Most undirected random graphs are amplifiers of selection for Birth-death dynamics, but suppressors of selection for death-Birth dynamics

We analyze evolutionary dynamics on graphs, where the nodes represent individuals of a population. The links of a node describe which other individuals can be displaced by the offspring of the individual on that node. Amplifiers of selection are graphs for which the fixation probability is increased for advantageous mutants and decreased for disadvantageous mutants. A few examples of such amplifiers have been developed, but so far it is unclear how many such structures exist and how to construct them. Here, we show that almost any undirected random graph is an amplifier of selection for Birth-death updating, where an individual is selected to reproduce with probability proportional to its fitness and one of its neighbors is replaced by that offspring at random. If we instead focus on death-Birth updating, in which a random individual is removed and its neighbors compete for the empty spot, then the same ensemble of graphs consists of almost only suppressors of selection for which the fixation probability is decreased for advantageous mutants and increased for disadvantageous mutants. Thus, the impact of population structure on evolutionary dynamics is a subtle issue that will depend on seemingly minor details of the underlying evolutionary process

Counterintuitive properties of the fixation time in network-structured populations

Evolutionary dynamics on graphs can lead to many interesting and counterintuitive findings. We study the Moran process, a discrete time birth-death process, that describes the invasion of a mutant type into a population of wild-type individuals. Remarkably, the fixation probability of a single mutant is the same on all regular networks. But non-regular networks can increase or decrease the fixation probability. While the time until fixation formally depends on the same transition probabilities as the fixation probabilities, there is no obvious relation between them. For example, an amplifier of selection, which increases the fixation probability and thus decreases the number of mutations needed until one of them is successful, can at the same time slow down the process of fixation. Based on small networks, we show analytically that (i) the time to fixation can decrease when links are removed from the network and (ii) the node providing the best starting conditions in terms of the shortest fixation time depends on the fitness of the mutant. Our results are obtained analytically on small networks, but numerical simulations show that they are qualitatively valid even in much larger populations

La contribución de las ingenierías en la reducción del riesgo en desastres.

Más de 300 millones de personas se ven afectadas cada año por desastres naturales, que son resultado de numerosos factores, y no simples casualidades estadísticas o caprichos de la naturaleza. La gravedad de sus efectos está relacionada con la gravedad del evento, pero, sobre todo, con la situación de vulnerabilidad de las poblaciones afectadas. La contribución de la ingeniería, una herramienta fundamental en todas las fases de la ayuda humanitaria, no pasa necesariamente por la implementación de grandes obras físicas ni inversiones. También desde la creatividad y la adaptación técnica y tecnológica al contexto es posible encontrar una contribución realmente propia.Peer Reviewe

Should tissue structure suppress or amplify selection to minimize cancer risk?

It has been frequently argued that tissues evolved to suppress the accumulation of growth enhancing cancer inducing mutations. A prominent example is the hierarchical structure of tissues with high cell turnover, where a small number of tissue specific stem cells produces a large number of specialized progeny during multiple differentiation steps. Another well known mechanism is the spatial organization of stem cell populations and it is thought that this organization suppresses fitness enhancing mutations. However, in small populations the suppression of advantageous mutations typically also implies an increased accumulation of deleterious mutations. Thus, it becomes an important question whether the suppression of potentially few advantageous mutations outweighs the combined effects of many deleterious mutations

Fixation times in graph-structured populations

The Moran process is widely used for modeling stochastic dynamics of finitely large populations. It describes the invasion process of a novel mutant into a resident population. Generally, the population is assumed to be well-mixed, which is a rather strong assumption. Studying the Moran process on graphs instead of unstructured populations is a recent approach to overcome this assumption. Some graph structures increase the fixation probability of a mutant that has a fitness advantage compared to the resident population. Graphs with this property are called amplifiers of selection. However, simulations show that the time until fixation increases considerably on those graphs. The objective of this thesis is to analyze different graphs of small size with respect to the fixation time. Simulations support the results for larger population size, where analytical approaches are unfeasible. We show that depending on the initial graph structure, the removal of one link can either lead to an increase or decrease in fixation time. This result is surprising and counterintuitive. Another interesting finding is that the shortest average fixation time does not only depend on the mutant’s starting node. But instead, different starting nodes are preferable, depending on the mutant’s fitness.1 Introduction 1 2 Background and Methods 5 2.1 Markov Chains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.1 Canonical Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.2 Graph Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.3 The Moran Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.3.1 Fixation Probability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.3.2 Isothermal Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.3.3 Amplification and Suppression of Selection . . . . . . . . . . . . . . . . . . 13 2.3.4 Fixation Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 2.3.5 Effective Rate of Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3 Small Population Size 17 3.1 Graph Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3.2 Fixation Probability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.2.1 Transition Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.2.2 Analytical and Simulated Fixation Probability . . . . . . . . . . . . . . . 27 3.3 Fixation Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 3.3.1 Analytical Results for Fixation Time . . . . . . . . . . . . . . . . . . . . . 31 3.3.2 Simulation of Fixation Time . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3.4 Sojourn Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 3.5 Effective Rate of Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 3.6 Location of the First Mutant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 4 Larger Graphs 45 4.1 Size Eight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 4.1.1 Removal of One and Two Links . . . . . . . . . . . . . . . . . . . . . . . . 46 4.1.2 Removal of Three Links . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 4.2 Influence of the "Five Links" on Fixation Time . . . . . . . . . . . . . . . . . . . 48 5 Discussion 49 5.1 Summary and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 5.2 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 References 5

Wnt/β-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours

We show that activation of Wnt/{beta}-catenin and attenuation of Bmp signals, by combined gain- and loss-of-function mutations of {beta}-catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that {beta}-catenin, CBP and Mll promote self-renewal and H3K4 tri-methylation in tumour propagating cells. Blocking {beta}-catenin-CBP interaction with the small molecule ICG-001 and small-interfering RNAs against {beta}-catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri-methylation, and induce differentiation of cultured tumour propagating cells into acini-like structures. ICG-001 decreases H3K4me3 at promoters of stem cell-associated genes in vitro and reduces tumour growth in vivo. Remarkably, high Wnt/{beta}-catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which {beta}-catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours

The Empirical Landscape of Trade Policy

This chapter surveys empirically the broad features of trade policy in goods for 31 major economies that collectively represented 83 percent of the world's population and 91 percent of the world's GDP in 2013. We address five questions: Do some countries have more liberal trading regimes than others? Within countries, which industries receive the most import protection? How do trade policies change over time? Do countries discriminate among their trading partners when setting trade policy? Finally, how liberalized is world trade? Our analysis documents the extent of cross-sectional heterogeneity in applied commercial policy across countries, their economic sectors, and their trading partners, over time. We conclude that substantial trade policy barriers remain as an important feature of the world economy.antidumpin

A Bi-Functional Anti-Thrombosis Protein Containing Both Direct-Acting Fibrin(ogen)olytic and Plasminogen-Activating Activities

Direct-acting fibrin(ogen)olytic agents such as plasmin have been proved to contain effective and safety thrombolytic potential. Unfortunately, plasmin is ineffective when administered by the intravenous route because it was neutralized by plasma antiplasmin. Direct-acting fibrin(ogen)olytic agents with resistance against antiplasmin will brighten the prospect of anti-thrombosis. As reported in ‘Compendium of Materia Medica’, the insect of Eupolyphaga sinensis Walker has been used as traditional anti-thrombosis medicine without bleeding risk for several hundreds years. Currently, we have identified a fibrin(ogen)olytic protein (Eupolytin1) containing both fibrin(ogen)olytic and plasminogen-activating (PA) activities from the beetle, E. sinensis. Objectives: To investigate the role of native and recombinant eupolytin1 in fibrin(ogen)olytic and plasminogen-activating processes. Methods and Results: Using thrombus animal model, eupolytin1 was proved to contain strong and rapid thrombolytic ability and safety in vivo, which are better than that of urokinase. Most importantly, no bleeding complications were appeared even the intravenous dose up to 0.12 µmol/kg body weight (3 times of tested dose which could completely lyse experimental thrombi) in rabbits. It is the first report of thrombolytic agents containing both direct-acting fibrin(ogen)olytic and plasminogen-activating activities. Conclusions: The study identified novel thrombolytic agent with prospecting clinical potential because of its bi-functional merits containing both plasmin- and PA-like activities and unique pharmacological kinetics in vivo