Genetic Architecture Promotes the Evolution and Maintenance of Cooperation

When cooperation has a direct cost and an indirect benefit, a selfish behavior is more likely to be selected for than an altruistic one. Kin and group selection do provide evolutionary explanations for the stability of cooperation in nature, but we still lack the full understanding of the genomic mechanisms that can prevent cheater invasion. In our study we used Aevol, an agent-based, in silico genomic platform to evolve populations of digital organisms that compete, reproduce, and cooperate by secreting a public good for tens of thousands of generations. We found that cooperating individuals may share a phenotype, defined as the amount of public good produced, but have very different abilities to resist cheater invasion. To understand the underlying genetic differences between cooperator types, we performed bio-inspired genomics analyses of our digital organisms by recording and comparing the locations of metabolic and secretion genes, as well as the relevant promoters and terminators. Association between metabolic and secretion genes (promoter sharing, overlap via frame shift or sense-antisense encoding) was characteristic for populations with robust cooperation and was more likely to evolve when secretion was costly. In mutational analysis experiments, we demonstrated the potential evolutionary consequences of the genetic association by performing a large number of mutations and measuring their phenotypic and fitness effects. The non-cooperating mutants arising from the individuals with genetic association were more likely to have metabolic deleterious mutations that eventually lead to selection eliminating such mutants from the population due to the accompanying fitness decrease. Effectively, cooperation evolved to be protected and robust to mutations through entangled genetic architecture. Our results confirm the importance of second-order selection on evolutionary outcomes, uncover an important genetic mechanism for the evolution and maintenance of cooperation, and suggest promising methods for preventing gene loss in synthetically engineered organisms.     

Alpha-lipoic acid affects the oxidative stress in various brain structures in mice with methionine and choline deficiency

Deficiency in methionine or choline can induce oxidative stress in various organs such as liver, kidney, heart, and brain. This study was to examine the effects of alpha-lipoic acid (LA) on oxidative stress induced by methionine and choline deficiency (MCD) in several brain structures. Male mice C57BL/6 (n = 28) were divided into four groups: (1) control – continuously fed with standard chow; (2) LA – fed with standard chow and receiving LA; (3) MCD2 – fed with MCD diet for two weeks, and (4) MCD2+LA – fed with MCD diet for two weeks and receiving LA (100 mg/kg/day intraperitonealy [i.p.]). Brain tissue (cortex, hypothalamus, striatum and hippocampus) was taken for determination of oxidative stress parameters. MCD diet induced a significant increase in malondialdehyde and NOx concentration in all brain regions, while LA restored their content to normal values. Similar to this, in MCD2 group, activity of total SOD, MnSOD, and Cu/ZnSOD was reduced by MCD diet, while LA treatment improved their activities in all brain structures. Besides, in MCD2 group a decrease in catalase activity in cortex and GSH content in hypothalamus was evident, while LA treatment induced an increase in catalase activity in cortex and striatum and GSH content in hypothalamus. LA treatment can significantly reduce lipid peroxidation and nitrosative stress, caused by MCD diet, in all brain regions by restoring antioxidant enzymes activities, predominantly total SOD, MnSOD, and Cu/ZnSOD, and to a lesser extent by modulating catalase activity and GSH content. LA supplementation may be used in order to prevent brain oxidative injury induced by methionine and choline deficiency.     

Predicting urban outdoor thermal comfort by the Universal Thermal Climate Index UTCI—a case study in Southern Brazil

Recognising that modifications to the physical attributes of urban space are able to promote improved thermal outdoor conditions and thus positively influence the use of open spaces, a survey to define optimal thermal comfort ranges for passers-by in pedestrian streets was conducted in Curitiba, Brazil. We applied general additive models to study the impact of temperature, humidity, and wind, as well as long-wave and short-wave radiant heat fluxes as summarised by the recently developed Universal Thermal Climate Index (UTCI) on the choice of clothing insulation by fitting LOESS smoothers to observations from 944 males and 710 females aged from 13 to 91 years. We further analysed votes of thermal sensation compared to predictions of UTCI. The results showed that females chose less insulating clothing in warm conditions compared to males and that observed values of clothing insulation depended on temperature, but also on season and potentially on solar radiation. The overall pattern of clothing choice was well reflected by UTCI, which also provided for good predictions of thermal sensation votes depending on the meteorological conditions. Analysing subgroups indicated that the goodness-of-fit of the UTCI was independent of gender and age, and with only limited influence of season and body composition as assessed by body mass index. This suggests that UTCI can serve as a suitable planning tool for urban thermal comfort in sub-tropical regions.     

Deriving the operational procedure for the Universal Thermal Climate Index (UTCI)

The Universal Thermal Climate Index (UTCI) aimed for a one-dimensional quantity adequately reflecting the human physiological reaction to the multi-dimensionally defined actual outdoor thermal environment. The human reaction was simulated by the UTCI-Fiala multi-node model of human thermoregulation, which was integrated with an adaptive clothing model. Following the concept of an equivalent temperature, UTCI for a given combination of wind speed, radiation, humidity and air temperature was defined as the air temperature of the reference environment, which according to the model produces an equivalent dynamic physiological response. Operationalising this concept involved (1) the definition of a reference environment with 50% relative humidity (but vapour pressure capped at 20 hPa), with calm air and radiant temperature equalling air temperature and (2) the development of a one-dimensional representation of the multivariate model output at different exposure times. The latter was achieved by principal component analyses showing that the linear combination of 7 parameters of thermophysiological strain (core, mean and facial skin temperatures, sweat production, skin wettedness, skin blood flow, shivering) after 30 and 120 min exposure time accounted for two-thirds of the total variation in the multi-dimensional dynamic physiological response. The operational procedure was completed by a scale categorising UTCI equivalent temperature values in terms of thermal stress, and by providing simplified routines for fast but sufficiently accurate calculation, which included look-up tables of pre-calculated UTCI values for a grid of all relevant combinations of climate parameters and polynomial regression equations predicting UTCI over the same grid. The analyses of the sensitivity of UTCI to humidity, radiation and wind speed showed plausible reactions in the heat as well as in the cold, and indicate that UTCI may in this regard be universally useable in the major areas of research and application in human biometeorology.     

Characterization of the bifunctional aminoglycoside-modifying enzyme ANT(3')-Ii/AAC(6')-IId from Serratia marcescens

A newly discovered bifunctional antibiotic resistance enzyme from Serratia marcescens catalyzes adenylation and acetylation of aminoglycoside antibiotics. The structure assignment of the enzymic products indicated that acetylation takes place on the 6'-amine of kanamycin A and the adenylation on 3'- and 9-hydroxyl groups of streptomycin and spectinomycin, respectively. The adenyltransferase domain appears to be highly specific to spectinomycin and streptomycin, while the acetyltransferase domain shows a broad substrate profile. Initial velocity patterns indicate that both domains follow a sequential kinetic mechanism. The use of dead-end and product inhibition, the solvent isotope effect, and the solvent viscosity effect reveals that the adenyltransferase domain catalyzes the reaction by a Theorell-Chance kinetic mechanism, where ATP binds to the enzyme prior to the aminoglycoside and the modified antibiotic is the last product to be released. The acetyltransferase domain follows an ordered bi-bi kinetic mechanism, in which the antibiotic is the first substrate that binds to the active site and CoASH is released prior to the modified aminoglycoside. The merging of two genes to create bifunctional resistance enzymes with expanded profiles has now been documented in four instances, including the subject of study in this report, which suggests a new trend in the emergence of resistance to aminoglycoside antibiotics among pathogens.     

Polyglutamine repeats and β‐helix structure: Molecular dynamics study

Neurodegenerative diseases are often associated with the formation of highly insoluble aggregates. Despite the efforts devoted to the characterization of these aggregates, their structure remains elusive. Several neurodegenerative diseases are characterized by the expansion of CAG repeats, which code for Gln. Among the structural models proposed for the aggregates observed in polyQ-linked diseases, the nanotube beta-helix model proposed by Perutz and colleagues Proc Natl Acad Sci U S A 2002;99:5591-5595 has been influential. In the present study, the stability of this beta-helix model has been investigated by performing molecular dynamics simulations on polyQ fragments of different lengths. The results indicate that models shorter than two full beta-helix turns are unstable and collapse toward irregular structures. On the other hand, longer beta-helix models, containing more than 40 residues, achieve a dynamic regular structure. This finding is in line with the observed threshold of Gln repeats (approximately 40) correlated with the insurgence of the disease. Notably, the structure of the final state of the models longer than 40 residues strictly depends on their size. A compact stable ellipsoidal structure is formed by the model made of two full helical turns (41 residues), whereas water filled tubular structures emerge from simulation on longer polypeptides. These results have been interpreted taking into account the experimental data on polyQ aggregates. A structural interpretation of the literature data has been proposed by assuming that different beta-helical models are involved in the different stages of the aggregation process.     

Sexual reproduction reshapes the genetic architecture of digital organisms

Modularity and epistasis, as well as other aspects of genetic architecture, have emerged as central themes in evolutionary biology. Theory suggests that modularity promotes evolvability, and that aggravating (synergistic) epistasis among deleterious mutations facilitates the evolution of sex. Here, by contrast, we investigate the evolution of different genetic architectures using digital organisms, which are computer programs that self-replicate, mutate, compete and evolve. Specifically, we investigate how genetic architecture is shaped by reproductive mode. We allowed 200 populations of digital organisms to evolve for over 10 000 generations while reproducing either asexually or sexually. For 10 randomly chosen organisms from each population, we constructed and analysed all possible single mutants as well as one million mutants at each mutational distance from 2 to 10. The genomes of sexual organisms were more modular than asexual ones; sites encoding different functional traits had less overlap and sites encoding a particular trait were more tightly clustered. Net directional epistasis was alleviating (antagonistic) in both groups, although the overall strength of this epistasis was weaker in sexual than in asexual organisms. Our results show that sexual reproduction profoundly influences the evolution of the genetic architecture.     

The mechanism of amyloid-fibril formation by stefin B: temperature and protein concentration dependence of the rates

Cystatins, a family of structurally related cysteine proteinase inhibitors, have proved to be useful model system to study amyloidogenesis. We have extended previous studies of the kinetics of amyloid-fibril formation by human stefin B (cystatin B) and some of its mutants, and proposed an improved model for the reaction. Overall, the observed kinetics follow the nucleation and growth behavior observed for many other amyloidogenic proteins. The minimal kinetic scheme that best fits measurements of changes in CD and thioflavin T fluorescence as a function of protein concentration and temperature includes nucleation (modeled as N(I) irreversible transitions with equivalent rates (k(I)), which fitted with N(I) = 64), fibril growth and nonproductive oligomerization, best explained by an off-pathway state with a rate-limiting escape rate. Three energies of activation were derived from global fitting to the minimal kinetic scheme, and independently through the fitting of the individual component rates. Nucleation was found to be a first-order process within an oligomeric species with an enthalpy of activation of 55 +/- 4 kcal mol(-1). Fibril growth was a second-order process with an enthalpy of activation (27 +/- 5 kcal mol(-1)), which is indistinguishable from that of tetramer formation by cystatins, which involves limited conformational changes including proline trans to cis isomerization. The highest enthalpy of activation (95 +/- 5 kcal mol(-1) at 35 degrees C), characteristic of a substantial degree of unfolding as observed prior to domain-swapping reactions, equated with the escape rate of the off-pathway oligomeric state.