Repetitive strain injury | EPFL Graph Search

A repetitive strain injury (RSI) is an injury to part of the musculoskeletal or nervous system caused by repetitive use, vibrations, compression or long periods in a fixed position. Other common names include repetitive stress injury, repetitive stress disorders, cumulative trauma disorders (CTDs), and overuse syndrome. Signs and symptoms Some examples of symptoms experienced by patients with RSI are aching, pulsing pain, tingling and extremity weakness, initially presenting with intermittent discomfort and then with a higher degree of frequency. Definition Repetitive strain injury (RSI) and associative trauma orders are umbrella terms used to refer to several discrete conditions that can be associated with repetitive tasks, forceful exertions, vibrations, mechanical compression, sustained or awkward positions, or repetitive eccentric contractions. The exact terminology is controversial, but the terms now used by the United States Department of

Lead Optimisation of a Novel Small Molecule Notch Inhibitor

Viktoria Reinmüller

Notch signalling represents a form of cell-to-cell communication that plays a pivotal role for cellular organisation during embryonic and postnatal development, as well as in the homeostasis of adult organs and tissues. Malfunction of this signalling pathway leads to aberrant regulation of the activities of the cells and may result in the loss of their integrity. The consequences include developmental defects, inherited disease syndromes as well as cancer. Accordingly, the discovery of Notch signalling regulating agents is highly desirable in order to extend the possibilities of clinical treatments providing benefits to patients suffering from Notch-associated diseases. In the frame of the present thesis, the initial steps in the lead optimisation of a novel small molecule Notch inhibitor were investigated. This compound, herein referred to as CB103, had been recently discovered in our laboratory by means of phenotypic high-throughput screenings of small molecule libraries for Notch regulators. CB103 turned out to exhibit an unconventional mode of action within the scope of known small molecule Notch inhibitors, due to its ability to block the NICD-mediated, thus activated form of the signalling pathway. However, the concrete cellular targets remained unknown. The aims of the present thesis comprised the structural optimisation and the concomitant retrospective identification of the cellular target molecules of CB103. This was pursued by implementing a repetitive cycle of the redesign of derivatives, their synthesis and their bioactivity assessment, leading to a comprehensive library of direct CB103 analogues. These investigations resulted not only in the identification of additional Notch inhibiting derivatives with in vivo activity, but surprisingly also in the discovery of molecules that appear to enhance Notch signalling. Moreover, the detailed knowledge about the structure-activity relationship was used to develop tagged versions of CB103 for target identification experiments entailing pull-down assays and yeast-three-hybrid (Y3H) screens. In this context, the Y3H system identified the enzyme soluble epoxide hydrolase (sEH) as a true cellular interaction partner of CB103. Additional interesting protein candidates were revealed by the diverse pull-down approaches and are currently under further investigation.

EPFL2015

How Vibrio cholerae adapts to the environment: from cell shape transitions to antagonistic behavior

Leonardo Filipe Lemos Rocha

The bacterium Vibrio cholerae is the causative agent of the diarrheal disease cholera, which affects millions of people every year. Apart from being a human pathogen, V. cholerae is also a common member of aquatic habitats. Whilst the mechanism that allow it to transit from an environmental to a pathogenic lifestyle is still understudied, it is well established that virulence induction is linked to the bacterium's ability to sense its surroundings. Therefore, this thesis aimed to shed new light on the general sensing capacity of V. cholerae and its adaptation to the surrounding environment. Specifically, we explored the functions of the virulence-associated regulatory two-component system VarS/VarA, which was shown to regulate the major virulence factors of V. cholerae. In this thesis, we identified a new function of this regulatory system in modulating the pathogen's cellular shape. Precisely, we demonstrated that a strain lacking the response regulator VarA loses its normal curve-shaped morphology and transits to spherical shape during stationary phase of growth. This rounding phenotype was not observed on cells lacking the sensor histidine kinase VarS, which suggests the existence of additional VarA activators. Through analysis of the cells's peptidoglycan (PG), we found that the cause of the atypical shape was due to high abundance of dipeptides and reduced peptide cross-links. This abnormal PG composition and consequent cell rounding could be abrogated through cell wall recycling of wild type-derived PG subunits. Through a transposon mutagenesis screen, we identified the carbon storage regulator A (CsrA) as a key player in this phenotype. We showed that varA-deficient cells have an increased activity of CsrA, which led to an overproduction of the aspartate ammonia lyase enzyme (AspA). Our results indicate that AspA overproduction likely reduced the pool of aspartate in varA-deficient cells, which subsequently impaired the biosynthesis of the cell wall precursor meso-diaminopimelic acid. Ultimately, this compromised production of PG precursors resulted in the altered PG composition and consequent cell rounding. Furthermore, and consistent with findings in Enterobacteriaceae, our results also suggest that the VarA-CsrA regulatory circuit modulates chemotaxis and motility in V. cholerae. Finally, in two different collaborative studies, we also addressed how V. cholerae might interact with other bacteria in the environment taking bacterial antagonism strategies into consideration. Firstly, we showed that a subset of human gut microbiota isolates is able to withstand type VI secretion system (T6SS)-mediated attacks by V. cholerae in an immunity protein-independent manner. Moreover, our preliminary data indicates a superior T6SS-mediated killing potential from a specific environmental strain of V. cholerae compared to a particular toxigenic strain. Secondly, we demonstrated that the environmental V. cholerae strain SA7G harbors a specific plasmid, pSA7G1, that confers a competitive advantage over neighboring bacteria likely through type IV secretion system-mediated killing. Collectively, the findings of this thesis contribute to better understanding how V. cholerae adapts to the environment, namely with specific sensing-response mechanisms such as the VarA-CsrA signaling pathway.

EPFL2022

A geometrically exact model for thin magneto-elastic shells

Pedro Miguel Nunes Pereira de Almeida Reis, Matteo Pezzulla, Dong Yan

We develop a reduced model for hard-magnetic, thin, linear-elastic shells that can be actuated through an external magnetic field, with geometrically exact strain measures. Assuming a reduced kinematics based on the Kirchhoff-Love assumption, we derive a reduced twodimensional magneto-elastic energy that can be minimized through numerical analysis. In parallel, we simplify the reduced energy by expanding it up to the second order in the displacement field and provide a physical interpretation. Our theoretical analysis allows us to identify and interpret the two primary mechanisms dictating the magneto-elastic response: a combination of equivalent magnetic pressure and forces at the first order, and distributed magnetic torques at the second order. We contrast our reduced framework against a threedimensional nonlinear model by investigating three test cases involving the indentation and the pressure buckling of shells under magnetic loading. We find excellent agreement between the two approaches, thereby verifying our reduced model for shells undergoing nonlinear and non-axisymmetric deformations. We believe that our model for magneto-elastic shells will serve as a valuable tool for the rational design of magnetic structures, enriching the set of reduced magnetic models.