We recently used drug-induced transcriptomic responses and whole-genome sequences in healthy human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to identify cellular pathways and genomic variants potentially associated with the cardiotoxic effects of tyrosine kinase inhibitors (TKIs) and anthracyclines. Here, we describe predicTox (www.predictox.org), an interactive website that organizes our data and its integration with knowledge from cell pathways and genomic databases. DrugTox summary cards give results of these analyses and metadata for each drug. Fields include cardiotoxicity risk scores curated from the FDA Adverse Event Reporting System, cell pathways, and genomic variants potentially associated with drug-induced cardiotoxicity. At a detailed level, predicTox provides a ranked list of up- and downregulated pathways that are predominantly induced by cardiotoxic TKIs as well as lists of their pathway genes and the specific cardiotoxic TKIs inducing those pathways. predicTox provides downloadable lists of drug-induced differentially expressed genes and pathways as well as drug-related genomic variants associated with cardiotoxicity. Statistical metrics are given. Mathematical models allow simulation of drug effects on heart physiology. Building on the results of our algorithm for independent reidentification of the well-known rs2229774 variant for anthracycline-induced cardiotoxicity, we describe how our data can be queried to identify potential variants associated with drug-induced cardiotoxicity by affecting a drug's pharmacodynamics and pharmacokinetics.

AbstractA prevailing problem in evolutionary biology is elucidating the genotype-to-phenotype map that characterizes how genomic activities regulate different aspects of organismal morphology and their variability in both space and time. Here, we explore potential causality between genome content and both morphological complexity and disparity by compiling the regulatory components (i.e., transcription factors, RNA-binding proteins, and microRNA families) as well as a representative set of nonregulatory housekeeping genes in 32 species belonging to a wide variety of animal phyla spanning a range of morphological, ecological, and genomic characteristics. A principal component analysis of these four nonoverlapping genomic components from each of these 32 species in relation to their last common ancestor revealed that no relationship exists between genome space and disparity, as changes to animal body plans appear to be largely the result of changes to the regulatory networks that govern animal development rather than gaining or losing specific sets of regulatory genes. However, using both phylogenetically correlated and phylogenetically uncorrelated statistical tests, we find a strong relationship between the loss of all considered gene types in some parasitic taxa, an exacerbation of a trend that characterizes animal genomes in general. We also find a strong correlation, and a likely causal relationship, between microRNA innovations and organismal complexity. While this analysis of genomic features suggests how complexity and disparity are each encoded in the genome, further analysis of the regulatory networks in which they participate should provide a more comprehensive description of how organisms diversify their morphologies through time.

Parasitism has independently evolved hundreds of times among metazoans. Nonetheless, parasites have explored only a limited range of ecologies, and they display frequent convergence in morphological, behavioral, and life-history traits. Although gene loss in particular parasitic species has been documented, it is not known if gene loss converges along the same lines as these other traits. To test for convergent gene loss, we characterized the housekeeping, regulatory, and DNA-repair complements of 48 bilaterian species, including 20 parasites belonging to 6 different bilaterian phyla. We found that different parasitic strategies do not display characteristic tempos or modes of gene loss. Further, the accelerated rates of gene loss seen in some parasites were almost always shared with their free-living relatives, indicating that the increased rate of loss preceded the rise of parasitism. Therefore, the convergent ecological strategies and adaptations that have arisen in distantly related parasitic lineages overlay contingent gene losses, which largely reflect their phylogenetic history. These results have important implications for how ecologists and evolutionary biologists should model the acquisition of parasitism, especially regarding the long-held assumption that reversion from a parasitic to a free-living state is impossible.

Environmental cues provide critical sensory information for the survival of animals. Understanding how distinct sensory cues elicit or modulate certain behaviour thus provides insights into the adaptations to rapid and continuous changes in the surrounding world. Intertidal ecosystems are particularly exposed to environmental fluctuations. Due to changing exposure to seawater, animals are subjected to continuous fluctuations of temperature or salinity during the course of day-night and tidal cycles. Animals in intertidal environments show physiological and behavioural adaptations to these changes. Acoel worms constitute an important component of intertidal ecosystems. Symsagittifera roscoffensis, a well-studied species inhabiting the Atlantic coastline, has been extensively described in terms of its anatomy and development, yet its physiological responses remain poorly understood. When the acoel S. roscoffensis are exposed to daylight during the tidal cycle, these animals are found at the surface of sandy beaches, which enhance the exposure of their photosynthetic algal symbionts to light. Moreover, S. roscoffensis shows a strong positive phototaxis as well as both positive and negative geotaxis, both being evolved behavioural adaptations to enhance light exposure for its photosymbiont. Currently little is known about other sensory systems and their functions in this, or any other acoel worm. In this study, we probe sensory capabilities of S. roscoffensis focusing on chemical and temperature cues. Using two-choice and barrier assays, our findings support that S. roscoffensis shows avoidance behaviours to increased temperature and salinity, preferring cooler environments with lower salinity. We demonstrate that early branching bilaterians possess the sensory capacity to identify specific chemical and environmental stimuli, adding to the knowledge that may prove useful in understanding marine ecosystems in a period of global climate change that greatly affects aquatic environments.

Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enables us to correctly reidentify a genomic variant causally linked to anthracycline-induced cardiotoxicity and predict genomic variants potentially associated with TKI-induced cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale signatures for cardiotoxicity that could be used for drug development and patient stratification. Using a new computational pipeline for identification of drug-selective transcriptomic responses and FAERS data, the authors identified potential pathways and genomic variants indicative of cancer drug cardiotoxicity in iPSC-derived cardiomyocytes.

Acoel flatworms have played a relevant role in classical (and current) discussions on the evolutionary origin of bilaterian animals. This is mostly derived from the apparent simplicity of their body architectures. This tenet has been challenged over the last couple of decades, mostly because detailed studies of their morphology and the introduction of multiple genomic technologies have unveiled a complexity of cell types, tissular arrangements and patterning mechanisms that were hidden below this 'superficial' simplicity. One tissue that has received a particular attention has been the nervous system (NS). The combination of ultrastructural and single cell methodologies has revealed unique cellular diversity and developmental trajectories for most of their neurons and associated sensory systems. Moreover, the great diversity in NS architectures shown by different acoels offers us with a unique group of animals where to study key aspects of neurogenesis and diversification od neural systems over evolutionary time.In this review we revisit some recent developments in the characterization of the acoel nervous system structure and the regulatory mechanisms that contribute to their embryological development. We end up by suggesting some promising avenues to better understand how this tissue is organized in its finest cellular details and how to achieve a deeper knowledge of the functional roles that genes and gene networks play in its construction.

A prevailing problem in evolutionary biology is elucidating the genotype-phenotype map that characterizes how genomic activities regulate different aspects of organismal morphology and their variability in both space and time. Here, we explore potential causality between genome content and both morphological complexity and disparity by compiling the regulatory components (i.e., transcription factors, RNA binding proteins, and microRNA families) as well as a representative set of non-regulatory housekeeping genes in 32 species belonging to a wide variety of animal phyla, altogether encapsulating a number of varying genomic characteristics and morphological diversities. A principal component analysis of these four non-overlapping genomic components from each of these 32 species in relation to their last common ancestor revealed that no relationship exists between genome space and disparity, as changes to animal body plans appear to be largely the result of changes to the gene regulatory networks that govern animal development rather than gaining or losing specific sets of regulatory genes. However, using both phylogenetically correlated as well as phylogenetically uncorrelated statistical tests, we find a strong relationship between the loss of all considered gene types and the advent of some parasitic taxa, as well as between microRNA innovations and organismal complexity. While this analysis of genomic features suggests how complexity and disparity are each encoded in the genome, further analysis of the regulatory networks in which they participate should provide a more comprehensive description of how organisms diversify their morphologies over time through alterations in their genomic components. ### Competing Interest Statement The authors have declared no competing interest.

Species within nearly all extant animal lineages are capable of regenerating body parts. However, it remains unclear whether the gene expression programme controlling regeneration is evolutionarily conserved. Brittle stars are a species-rich class of echinoderms with outstanding regenerative abilities, but investigations into the genetic bases of regeneration in this group have been hindered by the limited genomic resources. Here we report a chromosome-scale genome assembly for the brittle star Amphiura filiformis. We show that the brittle star genome is the most rearranged among echinoderms sequenced so far, featuring a reorganized Hox cluster reminiscent of the rearrangements observed in sea urchins. In addition, we performed an extensive profiling of gene expression during brittle star adult arm regeneration and identified sequential waves of gene expression governing wound healing, proliferation and differentiation. We conducted comparative transcriptomic analyses with other invertebrate and vertebrate models for appendage regeneration and uncovered hundreds of genes with conserved expression dynamics, particularly during the proliferative phase of regeneration. Our findings emphasize the crucial importance of echinoderms to detect long-range expression conservation between vertebrates and classical invertebrate regeneration model systems. A newly sequenced genome of the brittle star Amphiura filiformis and gene expression profiling of adult arm regeneration reveal genes with conserved expression dynamics across invertebrates and vertebrates.

HPA axis dysregulations are consistently reported in depression and other mood disorders, whereas previous studies examining HPA axis function in women with PMDD have yielded inconsistent findings. In this study, we characterized the HPA axis in women with PMDD using the combined dexamethasone suppression and CRH stimulation (Dex/CRH) test and 24-hour urine free cortisol (UFC).

Hyperactive and hyperreactive HPA axis functions are frequently reported in depressive disorders, particularly in major depression. However, research into HPA axis function in women with premenstrual dysphoric disorder (PMDD), which is also classified as a depressive disorder, has shown inconsistent results. This study aimed to characterize the HPA axis in women with PMDD using the combined dexamethasone suppression and CRH stimulation (Dex/CRH) test, alongside measurements of 24-hour urine free cortisol (UFC). We enrolled 26 women with prospectively confirmed PMDD and 25 asymptomatic controls (ACs), testing them during the midfollicular and luteal phases of the menstrual cycle. The primary outcomes included serial plasma cortisol and ACTH levels, their area-under-the-curve (AUC), and 24-hour UFC levels. We utilized a mixed model to compare serial cortisol and ACTH levels, and the Wilcoxon Signed Rank test for comparing UFC levels and cortisol and ACTH AUC. No significant effects related to diagnosis or menstrual cycle phase were observed on plasma cortisol or ACTH levels (from time 0 to +75 minutes), nor on the AUCs of plasma cortisol or ACTH (p > 0.05 for all comparisons). Notably, the PMDD group displayed significantly lower 24-hour UFC levels compared to the AC group during both the follicular and luteal phases (p = 0.0004 and p = 0.0007, respectively). The observed hyposecretion of cortisol in the PMDD group suggests a pathophysiology distinct from other depressive disorders, possibly aligning more closely with stress disorders such as PTSD. The unique symptom profile of PMDD, marked by significant irritability and a more rapid response to antidepressant treatment than is typical in major depression, further supports considering an alternative classification.

We present a major update of MirGeneDB (3.0), the manually curated animal microRNA gene database. Beyond moving to a new server and the creation of a computational mirror, we have expanded the database with the addition of 33 invertebrate species, including representatives of 5 previously unsampled phyla, and 6 mammal species. MirGeneDB now contains entries for 21 822 microRNA genes (5160 of these from the new species) belonging to 1743 microRNA families. The inclusion of these new species allowed us to refine both the evolutionary node of appearance of a number of microRNA genes/families, as well as MirGeneDB's phylogenetically informed nomenclature system. Updated covariance models of all microRNA families, along with all smallRNA read data are now downloadable. These enhanced annotations will allow researchers to analyze microRNA properties such as secondary structure and features of their biogenesis within a robust phylogenetic context and without the database plagued with numerous false positives and false negatives. In light of these improvements, MirGeneDB 3.0 will assume the responsibility for naming conserved novel metazoan microRNAs. MirGeneDB is part of RNAcentral and Elixir Norway and is publicly and freely available at mirgenedb.org.

Aquatic invertebrates play a pivotal role in (eco)toxicological assessments because they offer ethical, cost-effective and repeatable testing options. Additionally, their significance in the food chain and their ability to represent diverse aquatic ecosystems make them valuable subjects for (eco)toxicological studies. To ensure consistency and comparability across studies, international (eco)toxicology guidelines have been used to establish standardised methods and protocols for data collection, analysis and interpretation. However, the current standardised protocols primarily focus on a limited number of aquatic invertebrate species, mainly from Arthropoda, Mollusca and Annelida. These protocols are suitable for basic toxicity screening, effectively assessing the immediate and severe effects of toxic substances on organisms. For more comprehensive and ecologically relevant assessments, particularly those addressing long-term effects and ecosystem-wide impacts, we recommended the use of a broader diversity of species, since the present choice of taxa exacerbates the limited scope of basic ecotoxicological studies. This review provides a comprehensive overview of (eco)toxicological studies, focusing on major aquatic invertebrate taxa and how they are used to assess the impact of chemicals in diverse aquatic environments. The present work supports the use of a broad-taxa approach in basic environmental assessments, as it better represents the natural populations inhabiting various ecosystems. Advances in omics and other biochemical and computational techniques make the broad-taxa approach more feasible, enabling mechanistic studies on non-model organisms. By combining these approaches with in vitro techniques together with the broad-taxa approach, researchers can gain insights into less-explored impacts of pollution, such as changes in population diversity, the development of tolerance and transgenerational inheritance of pollution responses, the impact on organism phenotypic plasticity, biological invasion outcomes, social behaviour changes, metabolome changes, regeneration phenomena, disease susceptibility and tissue pathologies. This review also emphasises the need for harmonised data-reporting standards and minimum annotation checklists to ensure that research results are findable, accessible, interoperable and reusable (FAIR), maximising the use and reusability of data. The ultimate goal is to encourage integrated and holistic problem-focused collaboration between diverse scientific disciplines, international standardisation organisations and decision-making bodies, with a focus on transdisciplinary knowledge co-production for the One-Health approach.

The menopausal transition (MT) is associated with an increased risk of depression. However, it remains unclear if perimenopausal depression (PMD) is accompanied by abnormal secretion of ovarian hormones or by hot flushes (HF).

Sea urchins are emblematic models in developmental biology and display several characteristics that set them apart from other deuterostomes. To uncover the genomic cues that may underlie these specificities, we generated a chromosome-scale genome assembly for the sea urchin Paracentrotus lividus and an extensive gene expression and epigenetic profiles of its embryonic development. We found that, unlike vertebrates, sea urchins retained ancestral chromosomal linkages but underwent very fast intrachromosomal gene order mixing. We identified a burst of gene duplication in the echinoid lineage and showed that some of these expanded genes have been recruited in novel structures (water vascular system, Aristotle’s lantern, and skeletogenic micromere lineage). Finally, we identified gene-regulatory modules conserved between sea urchins and chordates. Our results suggest that gene-regulatory networks controlling development can be conserved despite extensive gene order rearrangement.

COPYRIGHT © 2023 Matassi, Mishra and Martinez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Current thoughts on the brain-computer analogy—All metaphors are wrong, but some are useful

Background: The development of adipose tissue during adolescence may provide valuable insights into obesity-associated diseases. We propose an automated convolutional neural network (CNN) approach using Dixon-based magnetic resonance imaging (MRI) to quantity abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in children and adolescents. Methods: 474 abdominal Dixon MRI scans of 136 young healthy volunteers (aged 8–18) were included in this study. For each scan, an axial fat-only Dixon image located at the L2–L3 disc space and another image at the L4–L5 disc space were selected for quantification. For each image, an outer and an inner region around the abdomen wall, as well as SAT and VAT pixel masks, were generated by expert readers as reference standards. A standard U-Net CNN architecture was then used to train two models: one for region segmentation and one for fat pixel classification. The performance was evaluated using the dice similarity coefficient (DSC) with fivefold cross-validation, and by Pearson correlation and the Student’s t-test against the reference standards. Results: For the DSC results, means and standard deviations of the outer region, inner region, SAT, and VAT comparisons were 0.974 ± 0.026, 0.997 ± 0.003, 0.981 ± 0.025, and 0.932 ± 0.047, respectively. Pearson coefficients were 1.000 for both outer and inner regions, and 1.000 and 0.982 for SAT and VAT comparisons, respectively (all p = NS). Conclusion: These results show that our method not only provides excellent agreement with the reference SAT and VAT measurements, but also accurate abdominal wall region segmentation. The proposed combined region- and pixel-based CNN approach provides automated abdominal wall segmentation as well as SAT and VAT quantification with Dixon MRI and enables objective longitudinal assessment of adipose tissues in children during adolescence.

The potential to regenerate a damaged body part is expressed to a different extent in animals. Echinoderms, in particular starfish, are known for their outstanding regenerating potential. Differently, humans have restricted abilities to restore organ systems being dependent on limited sources of stem cells. In particular, the potential to regenerate the central nervous system is extremely limited, explaining the lack of natural mechanisms that could overcome the development of neurodegenerative diseases and the occurrence of trauma. Therefore, understanding the molecular and cellular mechanisms of regeneration in starfish could help the development of new therapeutic approaches in humans. In this study, we tackle the problem of starfish central nervous system regeneration by examining the external and internal anatomical and behavioral traits, the dynamics of coelomocyte populations, and neuronal tissue architecture after radial nerve cord (RNC) partial ablation. We noticed that the removal of part of RNC generated several anatomic anomalies and induced behavioral modifications (injured arm could not be used anymore to lead the starfish movement). Those alterations seem to be related to defense mechanisms and protection of the wound. In particular, histology showed that tissue patterns during regeneration resemble those described in holothurians and in starfish arm tip regeneration. Flow cytometry coupled with imaging flow cytometry unveiled a new coelomocyte population during the late phase of the regeneration process. Morphotypes of these and previously characterized coelomocyte populations were described based on IFC data. Further studies of this new coelomocyte population might provide insights on their involvement in radial nerve cord regeneration.

EDITORIAL article Front. Ecol. Evol., 19 October 2023Sec. Evolutionary Developmental Biology Volume 11 - 2023 | https://doi.org/10.3389/fevo.2023.1307280

In this review essay, we give a detailed synopsis of the twelve contributions which are collected in a Special Issue in Frontiers Ecology and Evolution, based on the research topic “Current Thoughts on the Brain-Computer Analogy—All Metaphors Are Wrong, But Some Are Useful.” The synopsis is complemented by a graphical summary, a matrix which links articles to selected concepts. As first identified by Turing, all authors in this Special Issue recognize semantics as a crucial concern in the brain-computer analogy debate, and consequently address a number of such issues. What is missing, we believe, is the distinction between metaphor and analogy, which we reevaluate, describe in some detail, and offer a definition for the latter. To enrich the debate, we also deem necessary to develop on the evolutionary theories of the brain, of which we provide an overview. This article closes with thoughts on creativity in Science, for we concur with the stance that metaphors and analogies, and their esthetic impact, are essential to the creative process, be it in Sciences as well as in Arts.

Adrenarche is marked by increases in neuroactive adrenal androgens, including dehydroepiandrosterone sulfate (DHEAS). However, the specific impact of DHEAS on neurodevelopment is difficult to disambiguate from that of gonadal hormones as both systems overlap in maturational trajectories. Here, we investigate the relationship between DHEAS concentrations and gray matter volume in prepubertal children studied prior to increases in gonadal hormones (i.e., gonadarche). Fasting morning blood samples and neuroimaging data were collected on ninety-two healthy children (55 boys, 8.6±.3years; 37 girls, 8.6±.3years) ascertained by physical examination to be prepubertal. Children underwent structural T1-weighted MRI in a 3 T scanner, and serum DHEAS concentrations were measured with liquid chromatography-tandem mass-spectrometry. A whole-brain, voxel-wise multivariate-model analysis (AFNI) was used to examine log-transformed DHEAS effects on gray matter volume, controlling for sex and total brain volume. Post-hoc non-parametric correlations were conducted in SPSS. There was an effect of DHEAS on gray matter volume in the right superior frontal gyrus, anterior cingulate cortex, and right amygdala (p’s<0.001). Post-hoc analyses showed that DHEAS correlated positively with gray matter volume in the right superior frontal gyrus (p=0.002) and anterior cingulate cortex (p=0.003), but negatively in the right amygdala (p=0.001). Our results identified an association between serum DHEAS and gray matter volume prior to gonadarche and support previous studies documenting associations between DHEA and cortical thickness in prepubertal children. These data suggest that DHEA(S) may play a role in extending the window of neurodevelopmental plasticity commonly associated with gonadarche.