Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid

Duchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disease arising from mutations in the dystrophin gene. Upregulation of utrophin to compensate for the missing dystrophin offers a potential therapy independent of patient genotype. The first‐in‐class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial. Promising efficacy and evidence of target engagement was observed in DMD patients after 24 weeks of treatment, however trial endpoints were not met after 48 weeks. The objective of this study was to understand the mechanism of action of ezutromid which could explain the lack of sustained efficacy and help development of new generations of utrophin modulators. Using chemical proteomics and phenotypic profiling we show that the aryl hydrocarbon receptor (AhR) is a target of ezutromid. Several lines of evidence demonstrate that ezutromid binds AhR with an apparent K_D of 50 nm  and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies.     

Charge‐Induced Unzipping of Isolated Proteins to a Defined Secondary Structure

Here we present a combined experimental and theoretical study on the secondary structure of isolated proteins as a function of charge state. In infrared spectra of the proteins ubiquitin and cytochrome c, amide I (C=O stretch) and amide II (N–H bend) bands can be found at positions that are typical for condensed‐phase proteins. For high charge states a new band appears, substantially red‐shifted from the amide II band observed at lower charge states. The observations are interpreted in terms of Coulomb‐driven transitions in secondary structures from mostly helical to extended C₅‐type hydrogen‐bonded structures. Support for this interpretation comes from simple energy considerations as well as from quantum chemical calculations on model peptides. This transition in secondary structure is most likely universal for isolated proteins that occur in mass spectrometric experiments.     

The Early Scientific Contributions of J. Robert Oppenheimer: Why Did the Scientific Community Miss the Black Hole Opportunity?

We assess the scientific value of Oppenheimer’s research on black holes in order to explain its neglect by the scientific community, and even by Oppenheimer himself. Looking closely at the scientific culture and conceptual belief system of the 1930s, the present article seeks to supplement the existing literature by enriching the explanations and complicating the guiding questions. We suggest a rereading of Oppenheimer as a figure both more intriguing for the history of astrophysics and further ahead of his time than is commonly supposed.     

Gold nanoparticles produced in a microalga

An efficient biological route to production of gold nanoparticles which allows the nanoparticles to be easily recovered remains elusive. Live cells of the green microalga Chlorella vulgaris were incubated with a solution of gold chloride and harvested by centrifugation. Nanoparticles inside intact cells were identified by transmission electron microscopy and confirmed to be metallic gold by synchrotron based X-ray powder diffraction and X-ray absorption spectroscopy. These intracellular gold nanoparticles were 40–60 nm in diameter. At a concentration of 1.4% Au in the alga, a better than 97% recovery of the gold from solution was achieved. A maximum of 4.2% Au in the alga was obtained. Exposure of C. vulgaris to solutions containing dissolved salts of palladium, ruthenium, and rhodium also resulted in the production of the corresponding nanoparticles within the cells. These were surmised to be also metallic, but were produced at a much lower intracellular concentration than achieved with gold. Iridium was apparently toxic to the alga. No nanoparticles were observed using platinum solutions. C. vulgaris provides a possible route to large scale production of gold nanoparticles.     

Superdiffusion and encounter rates in diluted,low dimensional worlds

Rate limitation due to encounters is fundamental to many ecological interactions. Since encounter rate governs reaction rates, and thus, dynamics of systems, it deserves systematic study. In classical population biology, ecological dynamics rely on the assumption of perfectly mixed interacting entities (e.g., individuals, populations, etc.) in a spaceless world. The so-called mean field assumption assumes that encounter rates are driven exclusively by changes in the density of the interacting entities and not on how they are distributed or move in space. Therefore, the mean field assumption does not give any insight into relevant spatiotemporal statistical properties produced by the trajectories of moving entities through space. In the present study, we develop spatially explicit simulations of random walking particles (i.e., Lévy walkers) to evaluate encounter rate constraints beyond the mean field assumption. We show that encounter rate fluctuations are driven not only by physical aspects such as the size or the velocity of the interacting particles, but also by different motion patterns. In particular, superdiffusion phenomena might be relevant at low densities and/or low spatial dimensionality. Finally, we discuss potential adaptive responses of living organisms that may allow individuals to control how they diffuse through space and/or the spatial dimensions employed in the exploration process.     

Uniform and Lipschitz homotopy classes of maps

If is a compact connected polyhedron, we associate with each uniform homotopy class of uniformly continuous mappings from the real line into an element of where is the space of uniformly continuous functions from to and is the subspace of bounded uniformly continuous functions. This map from uniform homotopy classes of functions to is surjective. If is the -dimensional torus, it is bijective, while if is a compact orientable surface of genus 1$">, it is not injective.

In higher dimensions we have to consider smooth Lipschitz homotopy classes of smooth Lipschitz maps from suitable Riemannian manifolds to compact smooth manifolds With each such Lipschitz homotopy class we associate an element of where is the dimension of is the space of bounded continuous functions from the positive real axis to and is the set of all such that