Showing papers by "University of Zurich published in 2003"

The nature of human altruism

Abstract: Some of the most fundamental questions concerning our evolutionary origins, our social relations, and the organization of society are centred around issues of altruism and selfishness. Experimental evidence indicates that human altruism is a powerful force and is unique in the animal world. However, there is much individual heterogeneity and the interaction between altruists and selfish individuals is vital to human cooperation. Depending on the environment, a minority of altruists can force a majority of selfish individuals to cooperate or, conversely, a few egoists can induce a large number of altruists to defect. Current gene-based evolutionary theories cannot explain important patterns of human altruism, pointing towards the importance of both theories of cultural evolution as well as gene–culture co-evolution.

A Gateway Cloning Vector Set for High-Throughput Functional Analysis of Genes in Planta

Abstract: The current challenge, now that two plant genomes have been sequenced, is to assign a function to the increasing number of predicted genes. In Arabidopsis, approximately 55% of genes can be assigned a putative function, however, less than 8% of these have been assigned a function by direct experimental evidence. To identify these functions, many genes will have to undergo comprehensive analyses, which will include the production of chimeric transgenes for constitutive or inducible ectopic expression, for antisense or dominant negative expression, for subcellular localization studies, for promoter analysis, and for gene complementation studies. The production of such transgenes is often hampered by laborious conventional cloning technology that relies on restriction digestion and ligation. With the aim of providing tools for high throughput gene analysis, we have produced a Gateway-compatible Agrobacterium sp. binary vector system that facilitates fast and reliable DNA cloning. This collection of vectors is freely available, for noncommercial purposes, and can be used for the ectopic expression of genes either constitutively or inducibly. The vectors can be used for the expression of protein fusions to the Aequorea victoria green fluorescent protein and to the β-glucuronidase protein so that the subcellular localization of a protein can be identified. They can also be used to generate promoter-reporter constructs and to facilitate efficient cloning of genomic DNA fragments for complementation experiments. All vectors were derived from pCambia T-DNA cloning vectors, with the exception of a chemically inducible vector, for Agrobacterium sp.-mediated transformation of a wide range of plant species.

Diabetes and Vascular Disease Pathophysiology, Clinical Consequences, and Medical Therapy: Part I

Abstract: Diabetes mellitus affects approximately 100 million persons worldwide.1 Five to ten percent have type 1 (formerly known as insulin-dependent) and 90% to 95% have type 2 (non–insulin-dependent) diabetes mellitus. It is likely that the incidence of type 2 diabetes will rise as a consequence of lifestyle patterns contributing to obesity.2 Cardiovascular physicians are encountering many of these patients because vascular diseases are the principal causes of death and disability in people with diabetes. The macrovascular manifestations include atherosclerosis and medial calcification. The microvascular consequences, retinopathy and nephropathy, are major causes of blindness and end-stage renal failure. Physicians must be cognizant of the salient features of diabetic vascular disease in order to treat these patients most effectively. The present review will focus on the relationship of diabetes mellitus and atherosclerotic vascular disease, highlighting pathophysiology and molecular mechanisms (Part I) and clinical manifestations and management strategies (Part II). Abnormalities in endothelial and vascular smooth muscle cell function, as well as a propensity to thrombosis, contribute to atherosclerosis and its complications. Endothelial cells, because of their strategic anatomic position between the circulating blood and the vessel wall, regulate vascular function and structure. In normal endothelial cells, biologically active substances are synthesized and released to maintain vascular homeostasis, ensuring adequate blood flow and nutrient delivery while preventing thrombosis and leukocyte diapedesis.3 Among the important molecules synthesized by the endothelial cell is nitric oxide (NO), which is constitutively produced by endothelial NO synthase (eNOS) through a 5-electron oxidation of the guanidine-nitrogen terminal of l-arginine.4 The bioavailability of NO represents a key marker in vascular health. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells.4 In addition, NO protects the blood vessel from endogenous injury—ie, atherosclerosis—by mediating molecular signals that prevent platelet and leukocyte interaction with …

Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics

Abstract: Synthetic hydrogels have been molecularly engineered to mimic the invasive characteristics of native provisional extracellular matrices: a combination of integrin-binding sites and substrates for matrix metalloproteinases (MMP) was required to render the networks degradable and invasive by cells via cell-secreted MMPs. Degradation of gels was engineered starting from a characterization of the degradation kinetics (kcat and Km) of synthetic MMP substrates in the soluble form and after crosslinking into a 3D hydrogel network. Primary human fibroblasts were demonstrated to proteolytically invade these networks, a process that depended on MMP substrate activity, adhesion ligand concentration, and network crosslinking density. Gels used to deliver recombinant human bone morphogenetic protein-2 to the site of critical defects in rat cranium were completely infiltrated by cells and remodeled into bony tissue within 4 wk at a dose of 5 μg per defect. Bone regeneration was also shown to depend on the proteolytic sensitivity of the matrices. These hydrogels may be useful in tissue engineering and cell biology as alternatives for naturally occurring extracellular matrix-derived materials such as fibrin or collagen.

Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography.

Abstract: Background We compared the diagnostic accuracy of integrated positron-emission tomography (PET) and computed tomography (CT) with that of CT alone, that of PET alone, and that of conventional visual correlation of PET and CT in determining the stage of disease in non–small-cell lung cancer. Methods In a prospective study, integrated PET–CT was performed in 50 patients with proven or suspected non–small-cell lung cancer. CT and PET alone, visually correlated PET and CT, and integrated PET–CT were evaluated separately, and a tumor–node–metastasis (TNM) stage was assigned on the basis of image analysis. Nodal stations were identified according to the mapping system of the American Thoracic Society. The standard of reference was histopathological assessment of tumor stage and node stage. Extrathoracic metastases were confirmed histopathologically or by at least one other imaging method. A paired sign test was used to compare integrated PET–CT with the other imaging methods. Results Integrated PET–CT provided ...

Proliferating cell nuclear antigen (PCNA): a dancer with many partners.

Abstract: Proliferating cell nuclear antigen (PCNA) was originally characterised as a DNA sliding clamp for replicative DNA polymerases and as an essential component of the eukaryotic chromosomal DNA replisome. Subsequent studies, however, have revealed its striking ability to interact with multiple partners, which are involved in several metabolic pathways, including Okazaki fragment processing, DNA repair, translesion DNA synthesis, DNA methylation, chromatin remodeling and cell cycle regulation. PCNA in mammalian cells thus appears to play a key role in controlling several reactions through the coordination and organisation of different partners. Two major questions have emerged: how do these proteins access PCNA in a coordinated manner, and how does PCNA temporally and spatially organise their functions? Structural and biochemical studies are starting to provide a first glimpse of how both tasks can be achieved.

Stress-strain measurements of human and porcine corneas after riboflavin–ultraviolet-A-induced cross-linking

Abstract: Results: There was a significant increase in corneal rigidity after cross-linking, indicated by a rise in stress in treated porcine corneas (by 71.9%) and human corneas (by 328.9%) and in Young’s modulus by the factor 1.8 in porcine corneas and 4.5 in human corneas. The mean central corneal thickness was 850 m 70 (SD) in porcine corneas and 550 40 m in human corneas. Conclusions: RiboflavinUVA-induced collagen cross-linking led to an increase in mechanical rigidity in porcine corneas and an even greater increase in human corneas. As collagen cross-linking is maximal in the anterior 300 m of the cornea, the greater stiffening effect in human corneas can be explained by the relatively larger portion of the cornea being cross-linked in the overall thinner human cornea. J Cataract Refract Surg 2003; 29:1780 –1785 © 2003 ASCRS and ESCRS

The Inner Structure of LambdaCDM Halos III: Universality and Asymptotic Slopes

Abstract: We investigate the mass profile of LambdaCDM halos using a suite of numerical simulations spanning five decades in halo mass, from dwarf galaxies to rich galaxy clusters. Our analysis confirms the proposal of Navarro, Frenk & White (NFW) that the shape of LambdaCDM halo mass profiles differs strongly from a power law and depends little on mass. The logarithmic slope of the spherically-averaged density profile, as measured by beta=-dln(rho)/dln(r), decreases monotonically towards the center and becomes shallower than isothermal (beta<2) inside a characteristic radius, r_{-2}. Although the fitting formula proposed by NFW provides a reasonably good approximation to the density and circular velocity profiles of individual halos, systematic deviations from the best NFW fits are also noticeable. Inside r_{-2}, the profile of simulated halos gets shallower with radius more gradually than predicted and, as a result, NFW fits tend to underestimate the dark matter density in these regions. This discrepancy has been interpreted as indicating a steeply divergent cusp, but our results suggest a different interpretation. We use the density and enclosed mass at our innermost resolved radii to place strong constraints on beta_{0}: density cusps as steep as r^{-1.5} are inconsistent with most of our simulations, although beta_{0}=1 is still consistent with our data. Our density profiles show no sign of converging to a well-defined asymptotic inner power law. We propose a simple formula that reproduces the radial dependence of the slope better than the NFW profile, and so may minimize errors when extrapolating our results inward to radii not yet reliably probed by numerical simulations.

Repair of bone defects using synthetic mimetics of collagenous extracellular matrices.

Abstract: We have engineered synthetic poly(ethylene glycol) (PEG)-based hydrogels as cell-ingrowth matrices for in situ bone regeneration. These networks contain a combination of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for matrix metalloproteinase (MMP) as linkers between PEG chains. Primary human fibroblasts were shown to migrate within these matrices by integrin- and MMP-dependent mechanisms. Gels used to deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) to the site of critical- sized defects in rat crania were completely infiltrated by cells and were remodeled into bony tissue within five weeks. Bone regeneration was dependent on the proteolytic sensitivity of the matrices and their architecture. The cell-mediated proteolytic invasiveness of the gels and entrapment of rhBMP-2 resulted in efficient and highly localized bone regeneration.

Proposal for a New Classification of Outcome with Respect to Epileptic Seizures Following Epilepsy Surgery

Abstract: *Neurology Clinic, Epileptology & EEG, University Hospital, Zurich, Switzerland; †Department of Neurology, University Hospital, London, Ontario, Canada; ‡The National Hospital for Neurology and Neurosurgery, Queen Square, London, England; §Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, New York, U.S.A.; Department of Neurology, University of Essen, Essen, Germany; ¶Department of Neurology, Medical College of Georgia, Augusta, Georgia; **Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania; and ††Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

Detrimental effects of sanctions on human altruism

Abstract: The existence of cooperation and social order among genetically unrelated individuals is a fundamental problem in the behavioural sciences. The prevailing approaches in biology and economics view cooperation exclusively as self-interested behaviour--unrelated individuals cooperate only if they face economic rewards or sanctions rendering cooperation a self-interested choice. Whether economic incentives are perceived as just or legitimate does not matter in these theories. Fairness-based altruism is, however, a powerful source of human cooperation. Here we show experimentally that the prevailing self-interest approach has serious shortcomings because it overlooks negative effects of sanctions on human altruism. Sanctions revealing selfish or greedy intentions destroy altruistic cooperation almost completely, whereas sanctions perceived as fair leave altruism intact. These findings challenge proximate and ultimate theories of human cooperation that neglect the distinction between fair and unfair sanctions, and they are probably relevant in all domains in which voluntary compliance matters--in relations between spouses, in the education of children, in business relations and organizations as well as in markets.

Developmental robotics: a survey

Abstract: Developmental robotics is an emerging field located at the intersection of robotics, cognitive science and developmental sciences. This paper elucidates the main reasons and key motivations behind the convergence of fields with seemingly disparate interests, and shows why developmental robotics might prove to be beneficial for all fields involved. The methodology advocated is synthetic and two-pronged: on the one hand, it employs robots to instantiate models originating from developmental sciences; on the other hand, it aims to develop better robotic systems by exploiting insights gained from studies on ontogenetic development. This paper gives a survey of the relevant research issues and points to some future research directions.

Stepwise Multiple Testing as Formalized Data Snooping

Abstract: It is common in econometric applications that several hypothesis tests are carried out at the same time. The problem then becomes how to decide which hypotheses to reject, accounting for the multitude of tests. In this paper, we suggest a stepwise multiple testing procedure which asymptotically controls the familywise error rate at a desired level. Compared to related single-step methods, our procedure is more powerful in the sense that it often will reject more false hypotheses. Unlike some stepwise methods, our method implicitly captures the joint dependence structure of the test statistics, which results in increased ability to detect alternative hypotheses. We prove our method asymptotically controls the familywise error rate under minimal assumptions. Some simulation studies show the improvements of our methods over previous proposals. We also provide an application to a set of real data.

Androgens and Coronary Artery Disease

Abstract: A significant and independent association between endogenous testosterone (T) levels and coronary events in men and women has not been confirmed in large prospective studies, although cross-sectional data have suggested coronary heart disease can be associated with low T in men. Hypoandrogenemia in men and hyperandrogenemia in women are associated with visceral obesity; insulin resistance; low high-density lipoprotein (HDL) cholesterol (HDL-C); and elevated triglycerides, low-density lipoprotein cholesterol, and plasminogen activator type 1. These gender differences and confounders render the precise role of endogenous T in atherosclerosis unclear. Observational studies do not support the hypothesis that dehydroepiandrosterone sulfate deficiency is a risk factor for coronary artery disease. The effects of exogenous T on cardiovascular mortality or morbidity have not been extensively investigated in prospective controlled studies; preliminary data suggest there may be short-term improvements in electrocardiographic changes in men with coronary artery disease. In the majority of animal experiments, exogenous T exerts either neutral or beneficial effects on the development of atherosclerosis. Exogenous androgens induce both apparently beneficial and deleterious effects on cardiovascular risk factors by decreasing serum levels of HDL-C, plasminogen activator type 1 (apparently deleterious), lipoprotein (a), fibrinogen, insulin, leptin, and visceral fat mass (apparently beneficial) in men as well as women. However, androgen-induced declines in circulating HDL-C should not automatically be assumed to be proatherogenic, because these declines may instead reflect accelerated reverse cholesterol transport. Supraphysiological concentrations of T stimulate vasorelaxation; but at physiological concentrations, beneficial, neutral, and detrimental effects on vascular reactivity have been observed. T exerts proatherogenic effects on macrophage function by facilitating the uptake of modified lipoproteins and an antiatherogenic effect by stimulating efflux of cellular cholesterol to HDL. In conclusion, the inconsistent data, which can only be partly explained by differences in dose and source of androgens, militate against a meaningful assessment of the net effect of T on atherosclerosis. Based on current evidence, the therapeutic use of T in men need not be restricted by concerns regarding cardiovascular side effects. Available data also do not justify the uncontrolled use of T or dehydroepiandrosterone for the prevention or treatment of coronary heart disease.

On the Nature of Fair Behavior

Abstract: I. INTRODUCTION There is by now considerable evidence that fairness considerations affect economic behavior in many important areas. In bilateral bargaining situations, anonymously interacting agents frequently agree on rather egalitarian outcomes although the standard model with purely selfish preferences predicts rather unequal outcomes. (1) In competitive experimental labor markets with incomplete contracts, fairness considerations give rise to efficiency wage effects that generate stable deviations from the perfectly competitive outcome as shown in Fehr and Falk (1999). In several questionnaire studies, for example, in studies by Bewley (1999) and Campbell and Kamlani (1997), personnel managers indicate that despite an excess supply of labor, firms are unwilling to cut wages because they fear that pay cuts are perceived as unfair and hostile by the workers and will hence destroy work morale. Fehr et al. (1997) show that in principal-agent relationships reciprocally fair behavior causes a considerable increase in the set of enforceable contracts and hence large efficiency gains. To examine the forces that affect the perceptions of fairness and the determinants of fair behavior is thus not just of philosophical or academic interest. A common feature of fair behavior in the cited situations is that in response to an act of party A that is favorable for party B, B is willing to take costly actions to return at least part of the favor (positive reciprocity), and in response to an act that is perceived as harmful by B, B is willing to take costly actions to reduce A's material payoff (negative reciprocity). This suggests that reciprocal behavior is an important component of fairness-driven behavior. Reciprocally fair behavior has been shown to prevail in one-shot situations and under rather high-stake levels. (2) In this article we show that identical offers in an ultimatum game trigger vastly different rejection rates depending on the other offers available to the proposer. In particular, a given offer with an unequal distribution of material payoffs is much more likely to be rejected if the proposer could have proposed a more equitable offer than if the proposer could have proposed only more unequal offers. Thus it is not just the material payoff consequence of an offer that determines the acceptance but the set of available, yet not chosen offers is also decisive. This result casts serious doubt on the consequentialist practice in standard economic theory that defines the utility of an action solely in terms of the consequences of this action. It also shows that the recently developed models of fairness by Bolton and Ockenfels (2000) and Fehr and Schmidt (1999) are incomplete to the extent that they neglect "nonconsequentialist" reasons for reciprocally fair actions. These models assume that--in addition to their m aterial self-interest--people also value the distributive consequences of outcomes. The impressive feature of these models is that they are capable of correctly predicting a wide variety of seemingly contradictory facts. They predict, for example, why competitive experimental markets with complete contracts typically converge to the predictions of the selfish model, whereas in bilateral bargaining situations or in markets with incomplete contracts stable deviations in the direction of more equitable outcomes are the rule. However, despite their predictive success in important areas, our results indicate that legitimate doubts remain as to whether these models capture the phenomenon of reciprocal fairness in a fully satisfactory way. A parsimonious interpretation of our results, which is also suggested by psychological research, can be given in terms of intentions. (3) Identical actions by the proposer are--depending on the available alternatives--likely to signal different information about the intentions of the proposer. Hence, if responders take into account not only the distributive consequences of the proposers' actions but also the fairness of the proposers' intentions, their responses to identical offers may differ. …

General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.

Abstract: General anesthetics are widely used in clinical practice. On the molecular level, these compounds have been shown to modulate the activity of various neuronal ion channels. However, the functional relevance of identified sites in mediating essential components of the general anesthetic state, such as immobility and hypnosis, is still unknown. Using gene-targeting technology, we generated mice harboring a subtle point mutation (N265M) in the second transmembrane region of the beta3 subunit of the GABA(A) receptor. In these mice, the suppression of noxious-evoked movements in response to the intravenous anesthetics etomidate and propofol is completely abolished, while only slightly decreased with the volatile anesthetics enflurane and halothane. beta3(N265M) mice also display a profound reduction in the loss of righting reflex duration in response to intravenous but not volatile anesthetics. In addition, electrophysiological recordings revealed that anesthetic agents were significantly less effective in enhancing GABA(A) receptor-mediated currents, and in decreasing spontaneous action potential firing in cortical brain slices derived from mutant mice. Taken together, our results demonstrate that a single molecular target, and indeed a specific residue (N265) located within the GABA(A) receptor beta3 subunit, is a major determinant of behavioral responses evoked by the intravenous anesthetics etomidate and propofol, whereas volatile anesthetics appear to act via a broader spectrum of molecular targets.