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Load-bearing soft tissues normally show J-shaped stress–strain behaviors with high compliance at low strains yet high strength at high strains. They have high water content but are still tough and durable. By contrast, naturally derived hydrogels are weak and brittle. Although hydrogels prepared from synthetic polymers can be strong and tough, they do not have the desired bioactivity for emerging biomedical applications. Here, we present a thermomechanical approach to replicate the combinational properties of soft tissues in protein-based photocrosslinkable hydrogels. As a demonstration, we create a gelatin methacryloyl fiber hydrogel with soft tissue-like mechanical properties, such as low Young’s modulus (0.1 to 0.3 MPa), high strength (1.1 ± 0.2 MPa), high toughness (9,100 ± 2,200 J/m³), and high fatigue resistance (2,300 ± 500 J/m²). This hydrogel also resembles the biochemical and architectural properties of native extracellular matrix, which enables a fast formation of 3D interconnected cell meshwork inside hydrogels. The fiber architecture also regulates cellular mechanoresponse and supports cell remodeling inside hydrogels. The integration of tissue-like mechanical properties and bioactivity is highly desirable for the next-generation biomaterials and could advance emerging fields such as tissue engineering and regenerative medicine.

Single-cell RNA sequencing is a powerful tool to study developmental biology but does not preserve spatial information about tissue morphology and cellular interactions. Here, we combine single-cell and spatial transcriptomics with algorithms for data integration to study the development of the chicken heart from the early to late four-chambered heart stage. We create a census of the diverse cellular lineages in developing hearts, their spatial organization, and their interactions during development. Spatial mapping of differentiation transitions in cardiac lineages defines transcriptional differences between epithelial and mesenchymal cells within the epicardial lineage. Using spatially resolved expression analysis, we identify anatomically restricted expression programs, including expression of genes implicated in congenital heart disease. Last, we discover a persistent enrichment of the small, secreted peptide, thymosin beta-4, throughout coronary vascular development. Overall, our study identifies an intricate interplay between cellular differentiation and morphogenesis. Using single-cell and spatial transcriptomics in chicken hearts, here, the authors generate a census of cellular interactions from early to late four-chambered heart stage, identifying a distinct epicardial-mesenchymal cell population with a migratory phenotype.

Warming-induced changes in lake thermal and mixing regimes present risks to water quality and ecosystem services provided by U.S. lakes and reservoirs. Modulation of responses by different physical and hydroclimatic settings are not well understood. We explore the potential effects of climate change on 27 lake “archetypes” representative of a range of lakes and reservoirs occurring throughout the U.S. Archetypes are based on different combinations of depth, surface area, and water clarity. LISSS, a one-dimensional dynamic thermal simulation model, is applied to assess lake response to multiple mid-21st century change scenarios applied to nine baseline climate series from different hydroclimatic regions of the U.S. Results show surface water temperature increases of about 77 % of increase in average air temperature change. Bottom temperature changes are less (around 30 %) for deep lakes and in regions that maintain mid-winter air temperatures below freezing. Significant decreases in length of ice cover are projected, and the extent and strength of stratification will increase throughout the U.S., with systematic differences associated with depth, surface area, and clarity. These projected responses suggest a range of future challenges that lake managers are likely to face. Changes in thermal and mixing dynamics suggest increased risk of summer hypoxic conditions and cyanobacterial blooms. Increased water temperatures above the summer thermocline could be a problem for cold water fisheries management in many lakes. Climate-induced changes in water balance and mass inputs of nutrients may further exacerbate the vulnerability of lakes to climate change.

Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell–cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery.

Ischemic heart disease remains one of the most prominent causes of mortalities worldwide with heart transplantation being the gold-standard treatment option. However, due to the major limitations associated with heart transplants, such as an inadequate supply and heart rejection, there remains a significant clinical need for a viable cardiac regenerative therapy to restore native myocardial function. Over the course of the previous several decades, researchers have made prominent advances in the field of cardiac regeneration with the creation of human pluripotent stem cell-derived cardiomyocyte tissue engineered constructs. However, these engineered constructs exhibit a functionally immature, disorganized, fetal-like phenotype that is not equivalent physiologically to native adult cardiac tissue. Due to this major limitation, many recent studies have investigated approaches to improve pluripotent stem cell-derived cardiomyocyte maturation to close this large functionality gap between engineered and native cardiac tissue. This review integrates the natural developmental mechanisms of cardiomyocyte structural and functional maturation. The variety of ways researchers have attempted to improve cardiomyocyte maturation by mimicking natural development, known as natural engineering, is readily discussed. The main focus of this review involves the synergistic role of electrical and mechanical stimulation, extracellular matrix interactions, and non-cardiomyocyte interactions in facilitating cardiomyocyte maturation. Overall, even with these current natural engineering approaches, pluripotent stem cell-derived cardiomyocytes within three-dimensional engineered heart tissue still remain mostly within the early to late fetal stages of cardiomyocyte maturity. Therefore, although the end goal is to achieve adult phenotypic maturity, more emphasis must be placed on elucidating how the fetal microenvironment drives cardiomyocyte maturation. This information can then be utilized to develop natural engineering approaches that can emulate this fetal microenvironment and thus make prominent progress in pluripotent stem cell-derived maturity toward a more clinically relevant model for cardiac regeneration.

Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general acknowledgement of a hemodynamic-malformation link, the direct correlation between hemodynamics and PAA morphogenesis remains poorly understood. The elusiveness is largely due to difficulty in performing isolated hemodynamic perturbations and quantifying changes in-vivo. Previous in-vivo arch artery occlusion/ablation experiments either did not isolate the effects of hemodynamics, did not analyze the results in a 3D context or did not consider the effects of varying degrees of occlusion. Here, we overcome these limitations by combining minimally invasive occlusion experiments in the avian embryo with 3D anatomical models of development and in-silico testing of experimental phenomenon. We detail morphological and hemodynamic changes 24 hours post vessel occlusion. 3D anatomical models showed that occlusion geometries had more circular cross-sectional areas and more elongated arches than their control counterparts. Computational fluid dynamics revealed a marked change in wall shear stress-morphology trends. Instantaneous (in-silico) occlusion models provided mechanistic insights into the dynamic vessel adaptation process, predicting pressure-area trends for a number of experimental occlusion arches. We follow the propagation of small defects in a single embryo Hamburger Hamilton (HH) Stage 18 embryo to a more serious defect in an HH29 embryo. Results demonstrate that hemodynamic perturbation of the presumptive aortic arch, through varying degrees of vessel occlusion, overrides natural growth mechanisms and prevents it from becoming the dominant arch of the aorta.

Queer theory or critical gender studies are close relatives of critical race theory. The original critical race theorists stressed that their worldview also encapsulated radical theories on “gender.” The term “gender” is ambiguous. Humans are born male or female--designed to produce either sperm or eggs, even in cases of individuals with biological abnormalities. Individuals, including young children, can be confused about their biological sex, now a cultural contagion leading young people to make irreversible changes to their bodies. Culturally, a society should show empathy and offer to help young people through counseling and guidance, but we do not help children when we affirm his or her choice to assume a gender that conflicts with their biology.

Clinically serious congenital heart valve defects arise from improper growth and remodeling of endocardial cushions into leaflets. Genetic mutations have been extensively studied but explain less than 20% of cases. Mechanical forces generated by beating hearts drive valve development, but how these forces collectively determine valve growth and remodeling remains incompletely understood. Here, we decouple the influence of those forces on valve size and shape, and study the role of YAP pathway in determining the size and shape. The low oscillatory shear stress promotes YAP nuclear translocation in valvular endothelial cells (VEC), while the high unidirectional shear stress restricts YAP in cytoplasm. The hydrostatic compressive stress activated YAP in valvular interstitial cells (VIC), whereas the tensile stress deactivated YAP. YAP activation by small molecules promoted VIC proliferation and increased valve size. Whereas YAP inhibition enhanced the expression of cell-cell adhesions in VEC and affected valve shape. Finally, left atrial ligation was performed in chick embryonic hearts to manipulate the shear and hydrostatic stress in vivo. The restricted flow in the left ventricle induced a globular and hypoplastic left atrioventricular (AV) valves with an inhibited YAP expression. By contrast, the right AV valves with sustained YAP expression grew and elongated normally. This study establishes a simple yet elegant mechanobiological system by which transduction of local stresses regulates valve growth and remodeling. This system guides leaflets to grow into proper sizes and shapes with the ventricular development, without the need of a genetically prescribed timing mechanism.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1–2%) 1 – 3 that frequently presents with ascending aortic aneurysm (AscAA) 4 . BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1 , SMAD6 ) are known for ≤1% of nonsyndromic BAV cases with and without AscAA 5 – 8 , impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype. Individuals with biscuspid aortic valve and ascending aortic aneurysm show enrichment of rare variants in ROBO4 . Functional studies suggest that ROBO4 mutations disrupt endothelial cell performance and contribute to pathological remodeling of aortic tissues.

Background Videographic material of animals can contain inapparent signals, such as color changes or motion that hold information about physiological functions, such as heart and respiration rate, pulse wave velocity, and vocalization. Eulerian video magnification allows the enhancement of such signals to enable their detection. The purpose of this study is to demonstrate how signals relevant to experimental physiology can be extracted from non-contact videographic material of animals. Results We applied Eulerian video magnification to detect physiological signals in a range of experimental models and in captive and free ranging wildlife. Neotenic Mexican axolotls were studied to demonstrate the extraction of heart rate signal of non-embryonic animals from dedicated videographic material. Heart rate could be acquired both in single and multiple animal setups of leucistic and normally colored animals under different physiological conditions (resting, exercised, or anesthetized) using a wide range of video qualities. Pulse wave velocity could also be measured in the low blood pressure system of the axolotl as well as in the high-pressure system of the human being. Heart rate extraction was also possible from videos of conscious, unconstrained zebrafish and from non-dedicated videographic material of sand lizard and giraffe. This technique also allowed for heart rate detection in embryonic chickens in ovo through the eggshell and in embryonic mice in utero and could be used as a gating signal to acquire two-phase volumetric micro-CT data of the beating embryonic chicken heart. Additionally, Eulerian video magnification was used to demonstrate how vocalization-induced vibrations can be detected in infrasound-producing Asian elephants. Conclusions Eulerian video magnification provides a technique to extract inapparent temporal signals from videographic material of animals. This can be applied in experimental and comparative physiology where contact-based recordings (e.g., heart rate) cannot be acquired.