Automated model discovery for human brain using Constitutive Artificial Neural Networks.

The brain is our softest and most vulnerable organ, and understanding its physics is a challenging but significant task. Throughout the past decade, numerous competing models have emerged to characterize its response to mechanical loading. However, selecting the best constitutive model remains a heuristic process that strongly depends on user experience and personal preference. Here we challenge the conventional wisdom to first select a constitutive model and then fit its parameters to data. Instead, we propose a new strategy that simultaneously discovers both model and parameters. We integrate more than a century of knowledge in thermodynamics and state-of-the-art machine learning to build a Constitutive Artificial Neural Network that enables automated model discovery. Our design paradigm is to reverse engineer the network from a set of functional building blocks that are, by design, a generalization of popular constitutive models, including the neo Hookean, Blatz Ko, Mooney Rivlin, Demiray, Gent, and Holzapfel models. By constraining input, output, activation functions, and architecture, our network a priori satisfies thermodynamic consistency, objectivity, symmetry, and polyconvexity. We demonstrate that-out of more than 4000 models-our network autonomously discovers the model and parameters that best characterize the behavior of human gray and white matter under tension, compression, and shear. Importantly, our network weights translate naturally into physically meaningful parameters, such as shear moduli of 1.82kPa, 0.88kPa, 0.94kPa, and 0.54kPa for the cortex, basal ganglia, corona radiata, and corpus callosum. Our results suggest that Constitutive Artificial Neural Networks have the potential to induce a paradigm shift in soft tissue modeling, from user-defined model selection to automated model discovery. Our source code, data, and examples are available at https://github.com/LivingMatterLab/CANN. STATEMENT OF SIGNIFICANCE: Human brain is ultrasoft, difficult to test, and challenging to model. Numerous competing constitutive models exist, but selecting the best model remains a matter of personal preference. Here we automate the process of model selection. We formulate the problem of autonomous model discovery as a neural network and capitalize on the powerful optimizers in deep learning. However, rather than using a conventional neural network, we reverse engineer our own Constitutive Artificial Neural Network from a set of modular building blocks, which we rationalize from common constitutive models. When trained with tension, compression, and shear experiments of gray and white matter, our network simultaneously discovers both model and parameters that describes the data better than any existing invariant-based model. Our network could induce a paradigm shift from user-defined model selection to automated model discovery.

Sex Matters: A Comprehensive Comparison of Female and Male Hearts.

Cardiovascular disease in women remains under-diagnosed and under-treated. Recent studies suggest that this is caused, at least in part, by the lack of sex-specific diagnostic criteria. While it is widely recognized that the female heart is smaller than the male heart, it has long been ignored that it also has a different microstructural architecture. This has severe implications on a multitude of cardiac parameters. Here, we systematically review and compare geometric, functional, and structural parameters of female and male hearts, both in the healthy population and in athletes. Our study finds that, compared to the male heart, the female heart has a larger ejection fraction and beats at a faster rate but generates a smaller cardiac output. It has a lower blood pressure but produces universally larger contractile strains. Critically, allometric scaling, e.g., by lean body mass, reduces but does not completely eliminate the sex differences between female and male hearts. Our results suggest that the sex differences in cardiac form and function are too complex to be ignored: the female heart is not just a small version of the male heart. When using similar diagnostic criteria for female and male hearts, cardiac disease in women is frequently overlooked by routine exams, and it is diagnosed later and with more severe symptoms than in men. Clearly, there is an urgent need to better understand the female heart and design sex-specific diagnostic criteria that will allow us to diagnose cardiac disease in women equally as early, robustly, and reliably as in men. Systematic Review Registration: https://livingmatter.stanford.edu/.

Condensation tendency and planar isotropic actin gradient induce radial alignment in confined monolayers.

A monolayer of highly motile cells can establish long-range orientational order, which can be explained by hydrodynamic theory of active gels and fluids. However, it is less clear how cell shape changes and rearrangement are governed when the monolayer is in mechanical equilibrium states when cell motility diminishes. In this work, we report that rat embryonic fibroblasts (REF), when confined in circular mesoscale patterns on rigid substrates, can transition from the spindle shapes to more compact morphologies. Cells align radially only at the pattern boundary when they are in the mechanical equilibrium. This radial alignment disappears when cell contractility or cell-cell adhesion is reduced. Unlike monolayers of spindle-like cells such as NIH-3T3 fibroblasts with minimal intercellular interactions or epithelial cells like Madin-Darby canine kidney (MDCK) with strong cortical actin network, confined REF monolayers present an actin gradient with isotropic meshwork, suggesting the existence of a stiffness gradient. In addition, the REF cells tend to condense on soft substrates, a collective cell behavior we refer to as the 'condensation tendency'. This condensation tendency, together with geometrical confinement, induces tensile prestretch (i.e. an isotropic stretch that causes tissue to contract when released) to the confined monolayer. By developing a Voronoi-cell model, we demonstrate that the combined global tissue prestretch and cell stiffness differential between the inner and boundary cells can sufficiently define the cell radial alignment at the pattern boundary.

Patterning Neuroepithelial Cell Sheet via a Sustained Chemical Gradient Generated by Localized Passive Diffusion Devices.

Recent advances in human pluripotent stem cells (hPSCs)-derived in vitro models open a new avenue for studying early stage human development. While current approaches leverage the self-organizing capability of hPSCs, it remains unclear whether extrinsic morphogen gradients are sufficient to pattern neuroectoderm tissues in vitro. While microfluidics or hydrogel-based approaches to generate chemical gradients are well-established, these systems either require continuous pumping or encapsulating cells in gels, making it difficult for adaptation in standard biology laboratories and downstream analysis. In this work, we report a new device design that leverages localized passive diffusion, or LPaD for short, to generate a stable chemical gradient in an open environment. As LPaD is operated simply by media changing, common issues for microfluidic systems such as leakage, bubble formation, and contamination can be avoided. The device contains a slit carved in a film filled with solid gelatin and connected to a static aqueous morphogen reservoir. Concentration gradients generated by the device were visualized via DAPI fluorescent intensity and were found to be stable for up to 168 h. Using this device, we successfully induced cellular response of Madin-Darby canine kidney (MDCK) cells to the concentration gradient of a small-molecule drug, cytochalasin D. Furthermore, we efficiently patterned the dorsal-ventral axis of hPSC-derived forebrain neuroepithelial cells with the sonic hedgehog (Shh) signal gradient generated by the LPaD devices. Together, LPaD devices are powerful tools to control the local chemical microenvironment for engineering organotypic structures in vitro.

Knowledge and Knowledge Needs about Lyme Disease among Occupational and Recreational Users of the Outdoors.

As the prevalence of Lyme disease increases across Canada, it is imperative that the educational needs of at-risk groups be identified. The current study compared the level of knowledge and the knowledge needs about Lyme disease among individuals that spend time outdoors for work and for recreational purposes. Between December 2018 and February 2019, a survey was distributed to outdoor organizations across New Brunswick, Canada. Within the current sample of 137 individuals, 36% spent time outdoors for their occupation and 64% for recreational activities. Results showed no significant difference between these groups with regard to their level of knowledge, perceived efficacy and performance of various methods of prevention, and educational needs. Overall, the entire sample reported a low level of knowledge about Lyme disease. Participants perceived each prevention behavior to be at least somewhat effective, and behaviors perceived to be more effective were more likely to be carried out, but the performance of the behaviors varied. The most frequently performed behaviors included wearing long pants and protective footwear. Participants identified several aspects of Lyme disease about which they would like to have more information. The findings call attention to the specific needs of at-risk groups that must be considered when developing educational interventions.

Chest X-ray quantification of admission lung congestion as a prognostic factor in patients admitted for worsening heart failure from the ICALOR cohort study.

INTRODUCTION: Chest X-ray (CXR) widely used, but the prognostic value of congestion quantification using CXR remains uncertain. The main objective of the present study was to assess whether initial quantification of lung congestion evaluated by CXR [and its interplay with estimated plasma volume status (ePVS)] in patients with worsening heart failure (WHF) is associated with in-hospital and short-term clinical outcome. METHODS: We studied 117 patients hospitalized for WHF in the ICALOR HF disease management program. Pulmonary congestion was estimated using congestion score index (CSI, range 0 to 3) evaluated from 6 lung areas on CXR. Systemic congestion was assessed by ePVS. Logistic regression analysis was used to assess length of stay and the composite of all-cause death or HF re-hospitalization at 90 days. RESULTS: Patients were divided according to the median of admission CSI (median = 2.20) and ePVS (median = 5.38). Higher CSI was significantly associated with higher pulmonary arterial systolic pressure in multivariable models. Multivariable models showed patients with high CSI/high ePVS had a 6-day longer length of stay [OR (95% CI) = 6.78 (1.82-29.79), p < 0.01] and 5-fold higher risk of 90-day composite outcome [OR (95% CI) = 5.13 (1.26-25.11) p = 0.03] compared to patients with low CSI/low ePVS, while other configurations (either isolated high CSI or high ePVS) yielded neutral associations. Furthermore, CSI and ePVS significantly improved reclassification on top of clinical covariates for the composite outcome [Net reclassification index = 37.3% (0.52-87.0), p = 0.046]. CONCLUSION: An admission assessment of pulmonary and systemic congestion in WHF patients using CSI and ePVS can identify a cluster of high-risk patients at short-term outcomes.

Interactions between mitral valve and left ventricle analysed by 2D speckle tracking in patients with mitral valve prolapse: one more piece to the puzzle.

AIMS: Two-dimensional echocardiography often reveals abnormal left ventricle (LV) lateral wall kinetics in patients presenting with mitral valve prolapse (MVP). However, relations between MVP and LV deformation are not clearly established. The aim of this study was to assess and quantify mitral valve chordae, leaflets, and LV myocardial interactions using speckle tracking echocardiography (STE). METHODS AND RESULTS: Using STE-derived longitudinal strain curves, LV peak longitudinal strain (PLS, %), post-systolic index (PSI), and pre-stretch index (PST) were analysed in 100 patients with MVP and normal LV ejection fraction. Global, regional, and segmental values were compared according to mitral regurgitation severity and MVP location. Twenty healthy subjects served as control patients. There was no significant difference among control and MVP group for global and regional PLS (-23.7 ± 3.2 vs. -23.1 ± 2.2). In contrast, patients with MVP had significantly higher values of global PST (3.2 ± 4.1 vs. 1.3 ± 1.2; P = 0.01) and global PSI (3.2 ± 0.4 vs. 1.7 ± 1.1; P = 0.05) compared with controls, located mainly in the lateral wall and basal segments. Both anterior and posterior MVPs were responsible for PSI in basal inferior segments and PST in anterior ones. Mid-wall segmental deformation pattern changes were mainly observed at the level of the segments adjacent to the papillary muscle. CONCLUSION: This study supports the hypothesis that pathological early-systolic shortening and late systolic, post-systolic deformation are attributed to an increased interaction between wall deformation and mitral valve events in patients with MVP. STE is a useful tool in the assessment of interplays between MV leaflets and myocardium and helps to demonstrate changes in temporal pattern of myocardial deformation.