through the use of a partially effective vaccine or prophylactics. A demographic-epidemic model is formulated in which the combined size of the core and non-core population is constant. A simpler version models the epidemic in an isolated core population of constant size under the influence of educational programs and measures that reduce susceptibility. The threshold condition for an endemic infection is determined. Backward bifurcations, multiple infective stationary states, and hysteresis phenomena can be observed even in the simplified version. Abrupt changes in disease prevalence levels may result from small changes in the disease management parameters and do not occur in the absence of such a program. The general conclusion is that partially effective vaccination or education programs may increase the total number of cases while decreasing the relative frequency of cases in the core group. The study throws some new light on the role of the reproduction number in connection with elimination attempts. It shows that although the reproduction number defines the threshold for the spread of the disease in a susceptible population, it is of limited value when elimination of an existing epidemic is planned.

The HW95 tidal potential catalogue

Abstract: The catalogue named HW95 of the harmonic development of the Earth tide generating potential due to the Moon, the Sun and the planets Venus, Jupiter, Mars, Mercury and Saturn is presented here. This catalogue of the fully normalized potential coefficients contains 12935 waves, including 1483 waves due to the direct planetary effects (Hartmann and Wenzel 1994a,b). It is based on the DE200 numerical ephemerides of the planets and the Moon between the years 1850 and 2150. The error of gravity tides computed from the catalogue HW95 at mid-latitude stations between the years 1850 and 2150 is estimated to about 1.4 (12.3) pm/s² rms (at maximum) in time domain and 0.002 (0.11) pm/s² rms (at maximum) in frequency domain (1 pm/s²=10−12 m/s²=0.1 ngal) using a new bench-mark tidal gravity series (Wenzel 1996). An improvement in accuracy of a factor of 50 over the catalogues of Tamura (1987) and Xi (1989) has been achieved.

Local Fas/APO-1(CD95) ligand-mediated tumor cell killing in vivo

Abstract: Fas/APO-1 (CD95) is a cell surface receptor which mediates apoptosis when ligated by specific antibodies or by its recently cloned natural ligand, FasL. We have studied the cytotoxic potential of FasL in vivo using Fas/APO-1-expressing Yac-1 cells as targets. Supernatant harvested from Neuro-2a cells transfected with the murine FasL cDNA contains FasL and transduces a potent apoptotic signal to Yac-1 cells in vitro. Specificity of FasL-mediated cytotoxicity was confirmed by competition assays using soluble Fas or anti-Fas/APO-1 F(ab')2 fragments which specifically interfere with FasL-Fas/APO-1 interactions. Intraperitoneal injection of FasL-containing supernatant efficiently killed Yac-1 target cells which had been implanted in capsules into the peritoneal cavity of mice. Analysis of the target cells revealed DNA fragmentation and nuclear changes typical of apoptosis. As previously shown, intraperitoneal injection of anti-Fas/APO-1 antibodies caused liver failure (Ogasawara, J., Watanabe, F.R., Adachi, M., Matsuzawa, A., Kasugai, T., Kitamura, Y., Itoh, N., Suda, T. and Nagata, S., Nature 1993. 364:806) and was observed at doses which did not reduce Yac-1 cell viability. In contrast, FasL did not induce histopathology in the liver when applied intraperitoneally at doses cytotoxic for Yac-1 cells. However, intravenous administration of FasL induced lethal liver hemorrhages and hepatocyte apoptosis. Thus, locally applied FasL kills tumor cells very efficiently without systemic toxicity and may therefore represent a candidate for local tumor treatment.

A defect of kinesthesia in Parkinson's disease.

Abstract: Patients suffering from Parkinson's disease (PD) are more dependent on visual feedback during movement than are normals. Studying two-dimensional pointing movements, we recently found that PD patients undershoot targets when vision of their own moving hand is occluded but not when complete vision is provided or when the target is extinguished immediately before movement onset. In the absence of vision, information about position of the moving hand may originate from peripheral kinesthetic feedback and from corollary discharges derived from the efferent motor signal. To find out which of both mechanisms--kinesthetic feedback or corollary discharge--is defective in PD, we compared active movements with imposed movements in which the hand is passively moved by the experimenter, whereas vision of the hand was occluded under either condition. In agreement with our earlier findings, slow, active pointing movements of PD patients were hypometric. In addition, PD patients terminated passively imposed movements of comparable speed earlier than did normals, with the consequence that imposed movements were equally hypometric. Our results make it unlikely that disturbed corollary discharge is responsible for hypometria under nonvisual conditions. Instead, the data suggest that PD patients have a defect of kinesthesia in slowly executed movements.

The development of goal-directed reaching in infants: hand trajectory formation and joint torque control.

Abstract: Nine young infants were followed longitudinally from 4 to 15 months of age. We recorded early spontaneous movements and reaching movements to a stationary target. Time-position data of the hand (endpoint), shoulder, and elbow were collected using an optoelectronic measurement system (ELITE). We analyzed the endpoint kinematics and the intersegmental dynamics of the shoulder and elbow joint to investigate how changes in proximal torque control determined the development of hand trajectory formation. Two developmental phases of hand trajectory formation were identified: a first phase of rapid improvements between 16 and 24 weeks of age, the time of reaching onset for all infants. During that time period the number of movement units per reach and movement time decreased dramatically. In a second phase (28–64 weeks), a period of “fine-tuning” of the sensorimotor system, we saw slower, more gradual changes in the endpoint kinematics. The analysis of the underlying intersegmental joint torques revealed the following results: first, the range of muscular and motiondependent torques (relative to body weight) did not change significantly with age. That is, early reaching was not confined by limitations in producing task-adequate levels of muscular torque. Second, improvements in the endpoint kinematics were not accomplished by minimizing amplitude of muscle and reactive torques. Third, the relative timing of muscular and motion-dependent torque peaks showed a systematic development toward an adult timing profile with increasing age. In conclusion, the development toward invariant characteristics of the hand trajectory is mirrored by concurrent changes in the control of joint forces. The acquisition of stable patterns of intersegmental coordination is not achieved by simply regulating force amplitude, but more so by modulating the correct timing of joint force production and by the system's use of reactive forces. Our findings support the view that development of reaching is a process of unsupervised learning with no external or innate teacher prescribing the desired kinematics or kinetics of the movement.