Sensitivity of stress and strain calculations to passive material parameters in cardiac mechanical models using unloaded geometries

Cardiac stress (load) and strain (stretch) are widely studied indicators of cardiac function and outcome, but are difficult or impossible to directly measure in relation to the cardiac microstructure. An alternative approach is to estimate these states using computer methods and image-based measurements, but this still requires knowledge of the tissue material properties and the unloaded state, both of which are difficult to determine. In this work, we tested the sensitivity of these two interdependent unknowns (reference geometry and material parameters) on stress and strain calculations in cardiac tissue. Our study used a finite element model of the human ventricle, with a hyperelastic passive material model, and was driven by a cell model mediated active contraction. We evaluated 21 different published parameter sets for the five parameters of the passive material model, and for each set we optimised the corresponding unloaded geometry and contractility parameter to model a single pressure-volume loop. The resulting mechanics were compared, and calculated systolic stresses were largely insensitive to the chosen parameter set when an unloading algorithm was used. Meanwhile, material strain calculations varied substantially depending on the choice of material parameters. These results indicate that determining the correct material and unloaded configuration may be highly important to understand strain driven processes, but less so for calculating stress estimates.     

Label‐free multi‐parametric imaging of single cells: dual picosecond optoacoustic microscopy

Advances in microscopy with new visualization possibilities often bring dramatic progress to our understanding of the intriguing cellular machinery. Picosecond optoacoustic micro‐spectroscopy is an optical technique based on ultrafast pump‐probe generation and detection of hypersound on time durations of picoseconds and length scales of nanometers. It is experiencing a renaissance as a versatile imaging tool for cell biology research after a plethora of applications in solid‐state physics. In this emerging context, this work reports on a dual‐probe architecture to carry out real‐time parallel detection of the hypersound propagation inside a cell that is cultured on a metallic substrate, and of the hypersound reflection at the metal/cell adhesion interface. Using this optoacoustic modality, several biophysical properties of the cell can be measured in a noncontact and label‐free manner. Its abilities are demonstrated with the multiple imaging of a mitotic macrophage‐like cell in a single run experiment.      

Assessment of a large number of empirical plant species niche models by elicitation of knowledge from two national experts

Quantitative models play an increasing role in exploring the impact of global change on biodiversity. To win credibility and trust, they need validating. We show how expert knowledge can be used to assess a large number of empirical species niche models constructed for the British vascular plant and bryophyte flora. Key outcomes were (a) scored assessments of each modeled species and niche axis combination, (b) guidance on models needing further development, (c) exploration of the trade‐off between presenting more complex model summaries, which could lead to more thorough validation, versus the longer time these take to evaluate, (d) quantification of the internal consistency of expert opinion based on comparison of assessment scores made on a random subset of models evaluated by both experts. Overall, the experts assessed 39% of species and niche axis combinations to be “poor” and 61% to show a degree of reliability split between “moderate” (30%), “good” (25%), and “excellent” (6%). The two experts agreed in only 43% of cases, reaching greater consensus about poorer models and disagreeing most about models rated as better by either expert. This low agreement rate suggests that a greater number of experts is required to produce reliable assessments and to more fully understand the reasons underlying lack of consensus. While area under curve (AUC) statistics showed generally very good ability of the models to predict random hold‐out samples of the data, there was no correspondence between these and the scores given by the experts and no apparent correlation between AUC and species prevalence. Crowd‐sourcing further assessments by allowing web‐based access to model fits is an obvious next step. To this end, we developed an online application for inspecting and evaluating the fit of each niche surface to its training data.     

Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain

Virulent H5N1 strains of influenza virus often harbor a D92E point mutation in the nonstructural protein NS1. This crucial mutation has been correlated with increased virulence and/or cytokine resistance, but the structural implications of such a change are still unclear. Furthermore, NS1 protein could also be a potential target for the development of novel antiviral agents against H5N1 strains. Therefore, a reasonable 3D model of H5N1 NS1 is important for the understanding of the molecular basis of increased virulence and the design of novel antiviral agents. Based on the crystal structure of a non-H5N1 NS1 protein, a model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations. It was found that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues, thereby activating phosphorylation of NS1. Figure Superposition of snapshots picked from the two molecular dynamic (MD) trajectories: a H5N1 NS1 homology model and b non-H5N1 NS1 crystal structure after 0 (green ribbon), 5 (blue ribbon) and 10 ns (pink ribbon) MD simulation     

Bovine annulus fibrosus hydration affects rate-dependent failure mechanics in tension

The high water content of the intervertebral disc is essential to its load bearing function and viscoelastic mechanical behavior. One of the primary biochemical changes associated with disc degeneration is the loss of proteoglycans, which leads to tissue dehydration. While previous studies have reported the effects of in vivo degeneration on annulus fibrosus (AF) failure mechanics, the independent role of water remains unclear, as does the tissue’s rate-dependent failure response. Our first objective was to determine the effect of loading rate on AF failure properties in tension; our second objective was to quantify the effect of water content on failure properties. Water content was altered through enzymatic digestion of glycosaminoglycans (GAGs) and through osmotic loading. Bovine AF specimens were tested monotonically to failure along the circumferential direction at 0.00697%/s or 6.97%/s. Increased loading rate resulted in a ∼50% increase in linear-region modulus, failure stress, and strain energy density across all treatment groups (p < 0.001). Decreased GAG and water contents resulted in decreased modulus, failure stress, and strain energy density; however, these differences were only observed at the low loading rate (p < 0.05; no changes at high rate). Osmotic loading was used to evaluate the effect of hydration independently from GAG composition, resulting in similar decreases in water content, modulus, and strain energy density. This suggests that hydration is essential for maintaining tissue stiffness and energy absorption capacity, rather than strength, and that GAGs contribute to tissue strength independently from mediating water content.     

Intermediate fenestrations reduce flow reversal in a silicone model of Stanford Type B aortic dissection

Pulsatile, three-dimensional hemodynamic forces influence thrombosis, and may dictate progression of aortic dissection. Intimal flap fenestration and blood pressure are clinically relevant variables in this pathology, yet their effects on dissection hemodynamics are poorly understood. The goal of this study was to characterize these effects on flow in dissection models to better guide interventions to prevent aneurysm formation and false lumen flow. Silicone models of aortic dissection with mobile intimal flap were fabricated based on patient images and installed in a flow loop with pulsatile flow. Flow fields were acquired via 4-dimensional flow MRI, allowing for quantification and visualization of relevant fluid mechanics. Pulsatile vortices and jet-like structures were observed at fenestrations immediately past the proximal entry tear. False lumen flow reversal was significantly reduced with the addition of fenestrations, from 19.2 ± 3.3% in two-tear dissections to 4.67 ± 1.5% and 4.87 ± 1.7% with each subsequent fenestration. In contrast, increasing pressure did not cause appreciable differences in flow rates, flow reversal, and vortex formation. Increasing the number of intermediate tears decreased flow reversal as compared to two-tear dissection, which may prevent false lumen thrombosis, promoting persistent false lumen flow. Vortices were noted to result from transluminal fluid motion at distal tear sites, which may lead to degeneration of the opposing wall. Increasing pressure did not affect measured flow patterns, but may contribute to stress concentrations in the aortic wall. The functional and anatomic assessment of disease with 4D MRI may aid in stratifying patient risk in this population.     

Living with observational data in biological anthropology

The establishment of cause and effect relationships is a fundamental objective of scientific research. Many lines of evidence can be used to make cause–effect inferences. When statistical data are involved, alternative explanations for the statistical relationship need to be ruled out. These include chance (apparent patterns due to random factors), confounding effects (a relationship between two variables because they are each associated with an unmeasured third variable), and sampling bias (effects due to preexisting properties of compared groups). The gold standard for managing these issues is a controlled randomized experiment. In disciplines such as biological anthropology, where controlled experiments are not possible for many research questions, causal inferences are made from observational data. Methods that statisticians recommend for this difficult objective have not been widely adopted in the biological anthropology literature. Issues involved in using statistics to make valid causal inferences from observational data are discussed.     

Exploring the antimalarial potential of the methoxy-thiazinoquinone scaffold: Identification of a new lead candidate

A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action.     

ST6Gal-I–mediated sialylation of the epidermal growth factor receptor modulates cell mechanics and enhances invasion

Heterogeneity within the glycocalyx influences cell adhesion mechanics and signaling. However, the role of specific glycosylation subtypes in influencing cell mechanics via alterations of receptor function remains unexplored. It has been shown that the addition of sialic acid to terminal glycans impacts growth, development, and cancer progression. In addition, the sialyltransferase ST6Gal-I promotes epidermal growth factor receptor (EGFR) activity, and we have shown EGFR is an ‘allosteric mechano-organizer’ of integrin tension. Here, we investigated the impact of ST6Gal-I on cell mechanics. Using DNA-based tension gauge tether probes of variable thresholds, we found that high ST6Gal-I activity promotes increased integrin forces and spreading in Cos-7 and OVCAR3, OVCAR5, and OV4 cancer cells. Further, employing inhibitors and function-blocking antibodies against β1, β3, and β5 integrins and ST6Gal-I targets EGFR, tumor necrosis factor receptor, and Fas cell surface death receptor, we validated that the observed phenotypes are EGFR-specific. We found that while tension, contractility, and adhesion are extracellular-signal-regulated kinase pathway-dependent, spreading, proliferation, and invasion are phosphoinositide 3-kinase-Akt serine/threonine kinase dependent. Using total internal reflection fluorescence microscopy and flow cytometry, we also show that high ST6Gal-I activity leads to sustained EGFR membrane retention, making it a key regulator of cell mechanics. Our findings suggest a novel sialylation-dependent mechanism orchestrating cellular mechanics and enhancing cell motility via EGFR signaling.