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

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

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

Capturing age-related changes in functional contrast sensitivity with decreasing light levels in monocular and binocular vision

Purpose: It is challenging to separate the effects of normal aging of the retina and visual pathways independently from optical factors, decreased retinal illuminance and early stage disease. This study determined limits to describe the effect of light level on normal, age-related changes in monocular and binocular functional contrast sensitivity. Methods: 95 participants aged 20 to 85 were recruited. Contrast thresholds for correct orientation discrimination of the gap in a Landolt C optotype were measured using a 4 four-alternative, forced-choice (4AFC) procedure at screen luminances from 34 to 0.12 cd/m2, at the fovea and parafovea (0° and ±4°). Pupil size was measured continuously. The Health of the Retina index (HRindex) was computed to capture the loss of contrast sensitivity with decreasing light level. Participants were excluded if they exhibited performance outside the normal limits of interocular differences or HRindex values, or signs of ocular disease. Results: Parafoveal contrast thresholds showed a steeper decline and higher correlation with age at the parafovea than the fovea. 83% of participants with clinical signs of ocular disease had HRindex values outside the normal limits. Binocular summation of contrast signals declined with age, independent of interocular differences. Conclusion: The HRindex worsens more rapidly with age at the parafovea, consistent with histological findings of rod loss and its link to age-related degenerative disease of the retina. The HRindex, and interocular differences could be used to screen for and separate the earliest stages of sub-clinical disease from changes caused by normal aging