The Impact of Small Molecule Binding on the Energy Landscape of the Intrinsically Disordered Protein C-Myc

Intrinsically disordered proteins are attractive therapeutic targets owing to their prevalence in several diseases. Yet their lack of well-defined structure renders ligand discovery a challenging task. An intriguing example is provided by the oncoprotein c-Myc, a transcription factor that is over expressed in a broad range of cancers. Transcriptional activity of c-Myc is dependent on heterodimerization with partner protein Max. This protein-protein interaction is disrupted by the small molecule 10058-F4 (1), that binds to monomeric and disordered c-Myc. To rationalize the mechanism of inhibition, structural ensembles for the segment of the c-Myc domain that binds to 1 were computed in the absence and presence of the ligand using classical force fields and explicit solvent metadynamics molecular simulations. The accuracy of the computed structural ensembles was assessed by comparison of predicted and measured NMR chemical shifts. The small molecule 1 was found to perturb the composition of the apo equilibrium ensemble and to bind weakly to multiple distinct c-Myc conformations. Comparison of the apo and holo equilibrium ensembles reveals that the c-Myc conformations binding 1 are already partially formed in the apo ensemble, suggesting that 1 binds to c-Myc through an extended conformational selection mechanism. The present results have important implications for rational ligand design efforts targeting intrinsically disordered proteins

A discrete approach for modeling cell–matrix adhesions

During recent years the interaction between the extracellular matrix and the cytoskeleton of the cell has been object of numerous studies due to its importance in cell migration processes. These interactions are performed through protein clutches, known as focal adhesions. For migratory cells these focal adhesions along with force generating processes in the cytoskeleton are responsible for the formation of protrusion structures like lamellipodia or filopodia. Much is known about these structures: the different proteins that conform them, the players involved in their formation or their role in cell migration. Concretely, growth-cone filopodia structures have attracted significant attention because of their role as cell sensors of their surrounding environment and its complex behavior. On this matter, a vast myriad of mathematical models has been presented to explain its mechanical behavior. In this work, we aim to study the mechanical behavior of these structures through a discrete approach. This numerical model provides an individual analysis of the proteins involved including spatial distribution, interaction between them, and study of different phenomena, such as clutches unbinding or protein unfolding

Development of an Exhaust System for Agricultural Tractors

The main sources of sound emitted by vehicles are the engine and the rolling noise produced by the tires. In case agricultural tractors are considered, the engine and the transmission are responsible of the main emissions since they often work in the fields on soft ground at low speeds. This work focuses on the combined acoustic and mechanical development of a new exhaust system for an existing agricultural tractor, with the aim of providing a product with improved acoustic performances and a neater design. The host vehicle is equipped with a 300 hp diesel engine which can be particularly noisy at low rpm, with a further constraint being the “under the bonnet” available volume to fit the system into. The existing exhaust system is the baseline for the engineering process. The acoustic design is carried out by a 1D simulation software based on an electro-acoustic analogy, while the design modelling is performed by using Solidworks® 3D CAD. After the design stage a prototype has been manufactured and tested at the MWL/KTH laboratory. The engineering process gave the product a cleaner design and allowed to identify feasible solutions ensuring increased sound attenuation performances

Uncertainty analysis of acoustic and non-acoustic parameters derived from four-microphone impedance tube measurements

The uncertainty related to measurements is fundamental for qualifying the method applied to the esti-mation of the quantities derived from an experimental test. In this paper an uncertainty analysis is given for the estimation of the intrinsic properties of fibrous and porous materials, i.e. the characteristic impe-dance and the characteristic wavenumber, from measurement data obtained by a four-microphone impe-dance tube. In addition, an uncertainty analysis is given for some other derived material properties, amongst which the flow resistivity. The uncertainty analysis is based on the principles contained in the Guide to the Expression of Uncertainty in Measurements (GUM) and on its supplement 1, concerning the propagation of distributions using a Monte Carlo (MC) method. The GUM and the MC frameworks are compared with each other in terms of accuracy and in terms of flexibility of use. The uncertainty arising from the process of sampling is also evaluated by testing several samples cut from the same material batch.(c) 2022 Elsevier Ltd. All rights reserved

Acoustic Properties of Absorbing Materials

Thanks to the progress made in materials research and to the introduction of innovative manufacturing technologies, a wide range of sound-absorbing elements are currently available to adjust the acoustic features of an environment [...

The denorms round robin test: measurement procedure and post-processing of time data

The DENORMS Round Robin Test (RRT) is intended to study and improve the techniques used for the determination of the sound absorption coefficient of materials, with particular focus on the lowfrequency range and on measurements in reverberation rooms. It is well known that the main reason why it is difficult to extend the frequency range of interest below 100 Hz is the low modal density. The modal behavior of a room is dependent on its geometry and this is one of the reasons why a discrepancy of the results coming from different laboratories can be found even if the same material is tested. This paper describes the measurement procedure developed to allow uniform acquisition and post-processing of acoustic response data of laboratories participating in the RRT, with and without absorbing materials inside. The tests and the post-processing operations performed on the measured data are also discussed in the paper.status: accepte