Showing papers by "University of Basel published in 2000"

Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA

Abstract: Two small RNAs regulate the timing of Caenorhabditis elegans development. Transition from the first to the second larval stage fates requires the 22-nucleotide lin-4 RNA and transition from late larval to adult cell fates requires the 21-nucleotide let-7 RNA. The lin-4 and let-7 RNA genes are not homologous to each other, but are each complementary to sequences in the 3' untranslated regions of a set of protein-coding target genes that are normally negatively regulated by the RNAs. Here we have detected let-7 RNAs of ~21 nucleotides in samples from a wide range of animal species, including vertebrate, ascidian, hemichordate, mollusc, annelid and arthropod, but not in RNAs from several cnidarian and poriferan species, Saccharomyces cerevisiae, Escherichia coli or Arabidopsis. We did not detect lin-4 RNA in these species. We found that let-7 temporal regulation is also conserved: let-7 RNA expression is first detected at late larval stages in C. elegans and Drosophila , at 48 hours after fertilization in zebrafish, and in adult stages of annelids and molluscs. The let-7 regulatory RNA may control late temporal transitions during development across animal phylogeny.

Translating biomolecular recognition into nanomechanics.

Abstract: We report the specific transduction, via surface stress changes, of DNA hybridization and receptor-ligand binding into a direct nanomechanical response of microfabricated cantilevers. Cantilevers in an array were functionalized with a selection of biomolecules. The differential deflection of the cantilevers was found to provide a true molecular recognition signal despite large nonspecific responses of individual cantilevers. Hybridization of complementary oligonucleotides shows that a single base mismatch between two 12-mer oligonucleotides is clearly detectable. Similar experiments on protein A-immunoglobulin interactions demonstrate the wide-ranging applicability of nanomechanical transduction to detect biomolecular recognition.

Structural determinants of water permeation through aquaporin-1.

Abstract: Human red cell AQP1 is the first functionally defined member of the aquaporin family of membrane water channels. Here we describe an atomic model of AQP1 at 3.8A resolution from electron crystallographic data. Multiple highly conserved amino-acid residues stabilize the novel fold of AQP1. The aqueous pathway is lined with conserved hydrophobic residues that permit rapid water transport, whereas the water selectivity is due to a constriction of the pore diameter to about 3 A over a span of one residue. The atomic model provides a possible molecular explanation to a longstanding puzzle in physiology-how membranes can be freely permeable to water but impermeable to protons.

Happiness, Economy and Institutions

Abstract: A cross-regional econometric analysis is conducted suggesting that institutional factors in the form of direct democracy (via initiatives and referenda) and of federal structure (local autonomy) systematically and sizeably raise self-reported individual well-being. This positive effect can be attributed to political outcomes closer to voters' preferences as well as to the procedural utility of political participation. Moreover, the results of "standard" microeconometric well-being functions previously published are supported. Unemployment among economic variables and bad health among demographic variables have a strongly depressing effect on happiness. Income only significantly raises happiness for higher income groups.

Motivation crowding theory : a survey of empirical evidence

Abstract: The motivation crowding effect suggests that an external intervention via monetary incentives or punishments may undermine (and under different indentifiable conditions strengthen) intrinsic motivation. As of today, the theoretical possibility of crowding effects is widely accepted among economists. Many of them, however, have been critical about its empirical relevance. This survey shows that such scepticism is unwarranted and that there exists indeed compelling empirical evidence for the existence of crowding out and crowding in. It is based on circumstantial insight, laboratory studies by both psychologists and economists as well as field research by econometric studies. The presented pieces of evidence refer to a wide variety of areas of the economy and society and have been collected for many different countries and periods. Crowding effects thus are an empirically relevant phenomenon, which can, in specific cases, even dominate the traditional relative price effect.

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.

Universal quantum computation with the exchange interaction.

Abstract: Various physical implementations of quantum computers are being investigated, although the requirements that must be met to make such devices a reality in the laboratory at present involve capabilities well beyond the state of the art. Recent solid-state approaches have used quantum dots, donor-atom nuclear spins or electron spins; in these architectures, the basic two-qubit quantum gate is generated by a tunable exchange interaction between spins (a Heisenberg interaction), whereas the one-qubit gates require control over a local magnetic field. Compared to the Heisenberg operation, the one-qubit operations are significantly slower, requiring substantially greater materials and device complexity--potentially contributing to a detrimental increase in the decoherence rate. Here we introduced an explicit scheme in which the Heisenberg interaction alone suffices to implement exactly any quantum computer circuit. This capability comes at a price of a factor of three in additional qubits, and about a factor of ten in additional two-qubit operations. Even at this cost, the ability to eliminate the complexity of one-qubit operations should accelerate progress towards solid-state implementations of quantum computation.

Acute cortisone administration impairs retrieval of long-term declarative memory in humans.

Abstract: 1. Hazelrigg, T. Cell 95, 451–460 (1998). 2. Tiedge, H., Bloom, F. E. & Richter, D. Science 283, 186–187 (1999). 3. Huang, E. P. Curr. Biol. 9, R168–R170 (1999). 4. Gao, F. B. Bioessays 20, 7–78 (1998). 5. Kuhl, D. & Skehel, P. Curr. Opin. Neurobiol. 8, 600–606 (1998). 6. Palade, G. Science 189, 347–358 (1975). 7. Spacek, J. & Harris, K. M. J. Neurosci 17, 190–203 (1997). 8. Berridge, M. J. Neuron 21, 13–26 (1998). 9. Matlack, K. E. S., Mothes, W. & Rapoport, T. A. Cell 92, 381–390 (1998). 10. Gorlich, D. & Rapoport, T. A. Cell 75, 615–630 (1993). 11. Bailey, C. H., Bartsch, D. & Kandel, E. R. Proc. Natl. Acad. Sci. USA 93, 13445–13452 (1996). 12. Schuman, E. M. Neuron 18, 339–342 (1997). 13. Pelham, H. R. Trends. Biochem. Sci. 15, 483–486 (1990). 14. Lledo, P.M., Zhang, X., Sudhof, T. C., Malenka, R. C. & Nicoll, R. A. Science 279, 399–403 (1998). 15. Chan, J., Aoki, C. & Pickel, V. M. J. Neurosci. Methods 33, 113–127 (1990). brief communications

Multicenter investigation of 1,036 subjects using a standardized method for the assessment of olfactory function combining tests of odor identification, odor discrimination, and olfactory thresholds.

Abstract: “Sniffin’ Sticks” is a test of nasal chemosensory performance that is based on penlike odor-dispensing devices. It is comprised of three tests of olfactory function: tests for odor threshold, discrimination and identification. Previous work has already established its test-retest reliability and validity in comparison to established measures of olfactory sensitivity. The results of this test are presented as a composite TDI score – i.e., the sum of results obtained for threshold, discrimination and identification measures. The present multicenter investigation aimed at providing normative values in relation to different age groups. To this end, 966 patients were investigated in 11 centers. An additional study tried to establish values for the identification of anosmic patients, with 70 anosmics investigated in five specialized centers where the presence of anosmia was confirmed by means of olfactory evoked potentials. For healthy subjects, the TDI score at the 10th percentile was 24.5 in subjects younger than 15 years, 30.3 for ages from 16 to 35 years, 28.8 for ages from 36 to 55 years and 27.5 for subjects older than 55 years. While these data can be used to estimate individual olfactory abilities in relation to a subject’s age, hyposmia was defined as the 10th percentile score of 16- to 35-year-old subjects. Our latter study revealed that none of 70 anosmics reached a TDI score higher than 15. This score of 15 is regarded as the cut-off value for functional anosmia. These results provide the basis for the routine clinical evaluation of patients with olfactory disorders using “Sniffin’ Sticks.”

Life history evolution: successes, limitations, and prospects.

Abstract: Life history theory tries to explain how evolution designs organisms to achieve reproductive success. The design is a solution to an ecological problem posed by the environment and subject to constraints intrinsic to the organism. Work on life histories has expanded the role of phenotypes in evolutionary theory, extending the range of predictions from genetic patterns to whole-organism traits directly connected to fitness. Among the questions answered are the following: Why are organisms small or large? Why do they mature early or late? Why do they have few or many offspring? Why do they have a short or a long life? Why must they grow old and die? The classical approach to life histories was optimization; it has had some convincing empirical success. Recently non-equilibrium approaches involving frequency-dependence, density-dependence, evolutionary game theory, adaptive dynamics, and explicit population dynamics have supplanted optimization as the preferred approach. They have not yet had as much empirical success, but there are logical reasons to prefer them, and they may soon extend the impact of life history theory into population dynamics and interspecific interactions in coevolving communities.

Unfolding pathways of individual bacteriorhodopsins.

Abstract: Atomic force microscopy and single-molecule force spectroscopy were combined to image and manipulate purple membrane patches from Halobacterium salinarum. Individual bacteriorhodopsin molecules were first localized and then extracted from the membrane; the remaining vacancies were imaged again. Anchoring forces between 100 and 200 piconewtons for the different helices were found. Upon extraction, the helices were found to unfold. The force spectra revealed the individuality of the unfolding pathways. Helices G and F as well as helices E and D always unfolded pairwise, whereas helices B and C occasionally unfolded one after the other. Experiments with cleaved loops revealed the origin of the individuality: stabilization of helix B by neighboring helices.

Subcellular Localization of Wild-Type and Parkinson's Disease-Associated Mutant α-Synuclein in Human and Transgenic Mouse Brain

Abstract: Mutations in the alpha-synuclein (alphaSYN) gene are associated with rare cases of familial Parkinson's disease, and alphaSYN is a major component of Lewy bodies and Lewy neurites. Here we have investigated the localization of wild-type and mutant [A30P]alphaSYN as well as betaSYN at the cellular and subcellular level. Our direct comparative study demonstrates extensive synaptic colocalization of alphaSYN and betaSYN in human and mouse brain. In a sucrose gradient equilibrium centrifugation assay, a portion of betaSYN floated into lower density fractions, which also contained the synaptic vesicle marker synaptophysin. Likewise, wild-type and [A30P]alphaSYN were found in floating fractions. Subcellular fractionation of mouse brain revealed that both alphaSYN and betaSYN were present in synaptosomes. In contrast to synaptophysin, betaSYN and alphaSYN were recovered from the soluble fraction upon lysis of the synaptosomes. Synaptic colocalization of alphaSYN and betaSYN was directly visualized by confocal microscopy of double-stained human brain sections. The Parkinson's disease-associated human mutant [A30P]alphaSYN was found to colocalize with betaSYN and synaptophysin in synapses of transgenic mouse brain. However, in addition to their normal presynaptic localization, transgenic wild-type and [A30P]alphaSYN abnormally accumulated in neuronal cell bodies and neurites throughout the brain. Thus, mutant [A30P]alphaSYN does not fail to be transported to synapses, but its transgenic overexpression apparently leads to abnormal cellular accumulations.

Long-distance charge transport in DNA: the hopping mechanism.

Abstract: Long-distance charge transport from a guanine radical cation (G(+*)) to a G-rich sequence is of biological importance. This reaction was studied by selective charge injection into a G, monitoring the charge transport to a GGG sequence by competing H(2)O-trapping. The efficiency of the charge transport diminished dramatically with increasing number of A:T base pairs between G(+*) and GGG. But in DNA strands where G's are located between the G(+*) and GGG sequence, long-distance charge transport occurred by a multistep hopping mechanism.

Exposure to endotoxin or other bacterial components might protect against the development of atopy.

Abstract: Background Several recent studies have shown that growing up on a farm confers significant protection against the development of atopy. These findings point particularly towards the importance of exposure to stable dust and farm animals. It has furthermore been reported that endotoxin, an intrinsic part of the outer membrane of gram negative bacteria, is abundant in environments where livestock and poultry is kept. The aim of this study was therefore to measure the level of environmental endotoxin exposure in homes of farmers' children, children with regular contact to livestock and control children with no contact to farm animals. Methods Eighty-four farming and nonfarming families were identified in rural areas in Southern Germany and Switzerland. Samples of settled and airborne dust were collected in stables, and of settled dust indoors from kitchen floors and the children's mattresses. Endotoxin concentrations were determined by a kinetic Limulus assay. Results Endotoxin concentrations were highest in stables of farming families, but were also significantly higher indoors in dust from kitchen floors (143 EU/mg vs 39 EU/mg, P<0.001) and children's mattresses (49479 EU/m 2 vs 9383 EU/m 2 , P<0.001) as compared to control children from nonfarming families. In addition, endotoxin levels were also significantly higher in mattresses and dust from kitchen floors in households where children had regular contact to farm animals (38.6 EU/mg and 23340 EU/m 2 , respectively) as compared to control subjects. Conclusion We propose that the level of environmental exposure to endotoxin and other bacterial wall components is an important protective determinant for the development of atopic diseases in childhood.

The visual analog scale allows effective measurement of preoperative anxiety and detection of patients' anesthetic concerns.

Abstract: The advent of managed care, reduction of costs, and advances in medical technology place increasing demands on anesthesiologists. Preoperative anxiety may go unnoticed in an environment that stresses increased productivity. The present study compares different methods for measuring preoperative anxiety, identifies certain patient characteristics that predispose to high anxiety, and describes the quantity and quality of anxiety that patients experience preoperatively. Seven hundred thirty-four patients participated in the study. We assessed aspects of anxiety by means of visual analog scales (VAS) and the State Anxiety Score of the Spielberger State-Trait Anxiety Inventory (STAI). The mean STAI anxiety score was 39 6 1( n 5 486) and the mean VAS for fear of anesthesia was 29 6 1( n 5 539). Patients feared surgery significantly more than anesthesia (P , 0.001). The VAS measuring fear of anesthesia correlated well with the STAI score (r 5 0.55; P , 0.01). Young patients, female patients, and patients with no previous anesthetic experience or a previous negative anesthetic experience had higher anxiety scores. Patients worried most about the waiting period preceding surgery and were least concerned about possible awareness intraoperatively. Factor analysis of various anxiety items showed three distinct dimensions of fear: 1) the fear of the unknown 2) the fear of feeling ill, and 3) the fear for one’s life. Among these dimensions, fear of the unknown correlated highest with the anxiety measuring techniques STAI and VAS. The simple VAS proved to be a useful and valid measure of preoperative anxiety. Implications: The study of qualitative aspects of anxiety reveals three distinct dimensions of preoperative fear: fear of the unknown, fear of feeling ill, and fear for one’s life. Groups of patients with a higher degree of preoperative anxiety and their specific anesthetic concerns can be identified using the visual analog scale.

Constraints from Dynamical Friction on the Dark Matter Content of Barred Galaxies

Abstract: We show that bars in galaxy models having halos of moderate density and a variety of velocity distributions all experience a strong drag from dynamical friction unless the halo has large angular momentum in the same sense as the disk. The frictional drag decreases the bar pattern speed, driving the corotation point out to distances well in excess of those estimated in barred galaxies. The halo angular momentum required to avoid strong braking is unrealistically large, even when rotation is confined to the inner halo only. We conclude, therefore, that bars are able to maintain their observed high pattern speeds only if the halo has a central density low enough for the disk to provide most of the central attraction in the inner galaxy. We present evidence that this conclusion holds for all bright galaxies.

Velocity Dependence of Atomic Friction

Abstract: Sliding friction between the tip of a friction force microscope and NaCl(100) was studied to deduce the velocity dependence of friction forces on the atomic scale. A logarithmic dependence of the mean friction force is revealed at low velocities. The experimental data are interpreted in terms of a modified Tomlinson model which is based on reaction rate theory.

Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo- controlled, randomized phase II trial

Abstract: In this ‘double-blind’, randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing–remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

Neuropathology in Mice Expressing Human α-Synuclein

Abstract: The presynaptic protein α-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. α-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the α-synuclein gene are genetically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human α-synuclein in the nervous system of transgenic mice generated animals with neuronal α-synucleinopathy, features strikingly similar to those observed in human brains with Lewy pathology, neuronal degeneration, and motor defects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions in several muscles examined, suggesting that α-synuclein interfered with a universal mechanism of synapse maintenance. Thy1 transgene expression of wild-type human α-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild-type α-synuclein in familial and idiotypic forms of diseases with neuronal α-synucleinopathy and Lewy pathology. These mouse models provide a means to address fundamental aspects of α-synucleinopathy and test therapeutic strategies.

Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas.

Abstract: Background Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) are members of the neurotrophin gene family that support the survival of specific neuronal populations, including those that are affected by neurodegeneration in Alzheimer disease (AD). Objective To determine whether neurotrophin protein levels are altered in the AD-affected brain compared with control brains. Methods We quantitated protein levels of NGF, BDNF, NT-3, and NT-4/5, and calculated neurotrophin/NT-3 ratios in AD-affected postmortem hippocampus, frontal and parietal cortex, and cerebellum, and compared them with age-matched control tissue (patients with AD/controls: hippocampus, 9/9 cases; frontal cortex, 19/9; parietal cortex, 8/5; and cerebellum, 5/7, respectively). We applied highly sensitive and specific enzyme-linked immunosorbent assays in rapid-autopsy–derived brain tissue (mean±SD postmortem interval, 2.57±1.75 h, n=71) to minimize postmortem proteolytic activity. Results Levels of BDNF were significantly reduced in hippocampus and parietal cortex ( P P P P P P Conclusion Decreased levels of BDNF may constitute a lack of trophic support and, thus, may contribute to the degeneration of specific neuronal populations in the AD-affected brain, including the basal forebrain cholinergic system.

Biosphere responses to CO2 enrichment.

Abstract: Atmospheric changes such as elevated CO2 are of global extent, exert prime influences in the remaining wilderness areas, and are second in importance only to effects of land use on ecosystems in most parts of the world. This study is an attempt to summarize, from a biological viewpoint, knowledge of the influences of atmospheric CO2 enrichment on terrestrial ecosystems, as derived from empirical data. I first briefly recall key aspects of the global carbon cycle, mention important conceptual aspects and research tools, and then discuss in greater depth how elevated CO2 is likely to affect vegetation processes. Besides a stimulation of photosynthesis, the most robust findings on plant responses to elevated CO2 are changes in active tissue quality (wider C/N ratio) and effects on community dynamics. Results of experimental work offer a number of plausible projections with respect to future ecosystem processes and organismic interactions, but manipulative experiments appear unsuitable to prove or disprove C sequestration by terrestrial ecosystems. In certain regions, consequences of climatic changes and soluble-nitrogen deposition are likely to be greater than direct CO2 effects on the carbon balance of vegetation. The significance of the ecosystem approach, the use of fully coupled plant–soil systems, and the consideration of nonlinear responses are highlighted. The current understanding of the CO2 problem offers sufficient justification to urge measures for moderating human forcing of atmospheric change.

Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy.

Abstract: Background Reactivation of polyomavirus type BK (BK virus) is increasingly recognized as a cause of severe renal-allograft dysfunction Currently, patients at risk for nephropathy due to infection with the BK virus are identified by the presence of cells containing viral inclusion bodies (“decoy cells”) in the urine or by biopsy of allograft tissue Methods In a retrospective analysis, we performed polymerase-chain-reaction assays for BK virus DNA in plasma samples from 9 renal-allograft recipients with BK virus nephropathy; 41 renal-allograft recipients who did not have signs of nephropathy, 16 of whom had decoy cells in the urine; and as immunocompromised controls, 17 patients who had human immunodeficiency virus type 1 (HIV-1) infection (stage C3 according to the classification of the Centers for Disease Control and Prevention) and who had not undergone transplantation Results In all nine patients with BK virus nephropathy, BK virus DNA was detected in the plasma at the time of the initial histologic

Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors.

Abstract: BACKGROUND A new, internationally accepted histologic classification of renal cell carcinoma (RCC) and a new edition of the TNM staging system were introduced in 1997. In the latter, there was a dramatic change in the pT classification of organ-confined renal cancer in which the break point between category pT1 and pT2 was increased from 2.5 cm to 7 cm. METHODS To study the significance of the new pT classification and the new recommendations for histologic classification, 588 nephrectomy specimens were reevaluated to define morphologic prognostic parameters in RCC. pT classification (TNM 1997), histologic subtype, histologic tumor grade, presence of necrosis, and sarcomatoid differentiation were assessed. RESULTS The histopathologic review according to the new classification revealed 487 conventional (clear cell) (83%), 64 papillary (11%), 31 chromophobe (5%), and 6 collecting duct (1%) RCCs. Clinical follow-up was available for 470 RCCs. The new pT classification (1997) was strongly correlated with patient survival (P < 0.0001). Histologic grade, presence of necrosis, and sarcomatoid differentiation provided independent prognostic information on the clear cell subtype of renal cancer. Sarcomatoid differentiation, but not tumor necrosis, portended a dismal prognosis for patients with papillary RCC. Chromophobe RCC was associated with a significantly better prognosis than clear cell RCC (P = 0.05). Papillary RCC with scanty cytoplasm and small cells (type 1) behaved less aggressively than papillary tumors with eosinophilic cytoplasm and large cells (type 2; P < 0.001). CONCLUSIONS Accurate histologic classification according to the new recommendations has implications because the prognostic importance of other histologic features that are of independent significance varies with tumor subtype. The data suggest that the new pT classification allows good separation of prognostic groups of patients with renal cancer. Cancer 2000;89:604–14. © 2000 American Cancer Society.