Adaptive evolution of molecular phenotypes

Molecular phenotypes link genomic information with organismic functions, fitness, and evolution. Quantitative traits are complex phenotypes that depend on multiple genomic loci. In this paper, we study the adaptive evolution of a quantitative trait under time-dependent selection, which arises from environmental changes or through fitness interactions with other co-evolving phenotypes. We analyze a model of trait evolution under mutations and genetic drift in a single-peak fitness seascape. The fitness peak performs a constrained random walk in the trait amplitude, which determines the time-dependent trait optimum in a given population. We derive analytical expressions for the distribution of the time-dependent trait divergence between populations and of the trait diversity within populations. Based on this solution, we develop a method to infer adaptive evolution of quantitative traits. Specifically, we show that the ratio of the average trait divergence and the diversity is a universal function of evolutionary time, which predicts the stabilizing strength and the driving rate of the fitness seascape. From an information-theoretic point of view, this function measures the macro-evolutionary entropy in a population ensemble, which determines the predictability of the evolutionary process. Our solution also quantifies two key characteristics of adapting populations: the cumulative fitness flux, which measures the total amount of adaptation, and the adaptive load, which is the fitness cost due to a population's lag behind the fitness peak.Comment: Figures are not optimally displayed in Firefo

Universality in the Evolution of Molecular Phenotypes

With massive growth of biological sequence data and evolutionary experiments the quantitative modeling of evolutionary processes is made possible. These models aim to quantify the degree of conservation and the speed of adaptation in the evolution of biological systems. Evolutionary processes are driven by mutations, selection, and genetic drift. Mutations generate new variants, natural selection favors some of these, and genetic drift is the randomness in their reproduction success. In the early days of population genetics, it was identified that these processes can be described by employing mathematical models from statistical mechanics such as diffusion equations. Recent theoretical studies modeled and solved the dynamics for complex, interacting systems. The complexity arises through evolutionary interaction. On the one hand, mutations interact in their effect on selection. On the other hand, there is competing co-evolution of variants, if recombination cannot break up genomic links. Both problems arise naturally when considering the evolution of molecular phenotypes such as gene expression levels, protein stabilities, or biophysical binding properties. The inheritable information of these phenotypes is constituted by many sites of the DNA sequence. These sites give a large target to new mutational variants and, hence, a number of competing mutations. Since the sites are often confined to small regions of the DNA, beneficial variants in different individuals cannot be recombined through forms of horizontal gene transfer. Selection is further shaped by generically non-linear fitness landscapes, which is the mapping from the phenotypes to biological growth rates. Recent theoretical breakthroughs allowed for the description of the phenotypic dynamics decoupled from plenty of genomic details. These dynamics were solved in evolutionary equilibrium. In this thesis, we take up these models to describe various modes of their evolution, which are scenarios of time-dependent selection and in the co-evolution with other genes. We study for the first time the phenotypic evolution in time-dependent fitness landscapes, so called fitness seascapes, with underlying genomic sites that are genetically linked. We find universal properties that break down the relevant parameters to the stabilizing strength and the driving rate of the fitness seascape. These determine the divergence pattern on the phenotypic scale and the fitness flux, which is a measure for deviations from detailed balance and adaptation, on macro-evolutionary timescales. Therefore, we can read off the stabilizing strength and the fitness flux from the time-dependent phenotypic divergence/diversity ratio. Moreover, we study the impact of short-term constraining phenotypic selection on correlations in their constituting sequences. These correlations arise because sites compensate for the destructive effect from adaptation and genetic drift of other sites. We find that phenotypic evolution generates broad epistasis and correlation matrices across all trait sites, which are of low dimension. This kind of universality allows to read off from sequence correlations alone the number of traits under selection,the genotype–phenotype map, and single site adaptation. The latter can be identified from the asymmetry of time-ordered correlation measures, i.e. deviations from detailed balance. Furthermore, we join the dynamics with recent theories of asexual evolution. These showed universality in the scaling laws of fitness statistics under large mutational influx. With this, we make the step towards systems biology by studying for the first time the asexual co-evolution of biophysical phenotypes on a genome-wide level. We again find universality in the scaling of fitness statistics with the genome size, which decouples from the details of selection. This evolutionary mode induces a so far unknown and dramatic long-term cost of complexity, which can be overcome with small rates of horizontal gene transfer. Comparing this cost to actual biological genome sizes and recombination rates, this offers a new, feasible pathway for the evolution of sex. In all these modes we find so-far unknown laws of universality. These reduce the complexity of the processes on the higher level, e.g. the phenotypic or the overall fitness level and allow the inference of relevant parameters shaping the dynamics or to quantify scalings. Moreover, universalities are strongly related to the predictability of the evolutionary process

Comparison of Different Aerogel Granules for Use as Aggregate in Concrete

In previous work of this group, a structural lightweight concrete was developed by embedding silica aerogel granules in a high-strength cement matrix. This concrete, called high-performance aerogel concrete (HPAC), is a lightweight building material characterized by its simultaneous high compressive strength and very low thermal conductivity. Besides these features, high sound absorption, diffusion permeability, water repellence and fire resistance qualify HPAC as an interesting material for the construction of single-leaf exterior walls without any further insulation. During the development of HPAC, the type of silica aerogel was found to majorly influence both fresh and hardened concrete properties. To clarify these effects, a systematic comparison of SiO2 aerogel granules with different levels of hydrophobicity as well as different synthesis methods was conducted in the present study. The granules were analyzed for their chemical and physical properties as well as their compatibility in HPAC mixtures. These experiments included determinations of pore size distribution, thermal stability, porosity, specific surface and hydrophobicity, as well as fresh/hardened concrete experiments such as measurements of compressive strength, flexural bending strength, thermal conductivity and shrinking behavior. It was found that the type of aerogel has a major influence on the fresh and hardened concrete properties of HPAC, particularly compressive strength and shrinkage behavior, whereas the effect on thermal conductivity is not very pronounced

Phospho-Ser784-VCP is required for DNA damage response and is associated with poor prognosis of chemotherapy-treated breast cancer

Spatiotemporal protein reorganization at DNA damage sites induced by genotoxic chemotherapies is crucial for DNA damage response (DDR), which influences treatment response by directing cancer cell fate. This process is orchestrated by valosin-containing protein (VCP), an AAA+ ATPase that extracts polyubiquinated chromatin proteins and facilitates their turnover. However, because of the essential and pleiotropic effects of VCP in global proteostasis, it remains challenging practically to understand and target its DDR-specific functions. We describe a DNA-damage-induced phosphorylation event (Se

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Comparison of the effect of lps and pam3 on ventilated lungs

<p>Abstract</p> <p>Background</p> <p>While lipopolysaccharide (LPS) from Gram-negative bacteria has been shown to augment inflammation in ventilated lungs information on the effect of Gram-positive bacteria is lacking. Therefore the effect of LPS and a lipopetide from Gram-positive bacteria, PAM3, on ventilated lungs were investigated.</p> <p>Methods</p> <p>C57/Bl6 mice were mechanically ventilated. Sterile saline (sham) and different concentrations of LPS (1 μg and 5 μg) and PAM3 (50 nM and 200 nM) were applied intratracheally. Lung function parameters and expression of MIP-2 and TNFα as well as influx of neutrophils were measured.</p> <p>Results</p> <p>Mechanical ventilation increased resistance and decreased compliance over time. PAM3 but not LPS significantly increased resistance compared to sham challenge (P < 0.05). Both LPS and PAM3 significantly increased MIP-2 and TNFα mRNA expression compared to sham challenge (P < 0.05). The numbers of neutrophils were significantly increased after LPS at a concentration of 5 μg compared to sham (P < 0.05). PAM3 significantly increased the numbers of neutrophils at both concentrations compared to sham (P < 0.05).</p> <p>Conclusions</p> <p>These data suggest that PAM3 similar to LPS enhances ventilator-induced inflammation. Moreover, PAM3 but not LPS increases pulmonary resistance in ventilated lungs. Further studies are warranted to define the role of lipopetides in ventilator-associated lung injury.</p