Pinpointing dynamic coupling in enzymes for efficient drug design

Enzymes are proteins that catalyze almost every chemical reaction in living systems, achieving rate enhancements of up to 21 orders of magnitude relative to the uncatalyzed reactions. However, despite a century of intense investigation, the biophysical basis of the enormous catalytic power of enzymes is not completely understood. Enzymes are not only central to living systems, but also to many industrial processes such as the production of food, textiles, detergents, pharmaceuticals and other chemicals where environmentally friendly, green methods are of ever increasing importance. Because of their central role for life, enzymes are key drug targets and enzyme inhibition is a central strategy in the design of new drugs. Acetylsalicylic acid, azidothymidine, acyclovir, allopurinol, chloramphenicol, exemestane, fosfomycin, isoniazid, methotrexate, profens, proguanil, statins, thiouracil and warfarin are but a small subset of approved drug substances that are used in the clinic to treat, among others, pain, fever, inflammation, malaria, cancer, HIV, bacterial and viral infections, rheumatoid arthritis, osteoarthritis and heart disease, through the inhibition of key enzymes

Extinction, Persistence, and Evolution

Extinction can occur for many reasons. We have a closer look at the most basic form, extinction of populations with stable but insufficient reproduction. Then we move on to competing populations and evolutionary suicide

Exploring local immunological adaptation of two stickleback ecotypes by experimental infection and transcriptome-wide digital gene expression analysis

Understanding the extent of local adaptation in natural populations and the mechanisms that allow individuals to adapt to their native environment is a major avenue in molecular ecology research. Evidence for the frequent occurrence of diverging ecotypes in species that inhabit multiple ecological habitats is accumulating, but experimental approaches to understanding the biological pathways as well as the underlying genetic mechanisms are still rare. Parasites are invoked as one of the major selective forces driving evolution and are themselves dependent on the ecological conditions in a given habitat. Immunological adaptation to local parasite communities is therefore expected to be a key component of local adaptation in natural populations. Here, we use next-generation sequencing technology to compare the transcriptome-wide response of experimentally infected three-spined sticklebacks from a lake and a river population, which are known to evolve under selection by distinct parasite communities. By comparing overall gene expression levels as well as the activation of functional pathways in response to parasite exposure, we identified potential differences between the two stickleback populations at several levels. Our results suggest locally adapted patterns of gene regulation in response to parasite exposure, which may reflect different local optima in the trade-off between the benefits and the disadvantages of mounting an immune response because of quantitative differences of the local parasite communities

Evolution of surname distribution under gender-equality measurements

We consider a model for the evolution of the surnames distribution under a gender-equality measurement presently discussed in the Spanish parliament (the children take the surname of the father or the mother according to alphabetical order). We quantify how this would bias the alphabetical distribution of surnames, and analyze its effect on the present distribution of the surnames in Spain

Reconstructing pedigrees: some identifiability questions for a recombination-mutation model

Pedigrees are directed acyclic graphs that represent ancestral relationships between individuals in a population. Based on a schematic recombination process, we describe two simple Markov models for sequences evolving on pedigrees - Model R (recombinations without mutations) and Model RM (recombinations with mutations). For these models, we ask an identifiability question: is it possible to construct a pedigree from the joint probability distribution of extant sequences? We present partial identifiability results for general pedigrees: we show that when the crossover probabilities are sufficiently small, certain spanning subgraph sequences can be counted from the joint distribution of extant sequences. We demonstrate how pedigrees that earlier seemed difficult to distinguish are distinguished by counting their spanning subgraph sequences.Comment: 40 pages, 9 figure

Parasite avoidance behaviours in aquatic environments

Parasites, including macroparasites, protists, fungi, bacteria and viruses, can impose a heavy burden upon host animals. However, hosts are not without defences. One aspect of host defence, behavioural avoidance, has been studied in the terrestrial realm for over 50 years, but was first reported from the aquatic environment approximately 20 years ago. Evidence has mounted on the importance of parasite avoidance behaviours and it is increasingly apparent that there are core similarities in the function and benefit of this defence mechanism between terrestrial and aquatic systems. However, there are also stark differences driven by the unique biotic and abiotic characteristics of terrestrial and aquatic (marine and freshwater) environments. Here, we review avoidance behaviours in a comparative framework and highlight the characteristics of each environment that drive differences in the suite of mechanisms and cues that animals use to avoid parasites. We then explore trade-offs, potential negative effects of avoidance behaviour and the influence of human activities on avoidance behaviours. We conclude that avoidance behaviours are understudied in aquatic environments but can have significant implications for disease ecology and epidemiology, especially considering the accelerating emergence and re-emergence of parasites.peerReviewe

Estimation of a probability in inverse binomial sampling under normalized linear-linear and inverse-linear loss

Sequential estimation of the success probability $p$ in inverse binomial sampling is considered in this paper. For any estimator $\hat p$, its quality is measured by the risk associated with normalized loss functions of linear-linear or inverse-linear form. These functions are possibly asymmetric, with arbitrary slope parameters $a$ and $b$ for $\hat pp$ respectively. Interest in these functions is motivated by their significance and potential uses, which are briefly discussed. Estimators are given for which the risk has an asymptotic value as $p$ tends to $0$, and which guarantee that, for any $p$ in $(0,1)$, the risk is lower than its asymptotic value. This allows selecting the required number of successes, $r$, to meet a prescribed quality irrespective of the unknown $p$. In addition, the proposed estimators are shown to be approximately minimax when $a/b$ does not deviate too much from $1$, and asymptotically minimax as $r$ tends to infinity when $a=b$.Comment: 4 figure

A QTL on chromosome 3q23 influences processing speed in humans

Processing speed is a psychological construct that refers to the speed with which an individual can perform any cognitive operation. Processing speed correlates strongly with general cognitive ability, declines sharply with age, and is impaired across a number of neurological and psychiatric disorders. Thus, identifying genes that influence processing speed will likely improve understanding of the genetics of intelligence, biological aging, and the etiologies of numerous disorders. Previous genetics studies of processing speed have relied on simple phenotypes (e.g., mean reaction time) derived from single tasks. This strategy assumes, erroneously, that processing speed is a unitary construct. In the present study, we aimed to characterize the genetic architecture of processing speed by using a multi-dimensional model applied to a battery of cognitive tasks. Linkage and QTL-specific association analyses were performed on the factors from this model. The randomly ascertained sample comprised 1291 Mexican-American individuals from extended pedigrees. We found that performance on all three distinct processing-speed factors (Psychomotor Speed; Sequencing and Shifting and Verbal Fluency) were moderately and significantly heritable. We identified a genome-wide significant QTL on chromosome 3q23 for Psychomotor Speed (LOD = 4.83). Within this locus, we identified a plausible and interesting candidate gene for Psychomotor Speed (Z = 2.90, p = 1.86×10−03)