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Several case history failures of slope systems have highlighted that the instability onset in loose materials can be triggered under prevailed drained conditions and stress paths that can be represented by constant shear drained (CSD) loading. This study uses the anisotropic critical state theory (ACST) to assess the effect of fabric anisotropy and loading characteristics (e.g., Lode angle and principal stress direction) on the instability onset under CSD stress paths, comparing our numerical-based observations with available experimental information. Towards this end, the ACST-based SANISAND-F model’s performance under CSD stress paths is also assessed. In addition, multiaxial conditions are incorporated through the estimation of instability surfaces. The numerical simulations are useful in explaining that the instability onset under CSD loading is dictated by a trade-off of volumetric strain components. Moreover, the results show an important effect of fabric anisotropy on the instability stress ratio (𝜂𝑓 ). For conditions representative of common experimental setups, 𝜂𝑓 decreases with the increase of the Lode angle and the major principal stress inclination, and 𝜂𝑓 increases with the increase of initial fabric intensity, consistent with available experimental evidence. However, these trends can change based on the interaction between the Lode angle and loading/fabric directions; hence, departing from typical experimental observations. Finally, we discuss the potential of a simplified approach to estimate 𝜂𝑓 analytically, including fabric effects. 

ABSTRACT There is an urgent need for strategies to discover secondary drugs to prevent or disrupt antimicrobial resistance (AMR), which is causing >700,000 deaths annually. Here, we demonstrate that tetracycline-resistant (Tet R ) Escherichia coli undergoes global transcriptional and metabolic remodeling, including downregulation of tricarboxylic acid cycle and disruption of redox homeostasis, to support consumption of the proton motive force for tetracycline efflux. Using a pooled genome-wide library of single-gene deletion strains, at least 308 genes, including four transcriptional regulators identified by our network analysis, were confirmed as essential for restoring the fitness of Tet R E. coli during treatment with tetracycline. Targeted knockout of ArcA, identified by network analysis as a master regulator of this new compensatory physiological state, significantly compromised fitness of Tet R E. coli during tetracycline treatment. A drug, sertraline, which generated a similar metabolome profile as the arcA knockout strain, also resensitized Tet R E. coli to tetracycline. We discovered that the potentiating effect of sertraline was eliminated upon knocking out arcA , demonstrating that the mechanism of potential synergy was through action of sertraline on the tetracycline-induced ArcA network in the Tet R strain. Our findings demonstrate that therapies that target mechanistic drivers of compensatory physiological states could resensitize AMR pathogens to lost antibiotics. IMPORTANCE Antimicrobial resistance (AMR) is projected to be the cause of >10 million deaths annually by 2050. While efforts to find new potent antibiotics are effective, they are expensive and outpaced by the rate at which new resistant strains emerge. There is desperate need for a rational approach to accelerate the discovery of drugs and drug combinations that effectively clear AMR pathogens and even prevent the emergence of new resistant strains. Using tetracycline-resistant (Tet R ) Escherichia coli , we demonstrate that gaining resistance is accompanied by loss of fitness, which is restored by compensatory physiological changes. We demonstrate that transcriptional regulators of the compensatory physiologic state are promising drug targets because their disruption increases the susceptibility of Tet R E. coli to tetracycline. Thus, we describe a generalizable systems biology approach to identify new vulnerabilities within AMR strains to rationally accelerate the discovery of therapeutics that extend the life span of existing antibiotics. 

Spherically focused transducers have been long relied on to target acoustic energy delivery. Yet, these structures have limitations with respect to size and mobility for medical treatment applications. Recent developments in the field of reconfigurable structures reveal that the ancient art of origami inspires new platforms by which to enable spherical shapes that are additionally foldable for ease of transport. This research explores the opportunities for a unique, flat foldable doubly curved tessellated array to enable wave focusing capability similar to an ideal medical transducer shape: the spherical cap transducer. An analytical model of the doubly curved array is created and validated against data collected from a proof-of-concept array. The model is then leveraged to understand how the array design and complexity relatively govern the wave focusing capability. The findings show that doubly curved acoustic arrays do not require excessive facet refinement to achieve wave focusing similar to nominal spherically focused transducers. Yet, the optimal frequencies for which such capability is borne out vary substantially on the basis of array design. The discoveries of this research motivate future consideration of flat foldable doubly curved acoustic arrays for potential implementation into medical transducer development for hard-to-access surgical treatments.