Reducing Epistasis and Pleiotropy Can Avoid the Survival of the Flattest Tragedy.

This study investigates whether reducing epistasis and pleiotropy enhances mutational robustness in evolutionary adaptation, utilizing an indirect encoded model within the "survival of the flattest" (SoF) fitness landscape. By simulating genetic variations and their phenotypic consequences, we explore organisms' adaptive mechanisms to maintain positions on higher, narrower evolutionary peaks amidst environmental and genetic pressures. Our results reveal that organisms can indeed sustain their advantageous positions by minimizing the complexity of genetic interactions-specifically, by reducing the levels of epistasis and pleiotropy. This finding suggests a counterintuitive strategy for evolutionary stability: simpler genetic architectures, characterized by fewer gene interactions and multifunctional genes, confer a survival advantage by enhancing mutational robustness. This study contributes to our understanding of the genetic underpinnings of adaptability and robustness, challenging traditional views that equate complexity with fitness in dynamic environments.

Imaging mass cytometry analysis of Becker muscular dystrophy muscle samples reveals different stages of muscle degeneration.

Becker muscular dystrophy (BMD) is characterised by fiber loss and expansion of fibrotic and adipose tissue. Several cells interact locally in what is known as the degenerative niche. We analysed muscle biopsies of controls and BMD patients at early, moderate and advanced stages of progression using Hyperion imaging mass cytometry (IMC) by labelling single sections with 17 markers identifying different components of the muscle. We developed a software for analysing IMC images and studied changes in the muscle composition and spatial correlations between markers across disease progression. We found a strong correlation between collagen-I and the area of stroma, collagen-VI, adipose tissue, and M2-macrophages number. There was a negative correlation between the area of collagen-I and the number of satellite cells (SCs), fibres and blood vessels. The comparison between fibrotic and non-fibrotic areas allowed to study the disease process in detail. We found structural differences among non-fibrotic areas from control and patients, being these latter characterized by increase in CTGF and in M2-macrophages and decrease in fibers and blood vessels. IMC enables to study of changes in tissue structure along disease progression, spatio-temporal correlations and opening the door to better understand new potential pathogenic pathways in human samples.

Decoding the transcriptome of Duchenne muscular dystrophy to the single nuclei level reveals clinical-genetic correlations.

Duchenne muscular dystrophy is a genetic disease produced by mutations in the dystrophin gene characterized by early onset muscle weakness leading to severe and irreversible disability. The cellular and molecular consequences of the lack of dystrophin in humans are only partially known, which is crucial for the development of new therapies aiming to slow or stop the progression of the disease. Here we have analyzed quadriceps muscle biopsies of seven DMD patients aged 2 to 4 years old and five age and gender matched controls using single nuclei RNA sequencing (snRNAseq) and correlated the results obtained with clinical data. SnRNAseq identified significant differences in the proportion of cell population present in the muscle samples, including an increase in the number of regenerative fibers, satellite cells, and fibro-adipogenic progenitor cells (FAPs) and a decrease in the number of slow fibers and smooth muscle cells. Muscle samples from the younger patients with stable mild weakness were characterized by an increase in regenerative fibers, while older patients with moderate and progressive weakness were characterized by loss of muscle fibers and an increase in FAPs. An analysis of the gene expression profile in muscle fibers identified a strong regenerative signature in DMD samples characterized by the upregulation of genes involved in myogenesis and muscle hypertrophy. In the case of FAPs, we observed upregulation of genes involved in the extracellular matrix regeneration but also several signaling pathways. Indeed, further analysis of the potential intercellular communication profile showed a dysregulation of the communication profile in DMD samples identifying FAPs as a key regulator of cell signaling in DMD muscle samples. In conclusion, our study has identified significant differences at the cellular and molecular levels in the different cell populations present in skeletal muscle samples of patients with DMD compared to controls.

Differential expression of lipid metabolic genes in hypercholesterolemic rabbit placenta predisposes the offspring to develop atherosclerosis in early adulthood.

AIMS: Maternal hypercholesterolemia (MHC) is a pathological condition that may cause atherosclerosis in the adulthood of the offspring. The study aims to identify the role of in-utero programming by the placenta in atherogenesis and associated liver pathology in offspring. MAIN METHODS: Female New Zealand white rabbits with normal lipid profiles were fed a 0.3 % HFD after mating. Lipid levels were monitored, and pregnant rabbits were sacrificed at the end of trimester 1, trimester 2, and trimester 3. Placental histology and expression of lipid metabolism genes were studied. Lipid levels, aortic lesions, and mRNA expression of cholesterol synthesis genes were investigated in fetuses at the end of gestation. A group of fetuses was allowed to attain early adulthood to investigate the liver lipid metabolism and atherogenesis with and without an HFD. KEY FINDINGS: Elevated maternal lipid levels and placental gene expression were differentially modulated in HFD-fed mothers. HFD-fed rabbits demonstrated differential expression of the placental genes involved in receptor-mediated endocytosis of cholesterol, lipogenesis, and lipolysis in all three trimesters. It resulted in significant lipid depositions in the placenta, hyperlipidemia, and a decrease in hepatic cholesterol synthesis in fetuses at the end of gestation. There was no atherogenesis in the aorta of offspring at trimester 3, but such offspring of HFD-fed mothers developed atherosclerosis and non-alcoholic fatty liver (NAFL) with profound steatosis in their early adulthood with and without HFD. SIGNIFICANCE: Diet-induced MHC differentially expressed placental lipid genes that may program the offspring to develop atherosclerosis and associated NAFL in early adulthood.

Robustness of Sparsely Distributed Representations to Adversarial Attacks in Deep Neural Networks.

Deep learning models have achieved an impressive performance in a variety of tasks, but they often suffer from overfitting and are vulnerable to adversarial attacks. Previous research has shown that dropout regularization is an effective technique that can improve model generalization and robustness. In this study, we investigate the impact of dropout regularization on the ability of neural networks to withstand adversarial attacks, as well as the degree of "functional smearing" between individual neurons in the network. Functional smearing in this context describes the phenomenon that a neuron or hidden state is involved in multiple functions at the same time. Our findings confirm that dropout regularization can enhance a network's resistance to adversarial attacks, and this effect is only observable within a specific range of dropout probabilities. Furthermore, our study reveals that dropout regularization significantly increases the distribution of functional smearing across a wide range of dropout rates. However, it is the fraction of networks with lower levels of functional smearing that exhibit greater resilience against adversarial attacks. This suggests that, even though dropout improves robustness to fooling, one should instead try to decrease functional smearing.