Molecular Clock on a Neutral Network

The number of fixed mutations accumulated in an evolving population often displays a variance that is significantly larger than the mean (the overdispersed molecular clock). By examining a generic evolutionary process on a neutral network of high-fitness genotypes, we establish a formalism for computing all cumulants of the full probability distribution of accumulated mutations in terms of graph properties of the neutral network, and use the formalism to prove overdispersion of the molecular clock. We further show that significant overdispersion arises naturally in evolution when the neutral network is highly sparse, exhibits large global fluctuations in neutrality, and small local fluctuations in neutrality. The results are also relevant for elucidating the topological structure of a neutral network from empirical measurements of the substitution process.Comment: 10 page

Resolving Land Disputes in East Asia: Exploring the Limits of Law

Land disputes are increasing in East Asia as economic and demographic growth intensifies the demand for farmland and urban spaces. Nowhere is this more evident than in China and Vietnam. Reforms that brought Socialist Asia into the globalized economy and returned private property have also sparked intense competition between farmers and residents with outsiders, such as private developers and government agencies. From a legal perspective, the proliferation of land disputes is puzzling, because it is occurring at the same time as governments in China and Vietnam are clarifying property rights and improving formal dispute resolution institutions, such as the courts. Rather than promoting uniformity, order, and predictability, this paper shows that law reforms have produced mixed results. Land claims and property rights often conflict, producing unpredictable and multi-layered dispute resolution processes. Highly ambiguous and contested patterns of land access persist in these countries. Consequently, courts and administrative agencies such as grand mediation struggle to use property rights to find lasting solutions to land disputes. This paper draws on a body of empirical studies to explore why state laws and institutions struggle to gain the upper hand in many land cases.preprin

Stronger computational modelling of signalling pathways using both continuous and discrete-state methods

Starting from a biochemical signalling pathway model expresses in a process algebra enriched with quantitative information, we automatically derive both continuous-space and discrete-space representations suitable for numerical evaluation. We compare results obtained using approximate stochastic simulation thereby exposing a flaw in the use of the differentiation procedure producing misleading results

Number of adaptive steps to a local fitness peak

We consider a population of genotype sequences evolving on a rugged fitness landscape with many local fitness peaks. The population walks uphill until it encounters a local fitness maximum. We find that the statistical properties of the walk length depend on whether the underlying fitness distribution has a finite mean. If the mean is finite, all the walk length cumulants grow with the sequence length but approach a constant otherwise. Experimental implications of our analytical results are also discussed

Lack of self-averaging in neutral evolution of proteins

We simulate neutral evolution of proteins imposing conservation of the thermodynamic stability of the native state in the framework of an effective model of folding thermodynamics. This procedure generates evolutionary trajectories in sequence space which share two universal features for all of the examined proteins. First, the number of neutral mutations fluctuates broadly from one sequence to another, leading to a non-Poissonian substitution process. Second, the number of neutral mutations displays strong correlations along the trajectory, thus causing the breakdown of self-averaging of the resulting evolutionary substitution process.Comment: 4 pages, 2 figure

Improved power for TB phase IIa trials using a model-based pharmacokinetic-pharmacodynamic approach compared with commonly used analysis methods

The research leading to these results has received funding from the Swedish Research Council (grant number 521-2011-3442) in addition to the Innovative Medicines Initiative Joint Undertaking (www.imi.europe.eu) under grant agreement no. 115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in kind contribution.Background : The demand for new anti-TB drugs is high, but development programmes are long and costly. Consequently there is a need for new strategies capable of accelerating this process. Objectives : To explore the power to find statistically significant drug effects using a model-based pharmacokinetic–pharmacodynamic approach in comparison with the methods commonly used for analysing TB Phase IIa trials. Methods : Phase IIa studies of four hypothetical anti-TB drugs (labelled A, B, C and D), each with a different mechanism of action, were simulated using the multistate TB pharmacometric (MTP) model. cfu data were simulated over 14 days for patients taking once-daily monotherapy at four different doses per drug and a reference (10 mg/kg rifampicin). The simulated data were analysed using t-test, ANOVA, mono- and bi-exponential models and a pharmacokinetic–pharmacodynamic model approach (MTP model) to establish their respective power to find a drug effect at the 5% significance level. Results : For the pharmacokinetic–pharmacodynamic model approach, t-test, ANOVA, mono-exponential model and bi-exponential model, the sample sizes needed to achieve 90% power were: 10, 30, 75, 20 and 30 (drug A); 30, 75, 245, 75 and 105 (drug B); 70, >1250, 315, >1250 and >1250 (drug C); and 30, 110, 710, 170 and 185 (drug D), respectively. Conclusions : A model-based design and analysis using a pharmacokinetic–pharmacodynamic approach can reduce the number of patients required to determine a drug effect at least 2-fold compared with current methodologies. This could significantly accelerate early-phase TB drug development.Publisher PDFPeer reviewe

The detection of geothermal areas from Skylab thermal data

Skylab-4 X-5 thermal data of the geysers area was analyzed to determine the feasibility of using midday Skylab images to detect geothermal areas. The hottest ground areas indicated on the Skylab image corresponded to south-facing barren or sparsely vegetated slopes. A geothermal area approximately 15 by 30 m coincided with one of the hottest areas indicated by Skylab. This area could not be unambiguously distinguished from the other areas which are believed to be hotter than their surroundings as a result of their topography, and micrometeorological conditions. A simple modification of a previous thermal model was performed and the predicted temperatures for the hottest slopes using representative values was in general agreement with the observed data. It is concluded that data from a single midday Skylab pass cannot be used to locate geothermal areas

A large cockroach from the mesosaurbearing Konservat-Lagerstätte (Mangrullo Formation), Late Paleozoic of Uruguay

Barona arcuata, n.gen et n.sp., a left forewing of a relatively large cockroach of the Order Blattaria, is described from mesosaur-bearing lagoonal shales of the Mangrullo Formation (north-eastern Uruguay). While most of the insect remains recovered from the Mangrullo Formation come from sandy limestones, associated to scarce isolated mesosaur bones and pygocephalomorph crustaceans, the cockroach wing here described was found in the overlaying green to brownish, gray and dark black shales associated to intercalated bentonites and evaporitic gypsum crystals. Barona arcuata shares some features with typical Late Carboniferous taxa such as its general venation pattern and outline of the wing, four main and powerful veins arising close together from near the base of the wing, Sc simple forked, pectinate, reaching the costal border through a long fork, R and M bifurcating and terminating in the wing margin above and below the apex respectively, short and narrow CuA, and the presence of a broad interspace between CuP and AA. Cross venation seems to be absent or it was not preserved. Some characters might relate Barona arcuata to the Late CarboniferousEarly Permian Neothroblattinidae such as the presence of sigmoidal veins in the anal area, a condition not found in any of the remaining representatives of the Palaeozoic Blattaria. Intriguingly, the Uruguayan blattarian also presents a strong similarity with Qilianiblatta namurensis Zhang, Schneider & Hong, 2012 from the Westphalian of China, clearly a smaller taxon that is also difficult to relate to any of the preexistent families. The apparent plesiomorphic venation pattern of the new species which is reminiscent of that present in the oldest known blattarians, is in agreement with a Permo-Carboniferous (Gzhelian-Asselian) age for the Mangrullo Formation also supported by the presence of a macrofloral assemblage dominated by arborescent lepidondendrids and other lycopsids and the pygocephalid-like morphology of the pygocephalomorph crustaceans from the same levels