Denis Michel

Long considered neutral, synonymous codon usage is increasingly recognized as a regulatory layer of mRNA translation. Proteins expressed during proliferation are translated from mRNAs with codon compositions distinct from those encoding proteins in differentiated states, suggesting the existence of specialized translational programs. In hormone-receptor–positive breast cancer, estrogen receptor-alpha (ERα/ESR1) acts both as a driver of proliferation and as a maintainer of luminal identity, making its translational regulation particularly relevant. Here, we show that the transition of breast cancer cells from quiescent, differentiated states towards proliferative, less differentiated phenotypes, is accompanied by a systematic shift from G/C3- to A/U3-biased codon usage. ERα coding sequence architecture mirrors these translational programs through both global codon composition and position-dependent codon patterns. These features influence translational efficiency and likely modulate co-translational folding dynamics, thereby adjusting receptor abundance and functional outputs according to the prevailing translational program. Consistent with their functional importance, synonymous codon choices are subject to increased selective constraints within regions encoding structural and functional domains. Using engineer synonymous ERα variants, we demonstrate that codon usage fine-tunes receptor function across distinct cellular states. Together, our findings identify synonymous codon usage as a previously unrecognized mechanism linking translational programs to ERα expression and function.

Based on entropy considerations, Boltzmann proposed that our universe might be a fluctuation within an eternal background. Combined with gravitation, this idea leads to an alternative cosmological model, the Boltzmann Universe (BU), in which expansion and its apparent acceleration arise from gravitational free fall on hyperbolic trajectories. This collective inertial dispersion, in which cosmological redshift results from relativistic Doppler shifts along a geodesic congruence, reproduces key cosmological signatures such as the Hubble law, large-scale homogeneity and effective spatial flatness. Although its theoretical foundations differ from those of the standard cosmological model (Standard Universe, SU), the BU exhibits formal similarities with the SU, including analogous expansion descriptions and geometric representations, while leading to distinct distance-redshift relations. The BU provides an alternative special-relativistic parametrization of large-scale cosmic dispersion that does not require a cosmological constant or exotic fields, in which the role attributed in the SU to dark energy, driving expansion against gravity, is instead played by gravity itself.

The exponential factor of Arrhenius satisfactorily quantifies the energetic restriction of chemical reactions but is still awaiting a rigorous basis. Assuming that the Arrhenius equation should be based on statistical mechanics and is probabilistic in nature, two structures for this equation are compared, depending on whether the reactant energies are viewed as the mean values of specific energy distributions or as particular levels in a global energy distribution. In the first version, the Arrhenius exponential factor would be a probability that depends once on temperature, while in the second it is a ratio of probabilities that depends twice on temperature. These concurrent equations are tested using experimental data for the isomerization of 2-butene. This comparison reveals the fundamental structure of the Arrhenius law in isothermal systems and overlooked properties resulting from the introduction of reactant energies into the equation.

Under review since 2023-09-26 in Results in Optics

By depriving cancer cells of blood supplies of oxygen and nutrients, anti-angiogenic therapy is aimed at simultaneously asphyxiating and starving the cells. But in spite of its apparent logic, this strategy is generally counterproductive over the long term as the treatment seems to elicit malignancy. Since a defect of blood supply is expected to deprive tumours simultaneously of oxygen and nutrients naturally, we examine here these two deprivations, alone or in combination, on the phenotype and signalling pathways of moderately aggressive MCF7 cancer cells. Each deprivation induces some aspects of the aggressive and migratory phenotypes through activating several pathways, including HIF1-alpha as expected, but also SRF/MRTFA and TCF4/beta-catenin. Strikingly, the dual deprivation has strong cooperative effects on the upregulation of genes increasing the metastatic potential, such as four and a half LIM domains 2 (FHL2) and HIF1A-AS2 lncRNA, which have response elements for both pathways. Using anti-angiogenic agents as monotherapy is therefore questionable as it may give falsely promising short-term tumour regression, but could ultimately exacerbate aggressive phenotypes.

Estrogen receptor-alpha (ERα) is the driving transcription factor in 70% of breast cancers and its activity is associated with hormone dependent tumor cell proliferation and survival. Given the recurrence of hormone resistant relapses, understanding the etiological factors fueling resistance is of major clinical interest. Hypoxia, a frequent feature of the solid tumor microenvironment, has been described to promote endocrine resistance by triggering ERα down-regulation in both in vitro and in vivo models. Yet, the consequences of hypoxia on ERα genomic activity remain largely elusive. In the present study, transcriptomic analysis shows that hypoxia regulates a fraction of ERα target genes, underlying an important regulatory overlap between hypoxic and estrogenic signaling. This gene expression reprogramming is associated with a massive reorganization of ERα cistrome, highlighted by a massive loss of ERα binding sites. Profiling of enhancer acetylation revealed a hormone independent enhancer activation at the vicinity of genes harboring hypoxia inducible factor (HIFα) binding sites, the major transcription factors governing hypoxic adaptation. This activation counterbalances the loss of ERα and sustains hormone-independent gene expression. We describe hypoxia in luminal ERα (+) breast cancer as a key factor interfering with endocrine therapies, associated with poor clinical prognosis in breast cancer patients.

Although electromagnetic and acoustic waves profoundly differ in their nature, comparing their Doppler effects is instructive and reveals persistent conceptual traps. The principle of the Doppler effect was presented by Christian Doppler in 1842 long before the advent of relativity theory, but while the relativistic Doppler effect is now well established, its non-relativistic version retrospectively called classical, suffers from misleading intuitions such as: (1) there is no transverse classical Doppler effect; (2) the Galilean Doppler effect corresponds to the relativistic one without Lorentz dilation factor. Additional pitfalls concern the sound Doppler effect which, in addition to being Galilean, results from asymmetric contributions of the sources and receptors and depends on a material medium for its propagation, possibly modifying the effective velocity of the wave. Moreover, contrary to light, the information on the sound Doppler effect and the location of the source are transmitted through different channels, sound and light respectively, thereby complicating data interpretation and increasing confusion. A thorough revision is proposed here addressing these issues and providing a complete set of new candidate Doppler formulas, non-collinear, two- and three-dimensional and in their angular and linear versions.