Numerical and experimental study of overtopping and failure of rockfill dams

This paper aims to present and validate a numerical technique for the simulation of the overtopping and onset of failure in rockfill dams due to mass sliding. This goal is achieved by coupling a fluid dynamic model for the simulation of the free surface and through-flow problems, with a numerical technique for the calculation of the rockfill response and deformation. Both the flow within the dam body and in its surroundings are taken into account. An extensive validation of the resulting computational method is performed by solving several failure problems on physical models of rockfill dams for which experimental results have been obtained by the authors.

Static and dynamic lengths of neutrophil microvilli

Containing most of the L-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) on their tips, microvilli are believed to promote the initial arrest of neutrophils on endothelium. At the rolling stage following arrest, the lifetimes of the involved molecular bonds depend on the pulling force imposed by the shear stress of blood flow. With two different methods, electron microscopy and micropipette manipulation, we have obtained two comparable neutrophil microvillus lengths, both ≈0.3 μm in average. We have found also that, under a pulling force, a microvillus can be extended (microvillus extension) or a long thin membrane cylinder (a tether) can be formed from it (tether formation). If the force is ≤34 pN (± 3 pN), the length of the microvillus will be extended; if the force is >61 pN (± 5 pN), a tether will be formed from the microvillus at a constant velocity, which depends linearly on the force. When the force is between 34 pN and 61 pN (transition zone), the degree of association between membrane and cytoskeleton in individual microvilli will dictate whether microvillus extension or tether formation occurs. When a microvillus is extended, it acts like a spring with a spring constant of ≈43 pN/μm. In contrast to a rigid or nonextendible microvillus, both microvillus extension and tether formation can decrease the pulling force imposed on the adhesive bonds, and thus prolonging the persistence of the bonds at high physiological shear stresses.

The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21BAX expression

Radiation is the primary modality of therapy for all commonly occurring malignant brain tumors, including medulloblastoma and glioblastoma. These two brain tumors, however, have a distinctly different response to radiation therapy. Medulloblastoma is very sensitive to radiation therapy, whereas glioblastoma is highly resistant, and the long-term survival of medulloblastoma patients exceeds 50%, while there are few long-term survivors among glioblastoma patients. p53-mediated apoptosis is thought to be an important mechanism mediating the cytotoxic response of tumors to radiotherapy. In this study, we compared the response to radiation of five cell lines that have wild-type p53: three derived from glioblastoma and two derived from medulloblastoma. We found that the medulloblastoma-derived cell lines underwent extensive radiation-induced apoptotic cell death, while those from glioblastomas did not exhibit significant radiation-induced apoptosis. p53-mediated induction of p21BAX is thought to be a key component of the pathway mediating apoptosis after the exposure of cells to cytotoxins, and the expression of mRNA encoding p21BAX was correlated with these cell lines undergoing radiation-induced apoptosis. The failure of p53 to induce p21BAX expression in glioblastoma-derived cell lines is likely to be of biologic significance, since inhibition of p21BAX induction in medulloblastoma resulted in a loss of radiation-induced apoptosis, while forced expression of p21BAX in glioblastoma was sufficient to induce apoptosis. The failure of p53 to induce p21BAX in glioblastoma-derived cell lines suggests a distinct mechanism of radioresistance and may represent a critical factor in determining therapeutic responsiveness to radiation in glioblastomas.

Arrest of neuronal migration by excitatory amino acids in hamster developing brain

The influence of the excitotoxic cascade on the developing brain was investigated using ibotenate, a glutamatergic agonist of both N-methyl-d-aspartate (NMDA) ionotropic receptors and metabotropic receptors. Injected in the neopallium of the golden hamster at the time of production of neurons normally destined for layers IV, III, and II, ibotenate induces arrests of migrating neurons at different distances from the germinative zone within the radial migratory corridors. The resulting cytoarchitectonic patterns include periventricular nodular heterotopias, subcortical band heterotopias, and intracortical arrests of migrating neurons. The radial glial cells and the extracellular matrix are free of detectable damage that could suggest a defect in their guiding role. The migration disorders are prevented by coinjection of dl-2-amino-7-phosphoheptanoic acid, an NMDA ionotropic antagonist, but are not prevented by coinjection of l(+)-2-amino-3-phosphonopropionic acid, a metabotropic antagonist. This implies that an excess of ionic influx through the NMDA channels of neurons alters the metabolic pathways supporting neuronal migration. Ibotenate, a unique molecular trigger of the excitotoxic cascade, produces a wide spectrum of abnormal neuronal migration patterns recognized in mammals, including the neocortical deviations encountered in the human brain.

The elasticity and failure of fluid-filled cellular solids: Theory and experiment

We extend and apply theories of filled foam elasticity and failure to recently available data on foods. The predictions of elastic modulus and failure mode dependence on internal pressure and on wall integrity are borne out by photographic evidence of distortion and failure under compressive loading and under the localized stress applied by a knife blade, and by mechanical data on vegetables differing only in their turgor pressure. We calculate the dry modulus of plate-like cellular solids and the cross over between dry-like and fully fluid-filled elastic response. The bulk elastic properties of limp and aging cellular solids are calculated for model systems and compared with our mechanical data, which also show two regimes of response. The mechanics of an aged, limp beam is calculated, thus offering a practical procedure for comparing experiment and theory. This investigation also thereby offers explanations of the connection between turgor pressure and crispness and limpness of cellular materials.

Dynamical principles in biological processes: A model of charge migration in proteins and DNA

The generalized master equations (GMEs) that contain multiple time scales have been derived quantum mechanically. The GME method has then been applied to a model of charge migration in proteins that invokes the hole hopping between local amino acid sites driven by the torsional motions of the floppy backbones. This model is then applied to analyze the experimental results for sequence-dependent long-range hole transport in DNA reported by Meggers et al. [Meggers, E., Michel-Beyerle, M. E., & Giese, B. (1998) J. Am. Chem. Soc. 120, 12950–12955]. The model has also been applied to analyze the experimental results of femtosecond dynamics of DNA-mediated electron transfer reported by Zewail and co-workers [Wan, C., Fiebig, T., Kelley, S. O., Treadway, C. R., Barton, J. K. & Zewail, A. H. (1999) Proc. Natl. Acad. Sci. USA 96, 6014–6019]. The initial events in the dynamics of protein folding have begun to attract attention. The GME obtained in this paper will be applicable to this problem.

Biogeographic range expansion into South America by Coccidioides immitis mirrors New World patterns of human migration

Long-distance population dispersal leaves its characteristic signature in genomes, namely, reduced diversity and increased linkage between genetic markers. This signature enables historical patterns of range expansion to be traced. Herein, we use microsatellite loci from the human pathogen Coccidioides immitis to show that genetic diversity in this fungus is geographically partitioned throughout North America. In contrast, analyses of South American C. immitis show that this population is genetically depauperate and was founded from a single North American population centered in Texas. Variances of allele distributions show that South American C. immitis have undergone rapid population growth, consistent with an epidemic increase in postcolonization population size. Herein, we estimate the introduction into South America to have occurred within the last 9,000–140,000 years. This range increase parallels that of Homo sapiens. Because of known associations between Amerindians and this fungus, we suggest that the colonization of South America by C. immitis represents a relatively recent and rapid codispersal of a host and its pathogen.

Maximum likelihood estimation of a migration matrix and effective population sizes in n subpopulations by using a coalescent approach

A maximum likelihood estimator based on the coalescent for unequal migration rates and different subpopulation sizes is developed. The method uses a Markov chain Monte Carlo approach to investigate possible genealogies with branch lengths and with migration events. Properties of the new method are shown by using simulated data from a four-population n-island model and a source–sink population model. Our estimation method as coded in migrate is tested against genetree; both programs deliver a very similar likelihood surface. The algorithm converges to the estimates fairly quickly, even when the Markov chain is started from unfavorable parameters. The method was used to estimate gene flow in the Nile valley by using mtDNA data from three human populations.

On the failure of de novo-designed peptides as biocatalysts.

While the elegance and efficiency of enzymatic catalysis have long tempted chemists and biochemists with reductionist leanings to try to mimic the functions of natural enzymes in much smaller peptides, such efforts have only rarely produced catalysts with biologically interesting properties. However, the advent of genetic engineering and hybridoma technology and the discovery of catalytic RNA have led to new and very promising alternative means of biocatalyst development. Synthetic chemists have also had some success in creating nonpeptide catalysts with certain enzyme-like characteristics, although their rates and specificities are generally much poorer than those exhibited by the best novel biocatalysts based on natural structures. A comparison of the various approaches from theoretical and practical viewpoints is presented. It is suggested that, given our current level of understanding, the most fruitful methods may incorporate both iterative selection strategies and rationally chosen small perturbations, superimposed on frameworks designed by nature.

Failure of programmed cell death and differentiation as causes of tumors: some simple mathematical models.

Most models of tumorigenesis assume that the tumor grows by increased cell division. In these models, it is generally supposed that daughter cells behave as do their parents, and cell numbers have clear potential for exponential growth. We have constructed simple mathematical models of tumorigenesis through failure of programmed cell death (PCD) or differentiation. These models do not assume that descendant cells behave as their parents do. The models predict that exponential growth in cell numbers does sometimes occur, usually when stem cells fail to die or differentiate. At other times, exponential growth does not occur: instead, the number of cells in the population reaches a new, higher equilibrium. This behavior is predicted when fully differentiated cells fail to undergo PCD. When cells of intermediate differentiation fail to die or to differentiate further, the values of growth parameters determine whether growth is exponential or leads to a new equilibrium. The predictions of the model are sensitive to small differences in growth parameters. Failure of PCD and differentiation, leading to a new equilibrium number of cells, may explain many aspects of tumor behavior--for example, early premalignant lesions such as cervical intraepithelial neoplasia, the fact that some tumors very rarely become malignant, the observation of plateaux in the growth of some solid tumors, and, finally, long lag phases of growth until mutations arise that eventually result in exponential growth.

Cell-free activation of neutrophil NADPH oxidase by a phosphatidic acid-regulated protein kinase.

The phosphorylation-dependent mechanisms regulating activation of the human neutrophil respiratory-burst enzyme, NADPH oxidase, have not been elucidated. We have shown that phosphatidic acid (PA) and diacylglycerol (DG), products of phospholipase activation, synergize to activate NADPH oxidase in a cell-free system. We now report that activation by PA plus DG involves protein kinase activity, unlike other cell-free system activators. NADPH oxidase activation by PA plus DG is reduced approximately 70% by several protein kinase inhibitors [1-(5-isoquinolinesulfonyl)piperazine, staurosporine, GF-109203X]. Similarly, depletion of ATP by dialysis reduces PA plus DG-mediated NADPH oxidase activation by approximately 70%. Addition of ATP, but not a nonhydrolyzable ATP analog, to the dialyzed system restores activation levels to normal. In contrast, these treatments have little effect on NADPH oxidase activation by arachidonic acid or SDS plus DG. PA plus DG induces the phosphorylation of a number of endogenous proteins. Phosphorylation is largely mediated by PA, not DG. A predominant substrate is p47-phox, a phosphoprotein component of NADPH oxidase. Phosphorylation of p47-phox precedes activation of NADPH oxidase and is markedly reduced by the protein kinase inhibitors. In contrast, arachidonic acid alone or SDS plus DG is a poor activator of protein phosphorylation in the cell-free system. Thus, PA induces activation of one or more protein kinases that regulate NADPH oxidase activation in a cell-free system. This cell-free system will be useful for identifying a functionally important PA-activated protein kinase(s) and for dissecting the phosphorylation-dependent mechanisms responsible for NADPH oxidase activation.

Intrinsic changes in developing retinal neurons result in regenerative failure of their axons.

The failure of mature mammalian central nervous system axons to regenerate after transection is usually attributed to influences of the extraneuronal milieu. Using explant cocultures of retina and midbrain tectum from hamsters, we have found evidence that these influences account for failure of regrowth of only a small minority of retinal axons. For most of the axons, there is a programmed loss of ability to elongate in the central nervous system. We show that there is a precipitous decline in the ability of retinal axons to reinnervate tectal targets when the retina is derived from pups on or after postnatal day 2, even when the target is embryonic. By contrast, embryonic retinal axons can regrow into tectum of any age, overcoming growth-inhibiting influences of glial factors.

Founder-effect speciation theory: failure of experimental corroboration.

The theory of founder-effect speciation proposes that colonization by very few individuals of an empty habitat favors rapid genetic changes and the evolution of a new species. We report here the results obtained in a 10-year-long and large-scale experiment with Drosophila pseudoobscura designed to test the theory. In our experimental protocol, populations are established with variable numbers of very few individuals and allowed to expand greatly for several generations until conditions of severe competition for resources are reached and the population crashes. A few random survivors are then taken to start a new population expansion and thus initiate a new cycle of founding events, population flushes, and crashes. Our results provide no support for the theories proposing that new species are very likely to appear as by-products of founder events.

Steamboats and pleasure travels: success and failure of the first Spanish initiatives in the mid-nineteenth century

Steam technology revolutionised maritime transport during the nineteenth century. Together with the establishment of the first regular lines, steamers soon led to the commencement of pleasure navigation. The aim of this article is to analyse the impact and scope of this process in Spain, by means of a study of the first experiences in the mid-nineteenth century. In addition to a brief introduction and final conclusions, the paper is structured around four sections. The first contains an appraisal of the situation of passenger transport. Some information is then provided regarding the first cruise in 1854. Next, the essay highlights some of the features of short excursions that were very well received by the public, especially in the island of Majorca. Finally, attention is given to a very special type of travel, the main attraction of which lay in the opportunity to witness an event of a military nature.

Intraspecific Behavioural Diversity in a Freshwater Zooplankton: A study of the fitness consequences of vertical migration behaviour for distinct morphs of Daphnia pulicaria

The literature on niche separation and coexistence between species is large, but there is widespread variation in behavioural strategy between individuals of the same species that has received much less attention. Understanding what maintains this diversity is important because intraspecific behavioural diversity can affect population dynamics and community interactions. Multiple behavioural strategies can arise either as phenotype-dependent ‘conditional strategies’, where phenotypic variation causes individuals to adopt different strategies for optimizing fitness, or as internally-independent ‘alternative strategies’, where multiple fitness peaks exist for individuals and strategic ‘choice’ remains plastic. Though intraspecific variation in stable phenotypes is known to maintain intraspecific behavioural diversity through conditional strategies, when internal conditions are highly plastic or reversible, it is not clear whether individual behaviours are maintained as conditional strategies, or as alternative strategies of equal fitness. In this study, I combine an observational and experimental approach to identify the likely mechanisms maintaining behavioural diversity between hemoglobin-rich and hemoglobin-poor morphs in a natural population of Daphnia pulicaria. In Round Lake, individuals with low hemoglobin migrate daily from the hypolimnion to the epilimnion, whereas individuals with high hemoglobin remain in the hypolimnion. Using high-resolution depth and time sampling, I discovered behavioural diversity both within and among hemoglobin phenotypes. I tested the role of hemoglobin phenotype in maintaining behavioural diversity using automated migration robots that move individuals across the natural environmental gradients in the lake. By measuring the fitness of each morph undergoing either a natural migration behaviour, or the migration of the opposite morph, I found that the fitness of hemoglobin rich and poor morphs in their natural behaviour does not differ, but that Hb-rich individuals can obtain equal fitness from either behaviour, while Hb-poor morphs suffer substantial drops in survivorship in the alternate migration behaviour. Thus, migration behaviour in this system exists as a conditional strategy for some individuals, and as alternative strategies of equal fitness for others. The results of this study suggest that individual limits in the expression of highly flexible internal conditions can reinforce intraspecific behavioural diversity. Few studies have measured the fitness consequences of switching migration strategies and this study provides a rare example in the field.