Analysing Change: Complex Rather than Dialectical?

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.This article offers a discussion of dialectics from a complexity perspective. Dialectics is a term much utilized but infrequently defined. This article suggests that a spectrum of ideas exist concerning understandings of dialectics. We are particularly critical of Hegelian dialectics, which we see as anthropocentric and teleological. While Marxist approaches to dialectics, in the form of historical materialism, marked a break from the idealist elements of Hegelian dialectics, they retained traces of this approach. The article offers a partial discussion of essential elements of dialectics, which we consider to be the analysis of change, the centrality of contradiction, and the methodology of abstraction. Points of overlap with complexity thinking are highlighted, together with those points where complexity thinking and dialectical approaches diverge. We conclude with some suggestions as to how complexity thinking might contribute to a development of dialectical approaches

Molecular dynamics simulations and in silico peptide ligand screening of the Elk-1 ETS domain

Background: The Elk-1 transcription factor is a member of a group of proteins called ternary complex factors, which serve as a paradigm for gene regulation in response to extracellular signals. Its deregulation has been linked to multiple human diseases including the development of tumours. The work herein aims to inform the design of potential peptidomimetic compounds that can inhibit the formation of the Elk-1 dimer, which is key to Elk-1 stability. We have conducted molecular dynamics simulations of the Elk-1 ETS domain followed by virtual screening. Results: We show the ETS dimerisation site undergoes conformational reorganisation at the a1b1 loop. Through exhaustive screening of di- and tri-peptide libraries against a collection of ETS domain conformations representing the dynamics of the loop, we identified a series of potential binders for the Elk-1 dimer interface. The di-peptides showed no particular preference toward the binding site; however, the tri-peptides made specific interactions with residues: Glu17, Gln18 and Arg49 that are pivotal to the dimer interface. Conclusions: We have shown molecular dynamics simulations can be combined with virtual peptide screening to obtain an exhaustive docking protocol that incorporates dynamic fluctuations in a receptor. Based on our findings, we suggest experimental binding studies to be performed on the 12 SILE ranked tri-peptides as possible compounds for the design of inhibitors of Elk-1 dimerisation. It would also be reasonable to consider the score ranked tri-peptides as a comparative test to establish whether peptide size is a determinant factor of binding to the ETS domain

A Novel Network Profiling Analysis Reveals System Changes in Epithelial-Mesenchymal Transition

Patient-specific analysis of molecular networks is a promising strategy for making individual risk predictions and treatment decisions in cancer therapy. Although systems biology allows the gene network of a cell to be reconstructed from clinical gene expression data, traditional methods, such as Bayesian networks, only provide an averaged network for all samples. Therefore, these methods cannot reveal patient-specific differences in molecular networks during cancer progression. In this study, we developed a novel statistical method called NetworkProfiler, which infers patient-specific gene regulatory networks for a specific clinical characteristic, such as cancer progression, from gene expression data of cancer patients. We applied NetworkProfiler to microarray gene expression data from 762 cancer cell lines and extracted the system changes that were related to the epithelial-mesenchymal transition (EMT). Out of 1732 possible regulators of E-cadherin, a cell adhesion molecule that modulates the EMT, NetworkProfiler, identified 25 candidate regulators, of which about half have been experimentally verified in the literature. In addition, we used NetworkProfiler to predict EMT-dependent master regulators that enhanced cell adhesion, migration, invasion, and metastasis. In order to further evaluate the performance of NetworkProfiler, we selected Krueppel-like factor 5 (KLF5) from a list of the remaining candidate regulators of E-cadherin and conducted in vitro validation experiments. As a result, we found that knockdown of KLF5 by siRNA significantly decreased E-cadherin expression and induced morphological changes characteristic of EMT. In addition, in vitro experiments of a novel candidate EMT-related microRNA, miR-100, confirmed the involvement of miR-100 in several EMT-related aspects, which was consistent with the predictions obtained by NetworkProfiler

Meeting Report: Aging Research and Drug Discovery

Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community

Metal-specific Effects on Stream Macroinvertebrates--physiological and ecological approaches

The success of remediation of mining wastes in the upper Clark Fork River (CFR) will be measured by mitigation of metal exposures and reduction of risk to biological communities. Dissolved Cu concentrations at most sites in the upper 90 km of the CFR have declined during the period 1993-2002. Annual trends in benthic macroinvertebrate assemblage data indicate that in-stream ecological conditions have improved, also. Despite the general similarity in those patterns, correlation in year-to-year Cu exposure and changes in the benthos within sites is weak. These simple relationships are probably confounded by other factors acting on the benthos. Additionally, interpretation of metal effects is hindered by a vague understanding of how species composition reflects differences in the metal sensitivity of individual species. To better understand the metal-specific responses of species within the assemblage, metal bioaccumulation and detoxification were compared among five resident species. From these results, we characterized two species as sensitive and three as tolerant. These characterizations of tolerance were similar to tolerance values derived from species distributions. Species most sensitive to Cu do not occur at sites in the upper river. This suggests where metals-specific effects are most likely occurring. The physiological studies may provide a mechanistic explanation for why some species tolerate metals and others do not. This information should be considered within the context of ecological factors that might affect species distributions. Physiological and ecological studies are complementary approaches that strengthen understanding of metal-specific effects on stream benthos

Phylogeny and Size Differentially Influence Dissolved Cd and Zn Bioaccumulation Parameters among Closely Related Aquatic Insects

Evolutionarily distinct lineages can vary markedly in their accumulation of, and sensitivity to, contaminants. However, less is known about variability among closely related species. Here, we compared dissolved Cd and Zn bioaccumulation in 19 species spanning two species-rich aquatic insect families: Ephemerellidae (order Ephemeroptera (mayflies)), generalized to be metal sensitive, and Hydropsychidae (order Trichoptera (caddisflies)), generalized to be metal tolerant. Across all species, Zn and Cd uptake rate constants (<i>k</i>_us), efflux rate constants (<i>k</i>_es) and bioconcentration factors (BCFs) strongly covaried, suggesting that these metals share transport pathways in these distinct lineages. <i>K</i>_us and BCFs were substantially larger in Ephemerellidae than in Hydropsychidae, whereas <i>k</i>_es did not dramatically differ between the two families. Body size played an important role in driving <i>k</i>_u differences among species, but had no influence on <i>k</i>_es. While familial differences in metal bioconcentration were striking, each family exhibited tremendous variability in all bioaccumulation parameters. At finer levels of taxonomic resolution (within families), phylogeny did not account for differences in metal bioaccumulation. These findings suggest that intrafamily variability can be profound and have important practical implications in that we need to better understand how well “surrogate species” represent their fellow congeners and family members

Evolutionary Patterns in Trace Metal (Cd and Zn) Efflux Capacity in Aquatic Organisms

The ability to eliminate (efflux) metals is a physiological trait that acts as a major driver of bioaccumulation differences among species. This species specific trait plays a large role in determining the metal loads that species will need to detoxify to persist in chronically contaminated environments and, therefore, contributes significantly to differences in environmental sensitivity among species. To develop a better understanding of how efflux varies within and among taxonomic groupings, we compared Cd and Zn efflux rate constants (k(e) values) among members of two species-rich aquatic insect families, Ephemerellidae and Hydropsychidae, and discovered that k(e) values strongly covaried across species. This relationship allowed us to successfully predict Zn efflux from Cd data gathered from aquatic species belonging to other insect orders and families. We then performed a broader, comparative analysis of Cd and Zn k(e) values from existing data for arthropods, mollusks, annelids, and chordates (77 species total) and found significant phylogenetic patterns. Taxonomic groups exhibited marked variability in k(e) magnitudes and ranges, suggesting that some groups are more constrained than others in their abilities to eliminate metals. Understanding broader patterns of variability can lead to more rational extrapolations across species and improved protectiveness in water quality criteria and ecological assessment