Correlates of substitution rate variation in mammalian protein-coding sequences

<p>Abstract</p> <p>Background</p> <p>Rates of molecular evolution in different lineages can vary widely, and some of this variation might be predictable from aspects of species' biology. Investigating such predictable rate variation can help us to understand the causes of molecular evolution, and could also help to improve molecular dating methods. Here we present a comprehensive study of the life history correlates of substitution rate variation across the mammals, comparing results for mitochondrial and nuclear loci, and for synonymous and non-synonymous sites. We use phylogenetic comparative methods, refined to take into account the special nature of substitution rate data. Particular attention is paid to the widespread correlations between the components of mammalian life history, which can complicate the interpretation of results.</p> <p>Results</p> <p>We find that mitochondrial synonymous substitution rates, estimated from the 9 longest mitochondrial genes, show strong negative correlations with body mass and with maximum recorded lifespan. But lifespan is the sole variable to remain after multiple regression and model simplification. Nuclear synonymous substitution rates, estimated from 6 genes, show strong negative correlations with body mass and generation time, and a strong positive correlation with fecundity. In contrast to the mitochondrial results, the same trends are evident in rates of nonsynonymous substitution.</p> <p>Conclusion</p> <p>A substantial proportion of variation in mammalian substitution rates can be explained by aspects of their life history, implying that molecular and life history evolution are closely interlinked in this group. The strength and consistency of the nuclear body mass effect suggests that molecular dating studies may have been systematically misled, but also that methods could be improved by incorporating the finding as <it>a priori </it>information. Mitochondrial synonymous rates also show the body mass effect, but for apparently quite different reasons, and the strength of the relationship with maximum lifespan provides support for the hypothesis that mtDNA damage is causally linked to aging.</p

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

Peer reviewedPublisher PD

Diabetes MILES – The Netherlands: rationale, design and sample characteristics of a national survey examining the psychosocial aspects of living with diabetes in Dutch adults

Background : As the number of people with diabetes is increasing rapidly worldwide, a more thorough understanding of the psychosocial aspects of living with this condition has become an important health care priority. While our knowledge has grown substantially over the past two decades with respect to the physical, emotional and social difficulties that people with diabetes may encounter, many important issues remain to be elucidated. Under the umbrella of the Diabetes MILES (Management and Impact for Long-term Empowerment and Success) Study International Collaborative, Diabetes MILES &ndash; The Netherlands aims to examine how Dutch adults with diabetes manage their condition and how it affects their lives. Topics of special interest in Diabetes MILES - The Netherlands include subtypes of depression, Type D personality, mindfulness, sleep and sexual functioning. Methods/design : Diabetes MILES &ndash; The Netherlands was designed as a national online observational study among adults with diabetes. In addition to a main set of self-report measures, the survey consisted of five complementary modules to which participants were allocated randomly. From September to October 2011, a total of 3,960 individuals with diabetes (40% type 1, 53% type 2) completed the battery of questionnaires covering a broad range of topics, including general health, self-management, emotional well-being and contact with health care providers. People with self-reported type 1 diabetes (specifically those on insulin pump therapy) were over-represented, as were those using insulin among respondents with self-reported type 2 diabetes. People from ethnic minorities were under-represented. The sex distribution was fairly equal in the total sample, participants spanned a broad age range (19&ndash;90 years), and diabetes duration ranged from recent diagnosis to living with the condition for over fifty years. Discussion : The Diabetes MILES Study enables detailed investigation of the psychosocial aspects of living with diabetes and an opportunity to put these findings in an international context. With several papers planned resulting from a pooled Australian-Dutch dataset and data collections planned in other countries, the Diabetes MILES Study International Collaborative will contribute substantially to identifying potentially unmet needs of those living with diabetes and to inform clinical research and care across the globe. <br /

Internalisation Theory and outward direct investment by emerging market multinationals

The rise of multinational enterprises from emerging countries (EMNEs) poses an important test for theories of the multinational enterprise such as internalisation theory. It has been contended that new phenomena need new theory. This paper proposes that internalisation theory is appropriate to analyse EMNEs. This paper examines four approaches to EMNEs—international investment strategies, domestic market imperfections, international corporate networks and domestic institutions—and three case studies—Chinese outward FDI, Indian foreign acquisitions and investment in tax havens—to show the enduring relevance and predictive power of internalisation theory. This analysis encompasses many other approaches as special cases of internalisation theory. The use of internalisation theory to analyse EMNEs is to be commended, not only because of its theoretical inclusivity, but also because it has the ability to connect and to explain seemingly desperate phenomena

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Building International Business Theory: A Grounded Theory Approach

The field of international business (IB) is in need of more theory development (Morck & Yeung, 2007). As such, the main focus of our manuscript was to provide guidance on how to build IB specific theory using grounded theory (GT). Moreover, we contribute to future theory development by identifying areas within IB where GT can be applied and the type of research issues that can be addressed using this methodology. Finally, we make a noteworthy contribution by discussing some of GT’s caveats and limitations, particularly those relevant to IB. This effort is intended to spur further interest in the development of IB theory

Mathematical modelling of clostridial acetone-butanol-ethanol fermentation

Clostridial acetone-butanol-ethanol (ABE) fermentation features a remarkable shift in the cellular metabolic activity from acid formation, acidogenesis, to the production of industrial-relevant solvents, solventogensis. In recent decades, mathematical models have been employed to elucidate the complex interlinked regulation and conditions that determine these two distinct metabolic states and govern the transition between them. In this review, we discuss these models with a focus on the mechanisms controlling intra- and extracellular changes between acidogenesis and solventogenesis. In particular, we critically evaluate underlying model assumptions and predictions in the light of current experimental knowledge. Towards this end, we briefly introduce key ideas and assumptions applied in the discussed modelling approaches, but waive a comprehensive mathematical presentation. We distinguish between structural and dynamical models, which will be discussed in their chronological order to illustrate how new biological information facilitates the ‘evolution’ of mathematical models. Mathematical models and their analysis have significantly contributed to our knowledge of ABE fermentation and the underlying regulatory network which spans all levels of biological organization. However, the ties between the different levels of cellular regulation are not well understood. Furthermore, contradictory experimental and theoretical results challenge our current notion of ABE metabolic network structure. Thus, clostridial ABE fermentation still poses theoretical as well as experimental challenges which are best approached in close collaboration between modellers and experimentalists