[Cell therapy in muscular disorders: the future lies in comparisons of progenitors]. / Thérapie cellulaire des maladies musculaires - Un avenir à l'aune d'une comparaison des progéniteurs.

Cell therapy approaches dedicated to the treatment of dystrophinopathies and involving essentially myoblasts and mesoangioblasts have produced mitigated clinical results. If several types of alternative progenitors have been developed, no standardized comparison has been carried out yet to investigate their regenerative efficacy in vivo, at least at a local level. A comparative study has therefore been designed recently aiming at giving a new impetus to this therapeutic field.

TITLE: Thérapie cellulaire des maladies musculaires - Un avenir à l'aune d'une comparaison des progéniteurs. ABSTRACT: Les approches de thérapie cellulaire des dystrophinopathies basées sur l'utilisation de myoblastes ou de mésoangioblastes se sont traduites par des résultats cliniques mitigés. De nombreux candidats cellulaires alternatifs ont été décrits, mais aucune comparaison standardisée n'a pu encore établir leurs efficacités, ne serait-ce qu'en vue d'une régénération musculaire localisée. Une étude comparative a donc été décidée récemment et pourrait permettre de donner un nouvel élan à cette approche.

From Tusko to Titin: the role for comparative physiology in an era of molecular discovery.

As we approach the centenary of the term "comparative physiology," we reexamine its role in modern biology. Finding inspiration in Krogh's classic 1929 paper, we first look back to some timeless contributions to the field. The obvious and fascinating variation among animals is much more evident than is their shared physiological unity, which transcends both body size and specific adaptations. The "unity in diversity" reveals general patterns and principles of physiology that are invisible when examining only one species. Next, we examine selected contemporary contributions to comparative physiology, which provides the context in which reductionist experiments are best interpreted. We discuss the sometimes surprising insights provided by two comparative "athletes" (pronghorn and rattlesnakes), which demonstrate 1) animals are not isolated molecular mechanisms but highly integrated physiological machines, a single "rate-limiting" step may be exceptional; and 2) extremes in nature are rarely the result of novel mechanisms, but rather employ existing solutions in novel ways. Furthermore, rattlesnake tailshaker muscle effectively abolished the conventional view of incompatibility of simultaneous sustained anaerobic glycolysis and oxidative ATP production. We end this review by looking forward, much as Krogh did, to suggest that a comparative approach may best lend insights in unraveling how skeletal muscle stores and recovers mechanical energy when operating cyclically. We discuss and speculate on the role of the largest known protein, titin (the third muscle filament), as a dynamic spring capable of storing and recovering elastic recoil potential energy in skeletal muscle.

Mapping circuits beyond the models: integrating connectomics and comparative neuroscience.

The brain has been shaped by evolution, and its connectome reflects that history. Comparative neuroscience research, framed by evolutionary relationships, is key to interpreting connectome organization and can address fundamental circuit questions that are not accessible through single-species connectomics efforts.

What is biodiversity? Stepping forward from barcoding to understanding biological differences.

This opinion paper gives personal views of the direction that cataloguing biodiversity should be going in. Although molecular taxonomy enables rapid and high throughput identification of species, it needs to be anchored to traditional taxonomy, because without information of actual biological properties of species, DNA barcoding just reports differences in selected DNA sequences, which need not have anything to do with the biological properties of the organisms, and the reasons for the development of the species. Since functional differences are the most common reason behind species differences, the future of cataloguing biodiversity and biodiversity research is, in my opinion, in trying to integrate genomic research to comparative physiology in order to be able to evaluate which functional properties have likely been important in generating biodiversity. This task is overwhelming, and requires forgetting the traditional disciplines. Further, major problems associated with the present-day treatment of genomic data are presented from my viewpoint.

Comparative endocrinology of leptin: assessing function in a phylogenetic context.

As we approach the end of two decades of leptin research, the comparative biology of leptin is just beginning. We now have several leptin orthologs described from nearly every major clade among vertebrates, and are moving beyond gene descriptions to functional studies. Even at this early stage, it is clear that non-mammals display clear functional similarities and differences with their better-studied mammalian counterparts. This review assesses what we know about leptin function in mammals and non-mammals, and gives examples of how these data can inform leptin biology in humans.

Comparative cardiovascular physiology: future trends, opportunities and challenges.

The inaugural Kjell Johansen Lecture in the Zoophysiology Department of Aarhus University (Aarhus, Denmark) afforded the opportunity for a focused workshop comprising comparative cardiovascular physiologists to ponder some of the key unanswered questions in the field. Discussions were centred around three themes. The first considered function of the vertebrate heart in its various forms in extant vertebrates, with particular focus on the role of intracardiac shunts, the trabecular ('spongy') nature of the ventricle in many vertebrates, coronary blood supply and the building plan of the heart as revealed by molecular approaches. The second theme involved the key unanswered questions in the control of the cardiovascular system, emphasizing autonomic control, hypoxic vasoconstriction and developmental plasticity in cardiovascular control. The final theme involved poorly understood aspects of the interaction of the cardiovascular system with the lymphatic, renal and digestive systems. Having posed key questions around these three themes, it is increasingly clear that an abundance of new analytical tools and approaches will allow us to learn much about vertebrate cardiovascular systems in the coming years.

Comparative metabolic physiology in the 'omics' era: a call to arms, paws, flippers, and claws.

In nutrition, medicine, and animal science, metabolism research is often focused on solving questions using a single organism. Outcomes are most often linked to translational outcomes, understanding or treating a disease, optimizing nutritional status, improving select qualities of production animals, which have tremendous value to human and animal health as well as economic benefit. There is also value in clarifying basic biological principles and integrative systems that determine how organisms function and deal with their environment. Relevant to both translational and basic research questions, comparative metabolic physiology provides a context by which new "omics" technologies and other approaches can be coupled to multi-species metabolic phenotype diversity. These principles were highlighted at the "Adipose and Lipid Biology: Crossing Taxonomic Boundaries" symposium held at the 2013 Experimental Biology meeting in Boston, MA. By considering differences and shared physiology across a spectrum of phenotypes (especially when considering "extremes" that have emerged from evolutionary processes or breeding selection), one may unmask subtle processes and learn from natural adaptations.

IFPA Meeting 2011 workshop report III: Placental immunology; epigenetic and microRNA-dependent gene regulation; comparative placentation; trophoblast differentiation; stem cells.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At IFPA meeting 2011 there were twelve themed workshops, five of which are summarized in this report. These workshops related to various aspects of placental biology: 1) immunology; 2) epigenetics; 3) comparative placentation; 4) trophoblast differentiation; 5) stem cells.

The orbitofrontal cortex and the computation of subjective value: consolidated concepts and new perspectives.

Remarkable progress has been made in recent years toward understanding the functions of the orbitofrontal cortex (OFC). The finding that neurons in this area encode the subjective value monkeys assign to different goods while making choices has been confirmed and extended by numerous studies using both primate neurophysiology and human imaging. Moreover, new lesion studies demonstrated that subjective values computed in the OFC are causally and specifically related to choice behavior. Importantly, values in the OFC are attached to goods, not to actions or to spatial locations. Furthermore, subjective values appear to be computed in this area even if the situation does not require a choice. In the light of this growing body of work, we propose that the primary function of the OFC is the computation of good identities and subjective values in an abstract representation. In this view, OFC neurons compute the subjective value of a good whenever that good is behaviorally relevant.

Tutorial on physiologically based kinetic modeling in molecular nutrition and food research.

Studies in the field of molecular nutrition and food research often aim at identifying effects of bioactive ingredients on living organisms. When data from human studies are difficult to obtain, effects are often studied in relevant animal or cellular in vitro models. This poses the need for adequate extrapolation from the in vitro to the in vivo situation, from high-dose levels to realistic low-dose levels and from experimental animals to humans. Furthermore, effects of genetic polymorphisms or lifestyle factors may have to be taken into account. Physiologically based kinetic (PBK) modeling provides a means to support these kinds of extrapolations. The present paper illustrates the basic concepts of PBK modeling. PBK modeling includes six steps: (i) definition of the conceptual model, (ii) translation into a mathematical model, (iii) defining parameter values, (iv) solving the equations, (v) evaluation of model performance and (vi) making predictions. The paper provides an overview of these basic steps and presents examples to illustrate how PBK modeling can be applied. This reveals that PBK modeling provides an important tool in the field of the 3Rs aiming at Replacement, Reduction and Refinement of animal studies and may also be a useful tool for risk assessment.

Comparative physiology: a "crystal ball" for predicting consequences of global change.

Comparative physiology offers powerful approaches for developing causal, mechanistic explanations of shifts in biogeographic patterning occurring in concert with global change. These analyses can identify the cellular loci and intensities of stress-induced perturbation and generate predictions about ecosystem alterations in a changing world. Congeneric species adapted to different abiotic conditions offer excellent study systems for these purposes. Several findings have emerged from such comparative studies: 1) In aquatic and terrestrial habitats, the most heat-tolerant ectotherms may be most threatened by further increases in temperature, due to proximity of these species' thermal optima and tolerance limits to current maximal ambient temperatures and limited capacities for acclimatization to higher temperatures. 2) Cardiac function is a "weak link" in acute thermal tolerance. 3) Stress-induced changes in gene expression comprise a graded response involving genes linked to damage repair, lysis of irreversibly damaged molecules, and downregulation of cell proliferation. Transcriptomic and proteomic analyses provide "biomarkers" for diagnosing degrees of stress. 4) Different abiotic stresses may have synergistic or opposing effects on gene expression, a complexity needing consideration when developing integrated pictures of effects of global change. 5) Adaptation of proteins can result from one to a few amino acid substitutions, which can occur at many sites in a protein, a discovery with implications for rates of adaptive evolution. 6) Greater thermal tolerance of invasive species may favor their replacement of natives. 7) Losses of protein-coding genes and temperature-responsive gene regulatory abilities in stenothermal ectotherms of the Southern Ocean may lead to broad extinctions.

Molecules to migration: pressures of life.

The highly successful Fourth International Conference in Africa for Comparative Physiology and Biochemistry (ICA-CPB) was held in the Maasai Mara National Reserve in July 2008. The theme of the meeting was "Molecules to Migration: Pressures of Life." To enhance the theme, the venue and timing of the meeting were chosen to coincide with the arrival of approximately 1.4 million wildebeest on their annual migration from the Serengeti National Park in Tanzania. Like the three previous ICA-CPB meetings, the discussion topics and the resulting collection of synthesia presented here were very diverse. The articles in this special collection reflect the authors' interest in broadening our understanding of the field of comparative physiology and biochemistry and their commitment to engaging in global research with international colleagues. These articles are brief, synthetic reviews integrating information presented at and inspired by the meeting. From seasonal migration and reproduction in birds, to cardiovascular system development in vertebrates, to strategies for hypoxia survival, papers range from specific to broad interactions. What they all have in common: they increase our understanding of how animals are affected by and respond to the pressures of life.

Cats, "rats," and bats: the comparative biology of aging in the 21st century.

Laboratory models have suggested a link between metabolism and life span in vertebrates, and it is well known that the evolution of specific life histories can be driven by metabolic factors. However, little is known regarding how the adoption of specific life-history strategies can shape aging and life span in populations facing different energetic demands from either a theoretical or a mechanistic viewpoint but significant insight can be gained by using a comparative approach. Comparative biology plays several roles in our understanding of the virtually ubiquitous phenomenon of aging in animals. First, it provides a critical evaluation of broad hypotheses concerning the evolutionary forces underlying the modulation of aging rate. Second, it suggests mechanistic hypotheses about processes of aging. Third, it illuminates particularly informative species because of their exceptionally slow or rapid aging rates to be interrogated about potentially novel mechanisms of aging. Although comparative biology has played a significant role in research on aging for more than a century, the new comparative biology of aging is poised to dwarf those earlier contributions, because: (1) new cellular and molecular techniques for investigating novel species are in place and more are being continually generated, (2) molecular systematics has resolved the phylogenetic relationships among a wide range of species, which allow for the implementation of analytic tools specialized for comparative biology, and (3) in addition to facilitating the construction of accurate phylogenies, the dramatic acceleration in DNA-sequencing technology is providing us with new tools for a comparative genomic approach to understanding aging.