Showing papers by "University of Göttingen published in 1998"

Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein

Abstract: Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease. They result in a selective increase in the production of the amyloidogenic peptide amyloid-beta(1-42) by proteolytic processing of the amyloid precursor protein (APP). Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by alpha- and beta-secretase of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by gamma-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.

Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice

Abstract: Cathepsin K is a recently identified lysosomal cysteine proteinase. It is abundant in osteoclasts, where it is believed to play a vital role in the resorption and remodeling of bone. Pycnodysostosis is a rare inherited osteochondrodysplasia that is caused by mutations of the cathepsin-K gene, characterized by osteosclerosis, short stature, and acroosteolysis of the distal phalanges. With a view to delineating the role of cathepsin K in bone resorption, we generated mice with a targeted disruption of this proteinase. Cathepsin-K-deficient mice survive and are fertile, but display an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space. Cathepsin-K-deficient osteoclasts manifested a modified ultrastructural appearance: their resorptive surface was poorly defined with a broad demineralized matrix fringe containing undigested fine collagen fibrils; their ruffled borders lacked crystal-like inclusions, and they were devoid of collagen-fibril-containing cytoplasmic vacuoles. Assaying the resorptive activity of cathepsin-K-deficient osteoclasts in vitro revealed this function to be severely impaired, which supports the contention that cathepsin K is of major importance in bone remodeling.

Integration of endothelial cells in multicellular spheroids prevents apoptosis and induces differentiation

Abstract: Single endothelial cells (EC) seeded in suspension culture rapidly undergo apoptosis. Addition of survival factors, such as VEGF and FGF-2, does not prevent apoptosis of suspended EC. However, when cells are allowed to establish cell–cell contacts, they become responsive to the activities of survival factors. These observations have led to the development of a three-dimensional spheroid model of EC differentiation. EC spheroids remodel over time to establish a differentiated surface layer of EC and a center of unorganized EC that subsequently undergo apoptosis. Surface EC become quiescent, establish firm cell–cell contacts, and can be induced to express differentiation antigens (e.g., induction of CD34 expression by VEGF). In contrast, the unorganized center spheroid cells undergo apoptosis if they are not rescued by survival factors. The responsiveness to the survival factor activities of VEGF and FGF-2 was not dependent on cell shape changes since it was retained after cytochalasin D treatment. Taken together, these findings characterize survival factor requirements of unorganized EC and indicate that polarized surface EC differentiate to become independent of exogenous survival factors. Furthermore, they demonstrate that spheroid cell culture systems are useful not just for the study of tumor cells and embryonic stem cells but also for the analysis of differentiated functions of nontransformed cells.

Destabilization of beta catenin by mutations in presenilin-1 potentiates neuronal apoptosis

Abstract: Mutations of the presenilin-1 gene are a major cause of familial early-onset Alzheimer's disease. Presenilin-1 can associate with members of the catenin family of signalling proteins, but the significance of this association is unknown. Here we show that presenilin-1 forms a complex with beta-catenin in vivo that increases beta-catenin stability. Pathogenic mutations in the presenilin-1 gene reduce the ability of presenilin-1 to stabilize beta-catenin, and lead to increased degradation of beta-catenin in the brains of transgenic mice. Moreover, beta-catenin levels are markedly reduced in the brains of Alzheimer's disease patients with presenilin-1 mutations. Loss of beta-catenin signalling increases neuronal vulnerability to apoptosis induced by amyloid-beta protein. Thus, mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of beta-catenin, predisposing individuals to early-onset Alzheimer's disease.

Semiological Seizure Classification

Abstract: We propose an epileptic seizure classification based exclusively on ictal semiology. In this semiological seizure classification (SSC), seizures are classified as follows: a. Auras are ictal manifestations having sensory, psychosensory, and experiential symptoms. b. Autonomic seizures are seizures in which the main ictal manifestations are objectively documented autonomic alterations. c. "Dialeptic" seizures have as their main ictal manifestations an alteration of consciousness that is independent of ictal EEG manifestations. The new term "dialeptic" seizure has been coined to differentiate this concept from absence seizures (dialeptic seizures with a generalized ictal EEG) and complex partial seizures (dialeptic seizures with a focal ictal EEG). d. Motor seizures are characterized mainly by motor symptoms and are subclassified as simple or complex. Simple motor seizures are characterized by simple, unnatural movements that can be elicited by electrical stimulation of the primary and supplementary motor area (myoclonic, tonic, clonic and tonic-clonic, versive). Complex motor seizures are characterized by complex motor movements that resemble natural movements but that occur in an inappropriate setting ("automatisms"). e. Special seizures include seizures characterized by "negative" features (atonic, astatic, hypomotor, akinetic, and aphasic seizures). The SSC identifies in detail the somatotopic distribution of the ictal semiology as well as the seizure evolution. The advantages of a pure SSC, as opposed to the current classification of the International League Against Epilepsy (ILAE), which is actually a classification of electroclinical syndromes, are discussed.

Transduction Mechanisms in Vertebrate Olfactory Receptor Cells

Abstract: Schild, Detlev, and Diego Restrepo. Transduction Mechanisms in Vertebrate Olfactory Receptor Cells. Physiol. Rev. 78: 429–466, 1998. — Considerable progress has been made in the understanding of tr...

Animal models of human cardiovascular disease, heart failure and hypertrophy

Abstract: The progress made in our understanding of the pathophysiology and treatment of congestive heart failure (CHF) would not have been possible without a number of animal models of heart failure and hypertrophy, each one having unique advantages as well as disadvantages. The species and interventions used to create CHF depends on the scientific question as well as on factors such as ethical and economical considerations, accessibility and reproducibility or the model. How closely the model should mimic the human syndrome of CHF depends on the scientific question under investigation. If the goal is to study pathophysiological processes like remodeling or the function of subcellular systems such as excitation contraction-coupling processes, contractile protein function or energetics, the model of heart failure should mimic the clinical setting as closely as possible. However, if defined causal connections are under investigation such as structure–function analyses or regulation of gene expression, exact reflection of the clinical setting by the animal model may be less important. In this review, animal models of heart failure are discussed with particular focus on similarities between the animal model and the failing human heart regarding myocardial function as well as molecular and subcellular mechanisms. In addition, new models of heart failure and hypertrophy, and finally some recent animal models of myocarditis are reviewed.

Intravascular ultrasound-guided optimized stent deployment Immediate and 6 months clinical and angiographic results from the Multicenter Ultrasound Stenting in Coronaries Study (MUSIC Study)

Abstract: Objectives A study was set up to validate the safety and feasibility of intravascular ultrasound-guided stenting without subsequent anticoagulation, and its impact on the 6 months restenosis rate. Methods The study was designed to be multicentred, prospective, and observational. Results One hundred and sixty-one patients with stable angina and a de novo coronary artery lesion were enrolled. In four patients, the implantation of a Palmaz–Schatz (with spiral bridge) stent had failed. One of these four patients died 3 days following bypass surgery. In two other patients, intravascular ultrasound assessment was not performed. One hundred and twenty-five of the remaining 155 patients (81%) were treated with aspirin (100mg.day−1), because all three criteria for optimized stent expansion were met. Twenty-two of the remaining 38 patients (25%), in whom at least one criterion was not met were treated with aspirin and acenocoumarol (3 months, INR 2·5–3·5), while 16 patients only received aspirin. Stent thrombosis was documented in two patients (1·3%) for which repeat angioplasty was performed. During the hospital stay, there were no deaths or Q-wave myocardial infarctions. Five patients (3·2%) sustained a non-Q-wave myocardial infarction. During the follow-up period (198±38 days, complete for all patients, except one), one patient (0·6%) sustained a Q-wave myocardial infarction, one (0·6%) underwent bypass surgery, and repeat angioplasty was performed in nine patients (5·7%). In two of the nine patients, repeat angioplasty involved another lesion. Therefore, the target lesion revascularization rate during follow-up was 4·5% (seven patients).At quantitative coronary angiography, the minimal lumen diameter (mean±SD) increased from 1·12± 0·34mm before to 2·89±0·35mm after stenting. Repeat angiography at 6 months was performed in 144 patients (92%). The minimal lumen diameter at follow-up was 2·12±0·67mm. Restenosis (diameter stenosis of 50% or more) was documented in 12 patients or 8·3%. When the two patients with documented stent thrombosis are included, the restenosis rate amounts to 9·7%. Conclusions These data confirm that, in selected patients, stents can safely be implanted without the use of systemic anticoagulation, provided optimal stent expansion is achieved. The exact role of intravascular ultrasound in the achievement of these results needs to be established by appropriately designed studies. In the meantime, intra-vascular ultrasound coupled with the Palmaz–Schatz stent incorporating a spiral bridge, may have contributed considerably to the immediate angiographic outcome, which in turn may explain the favourable clinical and angiographic outcome at 6 months.

Detection of 14‐3‐3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt‐Jakob disease

Abstract: The analysis of 14-3-3 protein in cerebrospinal fluid (CSF) was shown to be highly sensitive and specific for the diagnosis of Creutzfeldt-Jakob disease (CJD). However, the predictive value of this test in the clinical diagnosis of, and its relation to, sporadic, genetic, and iatrogenic CJD cases have yet to be established. CSF samples of suspect CJD cases seen in the prospective German surveillance study were tested for the presence of 14-3-3 protein by using a modified western blot (WB) technique. WB detected 14-3-3 protein in 95.4% of definite and 92.8% of probable cases. In two patients classified initially as not having CJD the test was positive, and both were later proved to have definite CJD. The positive predictive value is 94.7% and the negative predictive value is 92.4%. False-positive results in a single CSF analysis were seen in patients with herpes simplex encephalitis, hypoxic brain damage, atypical encephalitis, intracerebral metastases of a bronchial carcinoma, metabolic encephalopathy, and progressive dementia of unknown cause. WB analysis for 14-3-3 protein was positive in only 5 of 10 cases of familial forms of spongiform encephalopathies. CSF analysis for 14-3-3 protein should thus be performed in any case suspect for CJD.

Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation

Abstract: 1 Transcranial magnetic stimulation (TMS) of the human motor cortex results in multiple discharges (D and I waves) in the corticospinal tract We tested whether these volleys can be explored non-invasively with paired TMS The intensity of the first stimulus (S1) was set to produce a motor-evoked potential (MEP) of 1 mV in the resting contralateral abductor digiti minimi (ADM) muscle; the second stimulus (S2) was set to 90 % of the resting motor threshold At interstimulus intervals of 11-15, 23-29 and 41-44 ms the MEP elicited by S1 plus S2 was larger than that produced by S1 alone 2 Varying the S1 intensity between 70 and 130 % resting motor threshold with S2 held constant at 90 % resting motor threshold showed that the threshold for the first MEP peak was <= 70 % resting motor threshold The second and third MEP peaks appeared only at higher S1 intensities The latency of all peaks decreased with increasing S1 intensity 3 Varying the S2 intensity with S1 held constant to produce a MEP of 1 mV on its own showed that the amplitude of all MEP peaks increased with S2 intensity, but that their timing remained unchanged 4 Paired TMS in the active ADM (S1 clearly suprathreshold, S2 just above threshold; interstimulus interval, 1 ms) produced strong MEP facilitation The onset of this facilitation occurred later by about 15 ms than the onset of the MEP evoked by S2 alone No MEP facilitation was seen if the magnetic S2 was replaced by anodal or cathodal transcranial electrical stimulation 5 It is concluded that the MEP facilitation after paired TMS, at least for the first MEP peak, is due to facilitatory interaction between I waves, and takes place in the motor cortex at or upstream from the corticospinal neurone

Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome.

Abstract: Townes-Brocks syndrome (IBS, OMIM #107480) is a rare autosomal-dominant malformation syndrome with a combination of anal, renal, limb and ear anomalies1. Cytogenetic findings2 suggested that the gene mutated in IBS maps to chromosome 16q12.1, where SALL1 (previously known as HSAL1), a human homologue of spa/t (sal), is located3. SAL is a developmental regulator in Drosophila melanogasfer4–8 and is conserved throughout evolution3,9–11. No phenotype has yet been attributed to mutations in vertebrate saMike genes. The expression patterns of saMike genes in mouse9, Xenopi/s10 and the fish Medaka11, and the finding that Medaka sal is regulated by Sonic hedgehog (Shh; ref. 11), prompted us to examine SALL1 as a TBS candidate gene. Here we demonstrate that SALL1 mutations cause TBS in a family with vertical transmission of TBS12 and in an unrelated family with a sporadic case of TBS. Both mutations are predicted to result in a prematurely terminated SALL1 protein lacking all putative DMA binding domains. TBS therefore represents another human developmental disorder caused by mutations in a putative C2H2 zinc–finger transcription factor.

Bioindication using trap-nesting bees and wasps and their natural enemies: community structure and interactions

Abstract: 1. Results from four field studies show that communities of trap-nesting bees and wasps and their natural enemies are promising bioindicators for ecological change or habitat quality. These small and easy-to-handle communities can be analysed with respect to (i) species richness and related parameters, and (ii) ecological functions or interactions. The communities comprise Hymenoptera (Apidae, Sphecidae, Eumenidae, Pompilidae) and natural enemies belonging to many insect taxa. Traps consisted of 150–200, 15–20-cm long, reed internodes, put into tins or plastic tubes of 13–15 cm diameter; wooden posts with 2–10 of such reed-filled tins were exposed in the target habitat. 2. Species richness and abundance of bees (but not wasps) were closely related to plant species richness of the habitat, a measure of the bees’ food resource. However, availability of nest sites of above-ground nesting species was equally important: meadows with old trees supported greater populations than meadows without trees. A threefold increase in exposed traps resulted in a twofold increase in species. 3. The sensitivity of this bioindicator system profits from the fact that evaluations rely not only on presence/absence data, descriptive population attributes or diversity indices, but also on interactions or ecological functions. Monitoring ecological responses or multitrophic interactions, and their relationship to species diversity, is rarely done but much needed. Ecological functions include (i) the percentage mortality of trap-nesting bees and wasps due to parasitoids and predators, which was correlated with the species richness of these natural enemies; (ii) seed set of allogamous plants due to successful pollination by trap-nesting bees; and (iii) biological control by the predacious wasps. 4. With increasing isolation of fragmented habitats (when traps were exposed in a cleared agricultural landscape), both species richness of natural enemies and percentage mortality (parasitism and predation) declined significantly. In a comparison of habitat types (grasslands and field margins), species richness of the trap-nest community correlated with plant diversity, but percentage mortality, due to parasitism and predation, with field age only. The threshold distance to the nearest habitat was 106–530 m for a 10–50% decrease in mean mortality, and the mortality increased greatly in habitats that were older than 5 years. Accordingly, these studies emphasize the significance of a continuum of old habitat patches for the augmentation of natural enemies. 5. Exposure of standardized traps is an experimental approach with a small, interacting and reproducing community that can be easily characterized by simple parameters. Taxonomy and biology are well known, and quick evaluations can be done using the close correlation between the number of occupied traps and species richness. Species richness of trap-nesting bees and wasps was closely correlated with that sampled by sweep nets. Further criteria of indicator taxa that apply to this system are discussed in the text.

Comparison of Aerobic Exercise, Clomipramine, and Placebo in the Treatment of Panic Disorder

Abstract: OBJECTIVE: The purpose of this study was to compare the therapeutic effect of exercise for patients with panic disorder to a drug treatment of proven efficacy and to placebo. METHOD: Forty-six outpatients suffering from moderate to severe panic disorder with or without agoraphobia (DSM-III-R criteria) were randomly assigned to a 10-week treatment protocol of regular aerobic exercise (running), clomipramine (112.5 mg/day), or placebo pills. RESULTS: The dropout rate was 31% for the exercise group, 27% for the placebo group, and 0% for the clomipramine group. In comparison with placebo, both exercise and clomipramine led to a significant decrease in symptoms according to all main efficacy measures (analysis of variance, last-observation-carried-forward method and completer analysis). A direct comparison of exercise and clomipramine revealed that the drug treatment improved anxiety symptoms significantly earlier and more effectively. Depressive symptoms were also significantly improved by exercise and clomip...

Influence of the Novel Inotropic Agent Levosimendan on Isometric Tension and Calcium Cycling in Failing Human Myocardium

Abstract: Background—Levosimendan was shown to increase calcium sensitivity by a novel mechanism and to inhibit phosphodiesterase III activity in animal myocardium. Methods and Results—We investigated the influence of levosimendan on isometric contractions and calcium transients (aequorin method) in muscle strips from human hearts with end-stage failing dilated or ischemic cardiomyopathy (n=27). Data were compared with the effects of the phosphodiesterase inhibitor milrinone (n=9). The average maximum increase in twitch tension was 47±14% (range, 6% to 150%) at a levosimendan concentration of 0.8±0.3 μmol/L (P<0.01). This was associated with significant increases in maximum rates of tension rise and fall and decreases in times to peak tension, to 50% relaxation, and to 95% relaxation. In aequorin-loaded muscles, levosimendan 10−6 mol/L increased average tension by 50% (P<0.02), associated with a nonsignificant increase in aequorin light (16%). With milrinone 10−5 mol/L, average tension increased by 58% and aequorin...

A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3

Abstract: Among the various coats involved in vesicular transport, the clathrin associated coats that contain the adaptor complexes AP-1 and AP-2 are the most extensively characterized. The function of the recently described adaptor complex AP-3, which is similar to AP-1 and AP-2 in protein composition but does not associate with clathrin, is not known. By monitoring surface plasmon resonance we observed that AP-3 is able to interact with the tail of the lysosomal integral membrane protein LIMP-II and that this binding depends on a DEXXXLI sequence in the LIMP-II tail. Furthermore, AP-3 bound to the cytoplasmic tail of the melanosome-associated protein tyrosinase which contains a related EEXXXLL sequence. The tails of LIMP-II and tyrosinase either did not interact, or only interacted poorly, with AP-1 or AP-2. In contrast, the cytoplasmic tails of other membrane proteins containing di-leucine and/or tyrosine-based sorting signals did not bind AP-3, but AP-1 and/or AP-2. This points to a function of AP-3 in intracellular sorting to lysosomes and melanosomes of a subset of cargo proteins via di-leucine-based sorting motifs.

The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis.

Abstract: We report an extended set of neuroimmunological data detected in cerebrospinal fluid (CSF) from n=267 patients with definite multiple sclerosis (MS). Known frequencies of oligoclonal IgG (98%), frequencies of intrathecal fractions of IgG, IgA and IgM (72%, 9% and 20%, respectively) were confirmed and quantitated as intrathecal fractions, IgIF or CSF concentrations, IgLoc. Eighty-nine per cent of the patients had a combined `MRZ-reaction', i.e. intrathecal antibody synthesis (Antibody Index, AI > 1.4) against measles, rubella and/or varicella zoster virus. Frequencies of single antibodies decreased from measles (78%) to rubella (60%), VZV (55%) and HSV (28%). This MRZ-reaction, indicating a chronic autoimmune type disease already at time of first clinical symptoms, is less sensitive but more specific than detection of oligoclonal IgG. With increasing intrathecal IgG synthesis the number of different locally synthesized antibody species were increased as well as the amount per species (increased mean AI val...

Reducing the renal uptake of radiolabeled antibody fragments and peptides for diagnosis and therapy: present status, future prospects and limitations

Abstract: Elevated renal uptake and prolonged retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. Over recent years, one of the focuses of research has therefore been to develop suitable methods to reduce this renal uptake, and to evaluate whether the resulting methodology will benefit therapy with antibody fragments and peptides. In these studies it has been shown that the kidney uptake of antibody fragments in animals can be reduced in a dose-dependent manner by almost one order of magnitude by the systemic administration of cationic amino acids and their derivatives, whereas the uptake in all other organs, as well as the tumor, remains unaffected. A similar reduction in renal retention is achieved for all intracellularly retained radionuclides (e.g., radiometals) or radioiodinated immunoconjugates, as well as for smaller peptides. Lysine is usually the preferred agent, and its d- and l-isomers are equally effective whether given intraperitoneally or orally. Amino sugars are effective, but their N-acetyl derivatives, lacking the positive charge, are not. Basic polypeptides are also effective, and their potency increases with increasing molecular weight (i.e., the amount of positive charges per molecule). Urine analysis of treated individuals shows the excretion of unmetabolized, intact fragments or peptides, in contrast to mostly low-molecular-weight metabolites in untreated controls. In therapy studies using radiometal-conjugated Fab fragments, the kidney is the first dose-limiting organ. Administration of cationic amino acids results in a substantial increase in the maximum tolerated dose of such Fab fragments. No biochemical or histological evidence of renal damage has been observed under these conditions. As was the case in animal studies, in pilot clinical trials the renal uptake in patients injected with Fab' fragments and given amino acids could be decreased significantly, whereas the uptake by all other organs remained unaffected. These recent studies indicate that a variety of basic compounds are capable of inhibiting the tubular reabsorption of peptides and proteins, thus significantly lowering the renal uptake of antibody fragments or peptides in both animals and patients. On a molecular basis, the effect seems to rely essentially on the presence of a positively charged amino group. Thus, radiation nephrotoxicity of antibody fragments and peptides can be overcome successfully; this may provide new prospects for cancer therapy with radiolabeled antibody fragments and peptides.

Emergence of a Novel Catalytic Radical Reaction: Titanocene-Catalyzed Reductive Opening of Epoxides

Abstract: The preparatively important catalytic opening of epoxides to β-titanoxy radicals via single-electron transfer (SET) is described. These radicals can be reduced to alcohols or participate in C−C bond-forming reactions. A key step in the catalytic cycle is the conceptually novel protonation of titanium−oxygen and −carbon bonds. Our method combines the advantages of radical reactions, e.g., high functional group tolerance and stability of radicals under protic conditions, with the ability of organometallic complexes to determine the course of transformations in reagent-controlled reactions.

Upper Critical Field Peculiarities of Superconducting YNi 2 B 2 C and LuNi 2 B 2 C

Abstract: We present new upper critical field ${H}_{c2}(T)$ data in a broad temperature region $0.3\mathrm{K}\ensuremath{\le}T\ensuremath{\le}{T}_{c}$ for ${\mathrm{LuNi}}_{2}{\mathrm{B}}_{2}\mathrm{C}$ and ${\mathrm{YNi}}_{2}{\mathrm{B}}_{2}\mathrm{C}$ single crystals with well characterized low impurity scattering rates. The absolute values for all $T$, in particular, ${H}_{c2}(0)$, and the sizable positive curvature (PC) of ${H}_{c2}(T)$ at high and intermediate $T$ are explained quantitatively within an effective two-band model. The failure of the isotropic single-band approach is discussed in detail. Supported by de Haas--van Alphen data, the superconductivity reveals direct insight into details of the electronic structure. The observed maximal PC near ${T}_{c}$ gives strong evidence for clean limit type-II superconductors.

Prion protein expression and superoxide dismutase activity.

Abstract: The function of the prion protein (PrPc) remains uncertain. It has been suggested that prion protein expression may aid cellular resistance to oxidative stress by influencing the activity of Cu/Zn superoxide dismutase (Cu,Zn SOD). The activity of Cu,Zn SOD was investigated in mice with different levels of PrPc expression. Increasing levels of PrPc expression were linked to increased levels of Cu,Zn SOD activity. Western-blot and Northern-blot analysis indicated that mice either lacking or overexpressing PrPc had levels of Cu,Zn SOD mRNA equivalent to those expressed in wild-type mice. Mice overexpressing the prion protein had lower levels of resistance to oxidative stress but higher expression levels of glutathione peroxidase, probably due to increased levels of hydrogen peroxide produced by increased Cu,Zn SOD activity. When cells were metabolically labelled with radioactive copper, increased radioactivity was immunoprecipitated with Cu,Zn SOD from mice with higher levels of PrPc. In addition, diethyldithiocarbamate, a copper chelator that inactivates Cu,Zn SOD by capturing copper from the molecule, is more able to inactivate Cu,Zn SOD expressed in animals with higher levels of PrPc. As recent studies have suggested that PrPc may regulate some aspect of copper metabolism, it is suggested that PrPc expression may regulate Cu,Zn SOD activity by influencing copper incorporation into the molecule.

Convergence order estimates of meshless collocation methods using radial basis functions

Abstract: We study meshless collocation methods using radial basis functions to approximate regular solutions of systems of equations with linear differential or integral operators. Our method can be interpreted as one of the emerging meshless methods, cf. T. Belytschko et al. (1996). Its range of application is not confined to elliptic problems. However, the application to the boundary value problem for an elliptic operator, connected with an integral equation, is given as an example. Although the method has been used for special cases for about ten years, cf. E.J. Kansa (1990), there are no error bounds known. We put the main emphasis on detailed proofs of such error bounds, following the general outline described in C. Franke and R. Schaback (preprint).

Consequences of Triplet Aromaticity in 4nπ-Electron Annulenes: Calculation of Magnetic Shieldings for Open-Shell Species

Abstract: The triplet states of 4nπ-electron annulenes, as suggested by Baird in 1972, should be regarded as aromatic rather than antiaromatic. Such triplet states show planarized, symmetrical geometries (see C9H9+ on the right), much lower energies than corresponding acylic triplet reference species, and evidence for diatropic ring currents (nucleus-independent chemical shifts and magnetic susceptibility exaltations).

On the superparamagnetic—stable single domain transition for magnetite, and frequency dependence of susceptibility

Abstract: SUMMARY Sediments and soils often contain superparamagnetic (SP) magnetite or maghemite grains that cause a frequency dependence of low-field susceptibility X fd which does not exceed 15 per cent/decade of frequency. Present models predict very diVerent volume distributions for samples with the largest observed frequency dependence of susceptibility. While Stephensons’ (1971) power-law model predicts most grains to be smaller than the stable single domain (SSD) threshold, the phenomenological model of Dearing et al. (1996) suggests that most grains are between 10 and 25 nm in diameter. Finally, the recent calculations of Eyre (1997) indicate very broad volume distributions. This study reviews the nature of the superparamagnetic‐stable single domain (SP‐SSD) transition. The change of AC susceptibilities with grain size (or temperature) at the SP‐SSD boundary is more gradual than commonly assumed. When distributions of particle coercivities and volumes are also considered, X fd values are much smaller than those calculated by Eyre (1997). Nonetheless, X fd can be larger than 15 per cent, and a larger frequency dependence has indeed been measured for some samples. The question whether the observed limited X fd of soils and sediments is a result of a broad distribution or of a bimodal distribution, where SP and SSD grains are restricted to a certain relative abundance, can potentially be answered by susceptibility determinations at more than two frequencies and by measurements of the temperature dependence of susceptibility.