A way forward with eco evo devo: an extended theory of resource polymorphism with postglacial fishes as model systems

A major goal of evolutionary science is to understand how biological diversity is generated and altered. Despite considerable advances, we still have limited insight into how phenotypic variation arises and is sorted by natural selection. Here we argue that an integrated view, which merges ecology, evolution and developmental biology (eco evo devo) on an equal footing, is needed to understand the multifaceted role of the environment in simultaneously determining the development of the phenotype and the nature of the selective environment, and how organisms in turn affect the environment through eco evo and eco devo feedbacks. To illustrate the usefulness of an integrated eco evo devo perspective, we connect it with the theory of resource polymorphism (i.e. the phenotypic and genetic diversification that occurs in response to variation in available resources). In so doing, we highlight fishes from recently glaciated freshwater systems as exceptionally well‐suited model systems for testing predictions of an eco evo devo framework in studies of diversification. Studies on these fishes show that intraspecific diversity can evolve rapidly, and that this process is jointly facilitated by (i) the availability of diverse environments promoting divergent natural selection; (ii) dynamic developmental processes sensitive to environmental and genetic signals; and (iii) eco evo and eco devo feedbacks influencing the selective and developmental environments of the phenotype. We highlight empirical examples and present a conceptual model for the generation of resource polymorphism – emphasizing eco evo devo, and identify current gaps in knowledge

30 years of collaboration

We highlight some of the most important cornerstones of the long standing and very fruitful collaboration of the Austrian Diophantine Number Theory research group and the Number Theory and Cryptography School of Debrecen. However, we do not plan to be complete in any sense but give some interesting data and selected results that we find particularly nice. At the end we focus on two topics in more details, namely a problem that origins from a conjecture of Rényi and Erdős (on the number of terms of the square of a polynomial) and another one that origins from a question of Zelinsky (on the unit sum number problem). This paper evolved from a plenary invited talk that the authors gaveat the Joint Austrian-Hungarian Mathematical Conference 2015, August 25-27, 2015 in Győr (Hungary)

The role of HoxA9 in breast cancer progression

Stromal-epithelial interactions drive development and maintain tissue homeostasis through a network of soluble and insoluble factors that operate within a three-dimensional (3D) tissue. Genetic and epigenetic changes in mammary epithelial cells (MECs) cooperate with a modified tissue microenvironment to drive malignant transformation of the breast. We have been studying how altered expression of developmental regulators contributes to breast tumorigenesis. Hox genes play a critical role in tissue development, are frequently lost in tumors, and can regulate integrin and ECM expression. Global expression analysis of matched tumor/normal breast tissue revealed that HoxA9 expression was significantly lower in the tumors. Q-RT-PCR, in situ hybridization and immunohistochemical analysis verified that HoxA9 expression was epithelial specific and significantly reduced in a cohort of primary breast tumors and breast cancer lines. Re-expression of HoxA9, and not HoxA10, in breast cancer cells significantly repressed their tumorigenic phenotype in culture and in vivo coincident with induction of the tumor suppressor BRCA1. In addition, we found that HoxA9 re-expression regulated adhesion by altering integrin expression and adhesion activity resulting in phenotypic reversion of breast tumor cells grown within a 3D reconstituted basement membrane (3D rBM). HoxA9 consensus binding sequences in the BRCA1 promoter were verified in breast cells by mutational studies and ChIP and luciferase analysis. Moreover, exogenous expression of BRCA1 phenocopied and BRCA1-Δexon11b expression and BRCA1 shRNA compromised HoxA9\u27s in vivo and in vitro breast tumor suppressor effects. Because we found that the HoxA9 gene is methylated in breast cancer cells, can repress breast cancer behavior, and is coordinately expressed with BRCA1 in normal and transformed breast tissue but not in endothelial cells, we conclude that HoxA9 is an attractive mammary-specific candidate tumor modifier gene

The role of HoxA9 in breast cancer progression

Stromal-epithelial interactions drive development and maintain tissue homeostasis through a network of soluble and insoluble factors that operate within a three-dimensional (3D) tissue. Genetic and epigenetic changes in mammary epithelial cells (MECs) cooperate with a modified tissue microenvironment to drive malignant transformation of the breast. We have been studying how altered expression of developmental regulators contributes to breast tumorigenesis. Hox genes play a critical role in tissue development, are frequently lost in tumors, and can regulate integrin and ECM expression. Global expression analysis of matched tumor/normal breast tissue revealed that HoxA9 expression was significantly lower in the tumors. Q-RT-PCR, in situ hybridization and immunohistochemical analysis verified that HoxA9 expression was epithelial specific and significantly reduced in a cohort of primary breast tumors and breast cancer lines. Re-expression of HoxA9, and not HoxA10, in breast cancer cells significantly repressed their tumorigenic phenotype in culture and in vivo coincident with induction of the tumor suppressor BRCA1. In addition, we found that HoxA9 re-expression regulated adhesion by altering integrin expression and adhesion activity resulting in phenotypic reversion of breast tumor cells grown within a 3D reconstituted basement membrane (3D rBM). HoxA9 consensus binding sequences in the BRCA1 promoter were verified in breast cells by mutational studies and ChIP and luciferase analysis. Moreover, exogenous expression of BRCA1 phenocopied and BRCA1-Δexon11b expression and BRCA1 shRNA compromised HoxA9\u27s in vivo and in vitro breast tumor suppressor effects. Because we found that the HoxA9 gene is methylated in breast cancer cells, can repress breast cancer behavior, and is coordinately expressed with BRCA1 in normal and transformed breast tissue but not in endothelial cells, we conclude that HoxA9 is an attractive mammary-specific candidate tumor modifier gene

Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease

Human tissues are remarkably adaptable and robust, harboring the collective ability to detect and respond to external stresses while maintaining tissue integrity. Following injury, many tissues have the capacity to repair the damage - and restore form and function - by deploying cellular and molecular mechanisms reminiscent of developmental programs. Indeed, it is increasingly clear that cancer and chronic conditions that develop with age arise as a result of cells and tissues re-implementing and deregulating a selection of developmental programs. Therefore, understanding the fundamental molecular mechanisms that drive cell and tissue responses is a necessity when designing therapies to treat human conditions. Extracellular matrix stiffness synergizes with chemical cues to drive single cell and collective cell behavior in culture and acts to establish and maintain tissue homeostasis in the body. This review will highlight recent advances that elucidate the impact of matrix mechanics on cell behavior and fate across these length scales during times of homeostasis and in disease states

Designing materials to direct stem-cell fate

Proper tissue function and regeneration rely on robust spatial and temporal control of biophysical and biochemical microenvironmental cues through mechanisms that remain poorly understood. Biomaterials are rapidly being developed to display and deliver stem-cell-regulatory signals in a precise and near-physiological fashion, and serve as powerful artificial microenvironments in which to study and instruct stem-cell fate both in culture and in vivo. Further synergism of cell biological and biomaterials technologies promises to have a profound impact on stem-cell biology and provide insights that will advance stem-cell-based clinical approaches to tissue regeneration

Global linking of cell tracks using the Viterbi algorithm

Automated tracking of living cells in microscopy image sequences is an important and challenging problem. With this application in mind, we propose a global track linking algorithm, which links cell outlines generated by a segmentation algorithm into tracks. The algorithm adds tracks to the image sequence one at a time, in a way which uses information from the complete image sequence in every linking decision. This is achieved by finding the tracks which give the largest possible increases to a probabilistically motivated scoring function, using the Viterbi algorithm. We also present a novel way to alter previously created tracks when new tracks are created, thus mitigating the effects of error propagation. The algorithm can handle mitosis, apoptosis, and migration in and out of the imaged area, and can also deal with false positives, missed detections, and clusters of jointly segmented cells. The algorithm performance is demonstrated on two challenging datasets acquired using bright-field microscopy, but in principle, the algorithm can be used with any cell type and any imaging technique, presuming there is a suitable segmentation algorithm.QC 20150518</p

Global linking of cell tracks using the Viterbi algorithm

Automated tracking of living cells in microscopy image sequences is an important and challenging problem. With this application in mind, we propose a global track linking algorithm, which links cell outlines generated by a segmentation algorithm into tracks. The algorithm adds tracks to the image sequence one at a time, in a way which uses information from the complete image sequence in every linking decision. This is achieved by finding the tracks which give the largest possible increases to a probabilistically motivated scoring function, using the Viterbi algorithm. We also present a novel way to alter previously created tracks when new tracks are created, thus mitigating the effects of error propagation. The algorithm can handle mitosis, apoptosis, and migration in and out of the imaged area, and can also deal with false positives, missed detections, and clusters of jointly segmented cells. The algorithm performance is demonstrated on two challenging datasets acquired using bright-field microscopy, but in principle, the algorithm can be used with any cell type and any imaging technique, presuming there is a suitable segmentation algorithm.QC 20150518</p