Do protein motifs read the histone code?

The existence of different patterns of chemical modifications (acetylation, methylation, phosphorylation, ubiquitination and ADP-ribosylation) of the histone tails led, some years ago, to the histone code hypothesis. According to this hypothesis, these modifications would provide binding sites for proteins that can change the chromatin state to either active or repressed. Interestingly, some protein domains present in histone-modifying enzymes are known to interact with these covalent marks in the histone tails. This was first shown for the bromodomain, which was found to interact selectively with acetylated lysines at the histone tails. More recently, it has been described that the chromodomain can be targeted to methylation marks in histone N-terminal domains. Finally, the interaction between the SANT domain and histones is also well documented. Overall, experimental evidence suggests that these domains could be involved in the recruitment of histone-modifying enzymes to discrete chromosomal locations, and/or in the regulation their enzymatic activity. Within this context, we review the distribution of bromodomains, chromodomains and SANT domains among chromatin-modifying enzymes and discuss how they can contribute to the translation of the histone code.     

Evolutionary physiology at 30+: Has the promise been fulfilled?

Three decades ago, interactions between evolutionary biology and physiology gave rise to evolutionary physiology. This caused comparative physiologists to improve their research methods by incorporating evolutionary thinking. Simultaneously, evolutionary biologists began focusing more on physiological mechanisms that may help to explain constraints on and trade-offs during microevolutionary processes, as well as macroevolutionary patterns in physiological diversity. Here we argue that evolutionary physiology has yet to reach its full potential, and propose new avenues that may lead to unexpected advances. Viewing physiological adaptations in wild animals as potential solutions to human diseases offers enormous possibilities for biomedicine. New evidence of epigenetic modifications as mechanisms of phenotypic plasticity that regulate physiological traits may also arise in coming years, which may also represent an overlooked enhancer of adaptation via natural selection to explain physiological evolution. Synergistic interactions at these intersections and other areas will lead to a novel understanding of organismal biology.     

Manipulating the genetic code for membrane protein production: What have we learnt so far?

With synthetic gene services, molecular cloning is as easy as ordering a pizza. However choosing the right RNA code for efficient protein production is less straightforward, more akin to deciding on the pizza toppings. The possibility to choose synonymous codons in the gene sequence has ignited a discussion that dates back 50years: Does synonymous codon use matter? Recent studies indicate that replacement of particular codons for synonymous codons can improve expression in homologous or heterologous hosts, however it is not always successful. Furthermore it is increasingly apparent that membrane protein biogenesis can be codon-sensitive. Single synonymous codon substitutions can influence mRNA stability, mRNA structure, translational initiation, translational elongation and even protein folding. Synonymous codon substitutions therefore need to be carefully evaluated when membrane proteins are engineered for higher production levels and further studies are needed to fully understand how to select the codons that are optimal for higher production. This article is part of a Special Issue entitled: Protein Folding in Membranes.     

Hope for a broken heart?

Heart failure affects 23 million people worldwide and results from cardiac dysfunction characterized by decreased responsiveness to beta-adrenergic stimulation. A recent publication by W.J. Koch and colleagues highlights evidence for targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer to improve contractile function and beta-adrenergic responsiveness in failing human myocardium. This proof-of-concept study has great importance for future heart failure therapy because it provides evidence for the therapeutic effectiveness of betaARK1 inhibition in failing human myocardium.     

Hope for a broken heart?

Heated debate has surrounded the issue of whether adult stem cells can differentiate into cardiac myocytes and contribute to the function of the heart. In this issue of Cell, demonstrate stem cells in the adult rat heart that differentiate into cardiac myocytes in vitro and, when injected into the adult rat heart, can reconstitute the injured myocardium and improve function. These findings should weigh heavily in future debates about the existence of stem cells in the adult heart and their capacity for functional repair after injury.     

Has the mist been peered through? Revisiting the building blocks of human health risk assessment for electronic cigarette use

Electronic cigarettes, battery-powered nicotine delivery devices, have been increasingly used in the past decade. This critical review provides a qualitative research synthesis of the human health risks associated with E-vapor inhalation in the peer-reviewed literature and our own preliminary experimental results. E-cigarettes may be as efficient as traditional cigarettes in nicotine delivery, especially for experienced users, and studies suggest lower emissions of air toxics from E-cigarette vapor and lower second- and third-hand vapor exposures. Some toxic emissions may however surpass those of traditional cigarettes, especially under high voltage vaping conditions. Experimentally, E-vapor/E-liquid exposures reduce cell viability and promote pro-inflammatory cytokine release. User vulnerability to concomitant environmental agent exposures, such as viruses and bacteria, may potentially be increased. While evidence to date suggests that E-cigarettes release fewer toxins and carcinogens compared to cigarettes, E-vapor is not safe and might adversely affect human immune functions. Major knowledge gaps hinder risk quantification and effective regulation of E-cigarette products including: lack of long-term exposure studies, lack of understanding of biological mechanisms associated with exposure, and lack of integration of exposure and toxicity assessments. Better data are needed to inform human health risk assessments and understand the public health impact of E-vapor exposures.     

Has the "Equal Environments" assumption been tested in twin studies?

A recurring criticism of the twin method for quantifying genetic and environmental components of human differences is the necessity of the so-called "equal environments assumption" (EEA) (i.e., that monozygotic and dizygotic twins experience equally correlated environments). It has been proposed to test the EEA by stratifying twin correlations by indices of the amount of shared environment. However, relevant environments may also be influenced by genetic differences. We present a model for the role of genetic factors in niche selection by twins that may account for variation in indices of the shared twin environment (e.g., contact between members of twin pairs). Simulations reveal that stratification of twin correlations by amount of contact can yield spurious evidence of large shared environmental effects in some strata and even give false indications of genotype x environment interaction. The stratification approach to testing the equal environments assumption may be misleading and the results of such tests may actually be consistent with a simpler theory of the role of genetic factors in niche selection.     

Does the 'non-coding' strand code?

The hypothesis that DNA strands complementary to the coding strand contain in phase coding sequences has been investigated. Statistical analysis of the 50 genes of bacteriophage T7 shows no significant correlation between patterns of codon usage on the coding and non-coding strands. In Bacillus and yeast genes the correlation observed is not different from that expected with random synonymous codon usage, while a high correlation seen in 52 E. coli genes can be explained in terms of an excess of RNY codons. A deficiency of UUA, CUA and UCA codons (complementary to termination) seems to be restricted to the E. coli genes, and may be due to low abundance of the relevant cognate tRNA species. Thus the analysis shows that the non-coding strand has the properties expected of a sequence complementary to a coding strand, with no indications that it encodes, or may have encoded, proteins.     

Has the inbreeding load for a condition‐dependent sexual signalling trait been purged in insular lizard populations?

Sexually selected traits are often condition‐dependent and are expected to be affected by genome‐wide distributed deleterious mutations and inbreeding. However, sexual selection is a powerful selective force that can counteract inbreeding through purging of deleterious mutations. Inbreeding and purging of the inbreeding load for sexually selected traits has rarely been studied across natural populations with different degrees of inbreeding. Here we investigate inbreeding effects (measured as marker‐based heterozygosity) on condition‐dependent sexually selected signalling trait and other morphological traits across islet‐ and mainland populations (n = 15) of an endemic lizard species (Podarcis gaigeae). Our data suggest inbreeding depression on a condition‐dependent sexually selected signalling character among mainland subpopulations with low or intermediate levels of inbreeding, but no sign of inbreeding depression among small and isolated islet populations despite their higher overall inbreeding levels. In contrast, there was no such pattern among ten other morphological traits which are primarily naturally selected and presumably not involved in sexual signalling. These results are in line with purging of recessive deleterious alleles, or purging in combination with stochastic fixation of alleles by genetic drift, for a sexual signalling character in the islet environment, which is characterized by low population sizes and strong sexual selection. Higher clutch sizes in islet populations also raise interesting questions regarding the possibility of antagonistic pleiotropy. Purging and other non‐exclusive explanations of our results are discussed.     

Has the kouprey (Bos sauveli Urbain, 1937) been domesticated in Cambodia?

The kouprey (Bos sauveli Urbain, 1937) is a very rare bovid species of Cambodia, which may be extinct in the wild, as no living specimen has been observed for a long time. Here, we describe a complete taxidermy mount, which presents astonishing morphological similarities with the kouprey. The animal was mounted in 1871 at the National Museum of Natural History in Paris, where it was referenced as No. 1871-576. It was deposited at the Natural History Museum of Bourges, France, in 1931, where it is still conserved today. To clarify the taxonomic status of the specimen of Bourges, DNA was extracted from a piece of bone taken on the mandible, and two different fragments of the mitochondrial cytochrome b gene were independently amplified and sequenced. The phylogenetic analyses show that the specimen of Bourges is robustly associated with the holotype of the kouprey, and that both are related to other wild species of Bos found in Indochina, i.e., banteng (B. javanicus) and gaur (B. frontalis). Because of doubts for sexing the animal, we applied a molecular test based on the PCR amplification of a DNA fragment specific to the Y chromosome. The results indicate that the specimen of Bourges is a male. The comparisons with male kouprey previously described in the literature reveal important differences concerning the body size, general coloration and horns. As these differences involve phenotypic traits that are strongly selected in case of domestication, we suggest that the specimen of Bourges was a domestic ox. This implies therefore that the kouprey may have been domesticated in Cambodia, and that several extant local races may be directly related to the kouprey.     

Has vertebrate chemesthesis been a selective agent in the evolution of arthropod chemical defenses?

Arthropods use a variety of chemical substances to repel potential predators, but how did they arrive at the suite of chemicals that they use? One way to explore this question is to map chemically defended arthropod species in a multidimensional "compound" space. Clustering within this space indicates species that share similar combinations of chemical compounds and can reflect a phylogenetic signal, common biochemical pathways, or both. More important for this study, clustering can help to identify allomone targets. We herein compare common arthropod allomones with known vertebrate trigeminal irritants. We argue that the degree of overlap between these two groups of compounds indicates that chemesthesis was an important determining factor in the evolution of many arthropod allomones. The multidimensional scaling methods used may also allow the identification of new irritant receptors.     

What are the baselines for protein fold recognition?

MOTIVATION: What constitutes a baseline level of success for protein fold recognition methods? As fold recognition benchmarks are often presented without any thought to the results that might be expected from a purely random set of predictions, an analysis of fold recognition baselines is long overdue. Given varying amounts of basic information about a protein-ranging from the length of the sequence to a knowledge of its secondary structure-to what extent can the fold be determined by intelligent guesswork? Can simple methods that make use of secondary structure information assign folds more accurately than purely random methods and could these methods be used to construct viable hierarchical classifications? EXPERIMENTS PERFORMED: A number of rapid automatic methods which score similarities between protein domains were devised and tested. These methods ranged from those that incorporated no secondary structure information, such as measuring absolute differences in sequence lengths, to more complex alignments of secondary structure elements. Each method was assessed for accuracy by comparison with the Class Architecture Topology Homology (CATH) classification. Methods were rated against both a random baseline fold assignment method as a lower control and FSSP as an upper control. Similarity trees were constructed in order to evaluate the accuracy of optimum methods at producing a classification of structure. RESULTS: Using a rigorous comparison of methods with CATH, the random fold assignment method set a lower baseline of 11% true positives allowing for 3% false positives and FSSP set an upper benchmark of 47% true positives at 3% false positives. The optimum secondary structure alignment method used here achieved 27% true positives at 3% false positives. Using a less rigorous Critical Assessment of Structure Prediction (CASP)-like sensitivity measurement the random assignment achieved 6%, FSSP-59% and the optimum secondary structure alignment method-32%. Similarity trees produced by the optimum method illustrate that these methods cannot be used alone to produce a viable protein structural classification system. CONCLUSIONS: Simple methods that use perfect secondary structure information to assign folds cannot produce an accurate protein taxonomy, however they do provide useful baselines for fold recognition. In terms of a typical CASP assessment our results suggest that approximately 6% of targets with folds in the databases could be assigned correctly by randomly guessing, and as many as 32% could be recognised by trivial secondary structure comparison methods, given knowledge of their correct secondary structures.     

Why the move to microfluidics for protein analysis?

There has been a recent trend towards the miniaturization of analytical tools, but what are the advantages of microfluidic devices and when is their use appropriate? Recent advances in the field of micro-analytical systems can be classified according to instrument performance (which refers here to the desired property of the analytical tool of interest) and two important features specifically related to miniaturisation, namely reduction of the sample volume and the time-to-result. Here we discuss the contribution of these different parameters and aim to highlight the factors of choice in the development and use of microfluidic devices dedicated to protein analysis.