Evolution of Robustness to Noise and Mutation in Gene Expression Dynamics

Phenotype of biological systems needs to be robust against mutation in order to sustain themselves between generations. On the other hand, phenotype of an individual also needs to be robust against fluctuations of both internal and external origins that are encountered during growth and development. Is there a relationship between these two types of robustness, one during a single generation and the other during evolution? Could stochasticity in gene expression have any relevance to the evolution of these robustness? Robustness can be defined by the sharpness of the distribution of phenotype; the variance of phenotype distribution due to genetic variation gives a measure of `genetic robustness' while that of isogenic individuals gives a measure of `developmental robustness'. Through simulations of a simple stochastic gene expression network that undergoes mutation and selection, we show that in order for the network to acquire both types of robustness, the phenotypic variance induced by mutations must be smaller than that observed in an isogenic population. As the latter originates from noise in gene expression, this signifies that the genetic robustness evolves only when the noise strength in gene expression is larger than some threshold. In such a case, the two variances decrease throughout the evolutionary time course, indicating increase in robustness. The results reveal how noise that cells encounter during growth and development shapes networks' robustness to stochasticity in gene expression, which in turn shapes networks' robustness to mutation. The condition for evolution of robustness as well as relationship between genetic and developmental robustness is derived through the variance of phenotypic fluctuations, which are measurable experimentally.Comment: 25 page

Airway cellularity, lipid laden macrophages and microbiology of gastric juice and airways in children with reflux oesophagitis

BACKGROUND: Gastroesophageal reflux disease (GORD) can cause respiratory disease in children from recurrent aspiration of gastric contents. GORD can be defined in several ways and one of the most common method is presence of reflux oesophagitis. In children with GORD and respiratory disease, airway neutrophilia has been described. However, there are no prospective studies that have examined airway cellularity in children with GORD but without respiratory disease. The aims of the study were to compare (1) BAL cellularity and lipid laden macrophage index (LLMI) and, (2) microbiology of BAL and gastric juices of children with GORD (G+) to those without (G-). METHODS: In 150 children aged <14-years, gastric aspirates and bronchoscopic airway lavage (BAL) were obtained during elective flexible upper endoscopy. GORD was defined as presence of reflux oesophagitis on distal oesophageal biopsies. RESULTS: BAL neutrophil% in G- group (n = 63) was marginally but significantly higher than that in the G+ group (n = 77), (median of 7.5 and 5 respectively, p = 0.002). Lipid laden macrophage index (LLMI), BAL percentages of lymphocyte, eosinophil and macrophage were similar between groups. Viral studies were negative in all, bacterial cultures positive in 20.7% of BALs and in 5.3% of gastric aspirates. BAL cultures did not reflect gastric aspirate cultures in all but one child. CONCLUSION: In children without respiratory disease, GORD defined by presence of reflux oesophagitis, is not associated with BAL cellular profile or LLMI abnormality. Abnormal microbiology of the airways, when present, is not related to reflux oesophagitis and does not reflect that of gastric juices

Behavioral Modernity and the Cultural Transmission of Structured Information: The Semantic Axelrod Model

Cultural transmission models are coming to the fore in explaining increases in the Paleolithic toolkit richness and diversity. During the later Paleolithic, technologies increase not only in terms of diversity but also in their complexity and interdependence. As Mesoudi and O'Brien (2008) have shown, selection broadly favors social learning of information that is hierarchical and structured, and multiple studies have demonstrated that teaching within a social learning environment can increase fitness. We believe that teaching also provides the scaffolding for transmission of more complex cultural traits. Here, we introduce an extension of the Axelrod (1997} model of cultural differentiation in which traits have prerequisite relationships, and where social learning is dependent upon the ordering of those prerequisites. We examine the resulting structure of cultural repertoires as learning environments range from largely unstructured imitation, to structured teaching of necessary prerequisites, and we find that in combination with individual learning and innovation, high probabilities of teaching prerequisites leads to richer cultural repertoires. Our results point to ways in which we can build more comprehensive explanations of the archaeological record of the Paleolithic as well as other cases of technological change.Comment: 24 pages, 7 figures. Submitted to "Learning Strategies and Cultural Evolution during the Paleolithic", edited by Kenichi Aoki and Alex Mesoudi, and presented at the 79th Annual Meeting of the Society for American Archaeology, Austin TX. Revised 5/14/1

A Theoretical Exploration of Birhythmicity in the p53-Mdm2 Network

Experimental observations performed in the p53-Mdm2 network, one of the key protein modules involved in the control of proliferation of abnormal cells in mammals, revealed the existence of two frequencies of oscillations of p53 and Mdm2 in irradiated cells depending on the irradiation dose. These observations raised the question of the existence of birhythmicity, i.e. the coexistence of two oscillatory regimes for the same external conditions, in the p53-Mdm2 network which would be at the origin of these two distinct frequencies. A theoretical answer has been recently suggested by Ouattara, Abou-Jaoudé and Kaufman who proposed a 3-dimensional differential model showing birhythmicity to reproduce the two frequencies experimentally observed. The aim of this work is to analyze the mechanisms at the origin of the birhythmic behavior through a theoretical analysis of this differential model. To do so, we reduced this model, in a first step, into a 3-dimensional piecewise linear differential model where the Hill functions have been approximated by step functions, and, in a second step, into a 2-dimensional piecewise linear differential model by setting one autonomous variable as a constant in each domain of the phase space. We find that two features related to the phase space structure of the system are at the origin of the birhythmic behavior: the existence of two embedded cycles in the transition graph of the reduced models; the presence of a bypass in the orbit of the large amplitude oscillatory regime of low frequency. Based on this analysis, an experimental strategy is proposed to test the existence of birhythmicity in the p53-Mdm2 network. From a methodological point of view, this approach greatly facilitates the computational analysis of complex oscillatory behavior and could represent a valuable tool to explore mathematical models of biological rhythms showing sufficiently steep nonlinearities

Proportionality between variances in gene expression induced by noise and mutation: consequence of evolutionary robustness

<p>Abstract</p> <p>Background</p> <p>Characterization of robustness and plasticity of phenotypes is a basic issue in evolutionary and developmental biology. The robustness and plasticity are concerned with changeability of a biological system against external perturbations. The perturbations are either genetic, i.e., due to mutations in genes in the population, or epigenetic, i.e., due to noise during development or environmental variations. Thus, the variances of phenotypes due to genetic and epigenetic perturbations provide quantitative measures for such changeability during evolution and development, respectively.</p> <p>Results</p> <p>Using numerical models simulating the evolutionary changes in the gene regulation network required to achieve a particular expression pattern, we first confirmed that gene expression dynamics robust to mutation evolved in the presence of a sufficient level of transcriptional noise. Under such conditions, the two types of variances in the gene expression levels, i.e. those due to mutations to the gene regulation network and those due to noise in gene expression dynamics were found to be proportional over a number of genes. The fraction of such genes with a common proportionality coefficient increased with an increase in the robustness of the evolved network. This proportionality was generally confirmed, also under the presence of environmental fluctuations and sexual recombination in diploids, and was explained from an evolutionary robustness hypothesis, in which an evolved robust system suppresses the so-called error catastrophe - the destabilization of the single-peaked distribution in gene expression levels. Experimental evidences for the proportionality of the variances over genes are also discussed.</p> <p>Conclusions</p> <p>The proportionality between the genetic and epigenetic variances of phenotypes implies the correlation between the robustness (or plasticity) against genetic changes and against noise in development, and also suggests that phenotypic traits that are more variable epigenetically have a higher evolutionary potential.</p

Thermal comfort in urban spaces: a cross-cultural study in the hot arid climate

This cross-cultural research is an inaugural attempt to investigate the outdoor thermal comfort and the effect of cultural and social differences in hot arid climates. Case studies were carefully selected in two different parts of the world (Marrakech in North Africa and Phoenix, Arizona, in North America) to represent two different cultures in similar climatic context. Field surveys, carried out during winter and summer, included structured interviews with a standard questionnaire, observations and microclimatic monitoring. The results demonstrate a wide thermal comfort zone and prevalence of air-conditioning influencing thermal comfort requirements. The work also provides evidence of substantial cross-cultural differences in thermal comfort requirements between residents in Marrakech and Phoenix. It shows that adaptive measures, such as level of clothing, changing place, cold drinks consumption and thermal experience, varies between cultures and this influences the thermal evaluation of visitors in outdoor spaces in the hot arid climate. Evidence between the time spent in outdoor spaces and thermal expectations has been found. Moreover, environmental variables such as air temperature and solar radiation have a great impact on the use of the outdoor spaces in the hot arid climate and may determine the number of people in urban spaces. The study also identified significant differences in thermal comfort requirements between different socio-economic groups, highlighting the need for comfortable open spaces

A double-blind placebo-controlled trial of azithromycin to reduce mortality and improve growth in high-risk young children with non-bloody diarrhoea in low resource settings: the Antibiotics for Children with Diarrhoea (ABCD) trial protocol

Background Acute diarrhoea is a common cause of illness and death among children in low- to middle-income settings. World Health Organization guidelines for the clinical management of acute watery diarrhoea in children focus on oral rehydration, supplemental zinc and feeding advice. Routine use of antibiotics is not recommended except when diarrhoea is bloody or cholera is suspected. Young children who are undernourished or have a dehydrating diarrhoea are more susceptible to death at 90 days after onset of diarrhoea. Given the mortality risk associated with diarrhoea in children with malnutrition or dehydrating diarrhoea, expanding the use of antibiotics for this subset of children could be an important intervention to reduce diarrhoea-associated mortality and morbidity. We designed the Antibiotics for Childhood Diarrhoea (ABCD) trial to test this intervention. Methods ABCD is a double-blind, randomised trial recruiting 11,500 children aged 2–23 months presenting with acute non-bloody diarrhoea who are dehydrated and/or undernourished (i.e. have a high risk for mortality). Enrolled children in Bangladesh, India, Kenya, Malawi, Mali, Pakistan and Tanzania are randomised (1:1) to oral azithromycin 10 mg/kg or placebo once daily for 3 days and followed-up for 180 days. Primary efficacy endpoints are all-cause mortality during the 180 days post-enrolment and change in linear growth 90 days post-enrolment. Discussion Expanding the treatment of acute watery diarrhoea in high-risk children to include an antibiotic may offer an opportunity to reduce deaths. These benefits may result from direct antimicrobial effects on pathogens or other incompletely understood mechanisms including improved nutrition, alterations in immune responsiveness or improved enteric function. The expansion of indications for antibiotic use raises concerns about the emergence of antimicrobial resistance both within treated children and the communities in which they live. ABCD will monitor antimicrobial resistance. The ABCD trial has important policy implications. If the trial shows significant benefits of azithromycin use, this may provide evidence to support reconsideration of antibiotic indications in the present World Health Organization diarrhoea management guidelines. Conversely, if there is no evidence of benefit, these results will support the current avoidance of antibiotics except in dysentery or cholera, thereby avoiding inappropriate use of antibiotics and reaffirming the current guidelines. Trial registration Clinicaltrials.gov, NCT03130114. Registered on April 26 2017

A Specific and Rapid Neural Signature for Parental Instinct

Darwin originally pointed out that there is something about infants which prompts adults to respond to and care for them, in order to increase individual fitness, i.e. reproductive success, via increased survivorship of one's own offspring. Lorenz proposed that it is the specific structure of the infant face that serves to elicit these parental responses, but the biological basis for this remains elusive. Here, we investigated whether adults show specific brain responses to unfamiliar infant faces compared to adult faces, where the infant and adult faces had been carefully matched across the two groups for emotional valence and arousal, as well as size and luminosity. The faces also matched closely in terms of attractiveness. Using magnetoencephalography (MEG) in adults, we found that highly specific brain activity occurred within a seventh of a second in response to unfamiliar infant faces but not to adult faces. This activity occurred in the medial orbitofrontal cortex (mOFC), an area implicated in reward behaviour, suggesting for the first time a neural basis for this vital evolutionary process. We found a peak in activity first in mOFC and then in the right fusiform face area (FFA). In mOFC the first significant peak (p<0.001) in differences in power between infant and adult faces was found at around 130 ms in the 10–15 Hz band. These early differences were not found in the FFA. In contrast, differences in power were found later, at around 165 ms, in a different band (20–25 Hz) in the right FFA, suggesting a feedback effect from mOFC. These findings provide evidence in humans of a potential brain basis for the “innate releasing mechanisms” described by Lorenz for affection and nurturing of young infants. This has potentially important clinical applications in relation to postnatal depression, and could provide opportunities for early identification of families at risk

A Modified Experimental Hut Design for Studying Responses of Disease-Transmitting Mosquitoes to Indoor Interventions: The Ifakara Experimental Huts

Differences between individual human houses can confound results of studies aimed at evaluating indoor vector control interventions such as insecticide treated nets (ITNs) and indoor residual insecticide spraying (IRS). Specially designed and standardised experimental huts have historically provided a solution to this challenge, with an added advantage that they can be fitted with special interception traps to sample entering or exiting mosquitoes. However, many of these experimental hut designs have a number of limitations, for example: 1) inability to sample mosquitoes on all sides of huts, 2) increased likelihood of live mosquitoes flying out of the huts, leaving mainly dead ones, 3) difficulties of cleaning the huts when a new insecticide is to be tested, and 4) the generally small size of the experimental huts, which can misrepresent actual local house sizes or airflow dynamics in the local houses. Here, we describe a modified experimental hut design - The Ifakara Experimental Huts- and explain how these huts can be used to more realistically monitor behavioural and physiological responses of wild, free-flying disease-transmitting mosquitoes, including the African malaria vectors of the species complexes Anopheles gambiae and Anopheles funestus, to indoor vector control-technologies including ITNs and IRS. Important characteristics of the Ifakara experimental huts include: 1) interception traps fitted onto eave spaces and windows, 2) use of eave baffles (panels that direct mosquito movement) to control exit of live mosquitoes through the eave spaces, 3) use of replaceable wall panels and ceilings, which allow safe insecticide disposal and reuse of the huts to test different insecticides in successive periods, 4) the kit format of the huts allowing portability and 5) an improved suite of entomological procedures to maximise data quality

Genome-Scale Analysis of Translation Elongation with a Ribosome Flow Model

We describe the first large scale analysis of gene translation that is based on a model that takes into account the physical and dynamical nature of this process. The Ribosomal Flow Model (RFM) predicts fundamental features of the translation process, including translation rates, protein abundance levels, ribosomal densities and the relation between all these variables, better than alternative (‘non-physical’) approaches. In addition, we show that the RFM can be used for accurate inference of various other quantities including genes' initiation rates and translation costs. These quantities could not be inferred by previous predictors. We find that increasing the number of available ribosomes (or equivalently the initiation rate) increases the genomic translation rate and the mean ribosome density only up to a certain point, beyond which both saturate. Strikingly, assuming that the translation system is tuned to work at the pre-saturation point maximizes the predictive power of the model with respect to experimental data. This result suggests that in all organisms that were analyzed (from bacteria to Human), the global initiation rate is optimized to attain the pre-saturation point. The fact that similar results were not observed for heterologous genes indicates that this feature is under selection. Remarkably, the gap between the performance of the RFM and alternative predictors is strikingly large in the case of heterologous genes, testifying to the model's promising biotechnological value in predicting the abundance of heterologous proteins before expressing them in the desired host