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At least 991 records · Page 55Linked to original sources
PubMed2001

Poor agreement in recognition of abnormal mitoses: requirement for standardized and robust definitions.

AIMS: The finding of abnormal mitoses is a helpful feature in differentiating between benign and malignant neoplasia and has prognostic significance for some tumours. As the use of a histopathological variable is limited by the reproducibility of its recognition, we tested the interobserver agreement in the classification of abnormal mitoses among histopathologists. METHODS adn RESULTS: Ten practising histopathologists were shown 30 potential mitotic figures and were asked to classify these as 'normal mitoses', 'abnormal mitoses' or 'not mitoses' according to the criteria each pathologist used in their routine practice. The results were analysed using kappa statistics. Overall agreement was only fair with a combined kappa of 0.31 and there was unanimous categorization of only four of 30 test items, none of which was called abnormal. The poorest result was obtained for the category 'abnormal mitosis' with only slight agreement (kappa 0.19). Agreement for the other categories varied from moderate (kappa = 0.45) for 'not a mitosis' to fair (kappa = 0.26) for 'normal mitosis'. Comparison of the results for observer pairs showed that for 12 out of the 45 possible pairings, there was no more agreement than might be expected by chance alone. CONCLUSION: Agreement is poor among practising histopathologists in the recognition of abnormal mitoses. A standardized and robust definition is needed if diagnostic and prognostic significance is accorded to the finding of an abnormal mitosis in the context of neoplasia.

Humans↗
PubMed2002

Involvement of Cajal-Retzius cells in robust and layer-specific regeneration of the entorhino-hippocampal pathways.

Severed adult CNS axons can extend over long distances when a permissive 'milieu', such as grafted Schwann cells or ensheathing cells, is provided. Moreover, functional blocking of endogenous inhibitory factors, such as Nogo-A or proteoglycans, enhances the regeneration of axotomized neurons. Here we examine whether guidance cues available during the development of axonal pathways could also potentiate the regeneration of lesioned adult circuits. The Cajal-Retzius cells in the hippocampus are transient pioneer neurons that guide entorhino-hippocampal afferents to their target layers. By using an in vitro model of axotomy of the entorhino-hippocampal pathway we show that Cajal-Retzius cells triggered the regeneration of the axotomized entorhino-hippocampal pathway. Furthermore, the regrowth induced by Cajal-Retzius cells was robust and its pattern was indistinguishable from that of the unlesioned entorhino-hippocampal pathway. Thus, regenerating axons regrew in a layer-specific fashion towards the appropriate target layers, making synaptic contacts with target pyramidal neurons. Interestingly, the ability of lesioned entorhinal axons to regrow was maintained for at least 9 days after axotomy. These results show that the growth-promoting cells controlling the development of neural circuits will be a relevant approach to promoting the regeneration of lesioned adult CNS pathways.

Aging↗
PubMed1997

A permutation test for the robust sib-pair linkage method.

The robust sib-pair method introduced by Haseman & Elston (1972) is one of the most widely circulated allele-sharing methods for linkage analysis. The procedure evaluates linkage by significance testing of a regression coefficient and, hence, a standard t-test has traditionally been applied despite known violations of the statistical assumptions underlying the test. We present a permutation based reference distribution for the estimate of the regression coefficient that is motivated by genetic principles rather than by standard regression testing procedures. The permutation test approximates Mendelian co-segregation under the null hypothesis of no linkage, making it a very natural approach. Theory and simulations show that the conventional t-test approximates the permutation test quite well, even when dependent sib pairs are used for analysis. These results thus indirectly address concerns over the t-test. To illustrate the permutation test using real data we applied the procedure to two lipoprotein systems that have been well characterized.

Animals↗
PubMed1999

The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS.

Differential display of mRNA was used to identify concordant changes in gene expression induced by two mood-stabilizing agents, lithium and valproate (VPA). Both treatments, on chronic administration, increased mRNA levels of the transcription factor polyomavirus enhancer-binding protein (PEBP) 2beta in frontal cortex (FCx). Both treatments also increased the DNA binding activity of PEBP2 alphabeta and robustly increased the levels of bcl-2 (known to be transcriptionally regulated by PEBP2) in FCx. Immunohistochemical studies revealed a marked increase in the number of bcl-2-immunoreactive cells in layers 2 and 3 of FCx. These novel findings represent the first report of medication-induced increases in CNS bcl-2 levels and may have implications not only for mood disorders, but also for long-term treatment of various neurodegenerative disorders.

Affect↗
PubMedDate not supplied

Hemichordates and deuterostome evolution: robust molecular phylogenetic support for a hemichordate + echinoderm clade.

Hemichordates were traditionally allied to the chordates, but recent molecular analyses have suggested that hemichordates are a sister group to the echinoderms, a relationship that has important consequences for the interpretation of the evolution of deuterostome body plans. However, the molecular phylogenetic analyses to date have not provided robust support for the hemichordate + echinoderm clade. We use a maximum likelihood framework, including the parametric bootstrap, to reanalyze DNA data from complete mitochondrial genomes and nuclear 18S rRNA. This approach provides the first statistically significant support for the hemichordate + echinoderm clade from molecular data. This grouping implies that the ancestral deuterostome had features that included an adult with a pharynx and a dorsal nerve cord and an indirectly developing dipleurula-like larva.

Animals↗
PubMed2006

Growth rings in the roots of temperate forbs are robust annual markers.

There is increasing interest in the analysis of annual growth rings in the secondary root xylem of perennial forbs (herb-chronology). Therefore, we need to verify whether these growth rings are always formed annually. To investigate the formation of root rings we performed common garden experiments at two distinct sites in Switzerland. We grew nine unrelated forb species from seed and subjected them to competition and clipping treatments. Anatomical developments in the roots of the individuals were tracked during five growing seasons. Across all species and treatments at least 94 % of the expected growth rings associated with full growing seasons were identifiable and the development of the anatomical patterns was consistently seasonal. While the distinctness of annual rings varied somewhat between species and sites, the treatments had no effect on the presence of annual rings. In no case were false rings developed. The results of this study demonstrate that the growth rings in the roots of northern temperate forbs represent robust annual growth increments and, hence, can reliably be used in herb-chronological studies of age- and growth-related questions in plant ecology.

Ecosystem↗
PubMed1986

Robustness in practice--the regional planning of health services.

Earlier work has criticized the dominant tendencies in operational research contributions to health services planning as characterized by optimization, implausible demands for data, depoliticization, hierarchy and inflexibility. This paper describes an effort which avoids at least some of these pitfalls. The project was to construct a planning system for a regional health council in Ontario, Canada, which would take account of the possible alternative future states of the health-care system's environment and would aim to keep options for future development open. The planning system devised is described in the paper. It is based on robustness analysis, which evaluates alternative initial action sets in terms of the useful flexibility they preserve. Other features include the explicit incorporation of pressures for change generated outside the health-care system, and a satisficing approach to the identification of both initial action sets and alternative future configurations of the health-care system. It was found possible to borrow and radically 're-use' techniques or formulations from the mainstream of O.R. contributions. Thus the 'reference projection' method was used to identify inadequacies in performance which future health-care system configurations must repair. And Delphi analysis, normally a method for generating consensus, was used in conjunction with cluster analysis of responses to generate meaningfully different alternative futures.

Health Planning Councils↗
PubMed1997

Cycles homoclinic to chaotic sets; robustness and resonance.

For dynamical systems possessing invariant subspaces one can have a robust homoclinic cycle to a chaotic set. If such a cycle is stable, it manifests itself as long periods of quiescent chaotic behaviour interrupted by sudden transient 'bursts'. The time between the transients increases as the trajectory approaches the cycle. This behavior for a cycle connecting symmetrically related chaotic sets has been called 'cycling chaos' by Dellnitz et al. [IEEE Trans. Circ. Sys. I 42, 821-823 (1995)]. We characterise such cycles and their stability by means of normal Lyapunov exponents. We find persistence of states that are not Lyapunov stable but still attracting, and also states that are approximately periodic. For systems possessing a skew-product structure (such as naturally arises in chaotically forced systems) we show that the asymptotic stability and the attractivity of the cycle depends in a crucial way on what we call the footprint of the cycle. This is the spectrum of Lyapunov exponents of the chaotic invariant set in the expanding and contracting directions of the cycle. Numerical simulations and calculations for an example system of a homoclinic cycle parametrically forced by a Rossler attractor are presented; here we observe the creation of nearby chaotic attractors at resonance of transverse Lyapunov exponents. (c) 1997 American Institute of Physics.

Journal Article↗
PubMed2005

Robust and accurate method for free-energy calculation of charged molecular systems.

A new approach is presented to eliminate the problem of creation and/or annihilation of atoms in free-energy calculations of charged molecular systems. The method employs a damping potential in the Ewald summation scheme, which is an exact solution of the electrostatics for three-dimensional periodic systems. The proposed method enables entire molecules to be mutated from a noninteracting (ideal) state in an efficient and robust way, thus providing a means by which accurate absolute free energies of structurally complex molecules can be determined. This methodology will enable chemical and phase equilibria to be determined for large molecular species with significant charge distributions, e.g., biomolecules and drugs.

Journal Article↗
PubMed2002

Complexity and robustness.

Highly optimized tolerance (HOT) was recently introduced as a conceptual framework to study fundamental aspects of complexity. HOT is motivated primarily by systems from biology and engineering and emphasizes, (i) highly structured, nongeneric, self-dissimilar internal configurations, and (ii) robust yet fragile external behavior. HOT claims these are the most important features of complexity and not accidents of evolution or artifices of engineering design but are inevitably intertwined and mutually reinforcing. In the spirit of this collection, our paper contrasts HOT with alternative perspectives on complexity, drawing on real-world examples and also model systems, particularly those from self-organized criticality.

Journal Article↗
PubMed2003

Robustness and the cycle of phosphorylation and dephosphorylation in a two-component regulatory system.

The EnvZ/OmpR system in Escherichia coli, which regulates the expression of the porins OmpF and OmpC, is one of the simplest and best-characterized examples of two-component signaling. Like many other histidine kinases, EnvZ is bifunctional; it phosphorylates and dephosphorylates the response regulator OmpR. We have analyzed a mathematical model of the EnvZ-mediated cycle of OmpR phosphorylation and dephosphorylation. The model predicts that when EnvZ is much less abundant than OmpR, as is the case in E. coli, the steady-state level of phosphorylated OmpR (OmpR-P) is insensitive to variations in the concentration of EnvZ. The model also predicts that the level of OmpR-P is insensitive to variations in the concentration of OmpR when the OmpR concentration is sufficiently high. To test these predictions, we have perturbed the porin regulatory circuit in E. coli by varying the expression levels of EnvZ and OmpR. We have constructed two-color fluorescent reporter strains in which ompF and ompC transcription can be easily measured in the same culture. Using these strains we have shown that, consistent with the predictions of our model, the transcription of ompC and ompF is indeed robust or insensitive to a wide range of expression levels of both EnvZ and OmpR.

Bacterial Outer Membrane Proteins↗
PubMed2004

Genetic variation in cancer predisposition: mutational decay of a robust genetic control network.

A computational model of cancer progression is used to study how mutations in genes that control tumor initiation and progression accumulate in populations. The model assumes that cancer occurs only after a cell lineage has progressed through a series of stages. The greater the number of stages, the more strongly the individual is protected against cancer. It is shown that an extra stage initially improves the survival of individuals by decreasing mortality from cancer. However, the additional buffering by an extra stage reduces the impact of any single hereditary mutation and therefore allows the accumulation of more nonlethal mutations in the population. Extra stages thereby lead to the evolution of partially decreased cancer mortality and significantly increased genetic predisposition to disease in the population as a whole. In general, the model illustrates how all robust control networks allow the accumulation of deleterious mutations. An increase in the number of buffering components leads to significant mutational decay in the protection provided by each buffering component and increased genetic predisposition to disease. An extra buffering component's net contribution to survival and reproduction is often small.

Aging↗
PubMed2005

Surviving heat shock: control strategies for robustness and performance.

Molecular biology studies the cause-and-effect relationships among microscopic processes initiated by individual molecules within a cell and observes their macroscopic phenotypic effects on cells and organisms. These studies provide a wealth of information about the underlying networks and pathways responsible for the basic functionality and robustness of biological systems. At the same time, these studies create exciting opportunities for the development of quantitative and predictive models that connect the mechanism to its phenotype then examine various modular structures and the range of their dynamical behavior. The use of such models enables a deeper understanding of the design principles underlying biological organization and makes their reverse engineering and manipulation both possible and tractable The heat shock response presents an interesting mechanism where such an endeavor is possible. Using a model of heat shock, we extract the design motifs in the system and justify their existence in terms of various performance objectives. We also offer a modular decomposition that parallels that of traditional engineering control architectures.

Escherichia coli↗
PubMed2004

Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors.

Stable genetic modification of adult stem cells is fundamental for both developmental studies and therapeutic purposes. Using in vivo marking studies, we showed that injection of lentiviral vectors (LVs) into the subventricular zone of the adult mouse brain enables efficient gene transfer into long-term self-renewing neural precursors and steady, robust vector expression in their neuronal progeny throughout the subventricular zone and its rostral extension, up to the olfactory bulb. By clonal and population analysis in culture, we proved that in vivo-marked neural precursors display self-renewal and multipotency, two essential characteristics of neural stem cells (NSCs). Thus, LVs efficiently target long-term repopulating adult NSCs, and the effect of the initial transduction is amplified by the continuous generation of NSC-derived, transduced progeny. LVs may thus allow novel studies on NSCs' physiology in vivo, and introduction of therapeutic genes into NSCs may allow the development of novel approaches for untreatable CNS diseases.

Animals↗
PubMed2005

Parkin-deficient mice are not a robust model of parkinsonism.

Mutations in the human parkin gene cause autosomal recessive juvenile parkinsonism, a heritable form of Parkinson's disease (PD). To determine whether mutations in the mouse parkin gene (Park2) also result in a parkinsonian phenotype, we generated mice with a targeted deletion of parkin exon 2. Using an extensive behavioral screen, we evaluated neurological function, motor ability, emotionality, learning, and memory in aged Parkin-deficient mice. The behavioral profile of Parkin-deficient mice on a B6;129S4 genetic background was strikingly similar to that of control mice, and most differences were not reproducible by using coisogenic mice on a 129S4 genetic background. Moreover, catecholamine levels in the striatum, olfactory bulb, and spinal cord of Parkin-deficient mice were normal. In contrast to previous studies using independently generated Parkin-deficient mice, we found no evidence for nigrostriatal, cognitive, or noradrenergic dysfunction. Understanding why Parkin-deficient mice do not exhibit robust signs of parkinsonism could advance knowledge and treatment of PD.

Amphetamines↗
PubMed2005

The "robust yet fragile" nature of the Internet.

The search for unifying properties of complex networks is popular, challenging, and important. For modeling approaches that focus on robustness and fragility as unifying concepts, the Internet is an especially attractive case study, mainly because its applications are ubiquitous and pervasive, and widely available exposition exists at every level of detail. Nevertheless, alternative approaches to modeling the Internet often make extremely different assumptions and derive opposite conclusions about fundamental properties of one and the same system. Fortunately, a detailed understanding of Internet technology combined with a unique ability to measure the network means that these differences can be understood thoroughly and resolved unambiguously. This article aims to make recent results of this process accessible beyond Internet specialists to the broader scientific community and to clarify several sources of basic methodological differences that are relevant beyond either the Internet or the two specific approaches focused on here (i.e., scale-free networks and highly optimized tolerance networks).

Journal Article↗
PubMed2006

On the origin and robustness of power-law species-area relationships in ecology.

We present an explanation for the widely reported power-law species-area relationship (SAR), which relates the area occupied by a biome to the number of species that it supports. We argue that power-law SARs are a robust consequence of a skewed species abundance distribution resembling a lognormal with higher rarity, together with the observation that individuals of a given species tend to cluster. We show that the precise form of the SAR transcends the specific details of organism interactions, enabling us to characterize its broad trends across taxa.

Animals↗
PubMed2006

A robust measure of food web intervality.

Intervality of a food web is related to the number of trophic dimensions characterizing the niches in a community. We introduce here a mathematically robust measure for food web intervality. It has previously been noted that empirical food webs are not strictly interval; however, upon comparison to suitable null hypotheses, we conclude that empirical food webs actually do exhibit a strong bias toward contiguity of prey, that is, toward intervality. Further, our results strongly suggest that empirically observed species and their diets can be mapped onto a single dimension. This finding validates a critical assumption in the recently proposed static niche model and provides guidance for ongoing efforts to develop dynamic models of ecosystems.

Computer Simulation↗