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Local haemodynamics control arterial homeostasis and dysfunction by generating wall shear stress (WSS) which regulates endothelial cell (EC) physiology. Here we use a zebrafish model to identify genes that regulate EC proliferation in response to flow. Suppression of blood flow in zebrafish embryos (by targeting cardiac troponin) reduced EC proliferation in the intersegmental vessels (ISVs) compared to controls exposed to flow. The expression of candidate regulators of proliferation was analysed in EC isolated from zebrafish embryos by qRT-PCR. Genes shown to be expressed in EC were analysed for the ability to regulate proliferation in zebrafish vasculature exposed to flow or no-flow conditions using a knockdown approach. wnk1 negatively regulated proliferation in no-flow conditions, whereas fzd5 , gsk3β , trpm7 and bmp2a promoted proliferation in EC exposed to flow. Immunofluorescent staining of mammalian arteries revealed that WNK1 is expressed at sites of low WSS in the murine aorta, and in EC overlying human atherosclerotic plaques. We conclude that WNK1 is expressed in EC at sites of low WSS and in diseased arteries and may influence vascular homeostasis by reducing EC proliferation.

Heart development involves the complex structural remodelling of a linear heart tube into an asymmetrically looped and ballooned organ. Previous studies have associated regional expansion of extracellular matrix (ECM) space with tissue morphogenesis during development. We have developed morphoHeart , a 3D tissue segmentation and morphometry software with a user-friendly graphical interface (GUI) that delivers the first integrated 3D visualisation and multiparametric analysis of both heart and ECM morphology in live embryos. morphoHeart reveals that the ECM undergoes regional dynamic expansion and reduction during cardiac development, concomitant with chamber-specific morphological maturation. We use morphoHeart to demonstrate that regionalised ECM expansion driven by the ECM crosslinker Hapln1a promotes atrial lumen expansion during heart development. Finally, morphoHeart ’s GUI expands its use beyond that of cardiac tissue, allowing its segmentation and morphometric analysis tools to be applied to z -stack images of any fluorescently labelled tissue.

In vertebrates, left-right (LR) axis specification is determined by a ciliated structure in the posterior region of the embryo. Fluid flow in this ciliated structure is responsible for the induction of unilateral left-sided Nodal activity in the lateral plate mesoderm, which in turn regulates organ laterality. Bmp signalling activity has been implied in repressing Nodal expression on the right side, however its mechanism of action has been controversial. In a forward genetic screen for mutations that affect LR patterning, we identified the zebrafish linkspoot (lin) mutant, characterized by cardiac laterality and mild dorsoventral patterning defects. Mapping of the lin mutation revealed an inactivating missense mutation in the Bmp receptor 1aa (bmpr1aa) gene. Embryos with a mutation in lin/bmpr1aa and a novel mutation in its paralogue, bmpr1ab, displayed a variety of dorsoventral and LR patterning defects with increasing severity corresponding with a decrease in bmpr1a dosage. In Bmpr1a-deficient embryos we observed bilateral expression of the Nodal-related gene, spaw, coupled with reduced expression of the Nodal-antagonist lefty1 in the midline. Using genetic models to induce or repress Bmp activity in combination with Nodal inhibition or activation, we found that Bmp and Nodal regulate lefty1 expression in the midline independently of each other. Furthermore, we observed that the regulation of lefty1 by Bmp signalling is required for its observed downregulation of Nodal activity in the LPM providing a novel explanation for this phenomenon. From these results we propose a two-step model in which Bmp regulates LR patterning. Prior to the onset of nodal flow and Nodal activation, Bmp is required to induce lefty1 expression in the midline. When nodal flow has been established and Nodal activity is apparent, both Nodal and Bmp independently are required for lefty1 expression to assure unilateral Nodal activation and correct LR patterning.

Cadherin complexes mediate cell-cell adhesion and are crucial for embryonic development. Besides their structural function, cadherin complexes also transduce tension across the junction-actomyosin axis into proportional biochemical responses. Central to this mechanotransduction is the stretching of the cadherin-F-actin-linker α-catenin, which opens its central domain for binding to effectors such as vinculin. Mechanical unfolding of α-catenin leads to force-dependent reinforcement of cadherin-based junctions as studied in cell culture. The importance of cadherin mechanotransduction for embryonic development has not been studied yet. Here we used TALEN-mediated gene disruption to perturb endogenous αE-catenin in zebrafish development. Zygotic α-catenin mutants fail to maintain their epithelial barrier, resulting in tissue rupturing. We then specifically disrupted mechanotransduction, while maintaining cadherin adhesion, by expressing an αE-catenin construct in which the mechanosensitive domain was perturbed. Expression of either wild-type or mechano-defective α-catenin fully rescues barrier function in α-catenin mutants; however, expression of mechano-defective α-catenin also induces convergence and extension defects. Specifically, the polarization of cadherin-dependent, lamellipodia-driven cell migration of the lateral mesoderm was lost. These results indicate that cadherin mechanotransduction is crucial for proper zebrafish morphogenesis, and uncover one of the essential processes affected by its perturbation.

Breaking left–right symmetry in bilateria is a major event during embryo development that is required for asymmetric organ position, directional organ looping and lateralized organ function in the adult. Asymmetric expression of Nodal-related genes is hypothesized to be the driving force behind regulation of organ laterality. Here we identify a Nodal-independent mechanism that drives asymmetric heart looping in zebrafish embryos. In a unique mutant defective for the Nodal-related southpaw gene, preferential dextral looping in the heart is maintained, whereas gut and brain asymmetries are randomized. As genetic and pharmacological inhibition of Nodal signalling does not abolish heart asymmetry, a yet undiscovered mechanism controls heart chirality. This mechanism is tissue intrinsic, as explanted hearts maintain ex vivo retain chiral looping behaviour and require actin polymerization and myosin II activity. We find that Nodal signalling regulates actin gene expression, supporting a model in which Nodal signalling amplifies this tissue-intrinsic mechanism of heart looping. Nodal signalling has been implicated in the asymmetric positioning of various organs. Here, Noël et al. show that the asymmetry of the embryonic zebrafish heart is also established in the absence of Nodal signalling, suggesting a Nodal-independent mechanism that relies on actomyosin activity.

Adverse Childhood Experiences (ACEs) and their effects on human behavior have become increasingly relevant and important in the United States. Trauma Informed Care (TIC) and Applied Behavior Analysis (ABA) are two approaches which commonly address the symptoms of ACEs in different ways, with TIC focusing on intermediating the impact of trauma and ABA focusing on building adaptive behavior and reducing maladaptive behaviors. While ABA has been shown to be effective in various areas for many years, it has been met with much criticism by the communities which it serves. Current criticism specifically highlights trauma and retraumatization resulting from ABA practices. This is especially important when considering the most common population served by ABA, those with autism spectrum disorder (ASD), whose behaviors could be masking their trauma and preventing appropriate treatment. The TIC framework has been applied to various systems to improve treatment for victims of trauma and could possibly be incorporated into ABA practices to improve care for all clients, but especially those with a history of trauma. The field of ABA has taken some steps toward improving its practice and approaching TIC but has not formally adopted TIC practices or principles in the fifth edition task list put forth by the Behavior Analysis Certification Board (BACB, 2017) or the verified course sequence set forth by the Association of Behavior Analysis International (ABAI, 2022). The current study first explores ABA practitioners’ attitudes and perceptions of TIC in ABA practices, as well as the barriers and pathways to possible implementation through focus group interviews. This study used a qualitative method approach to explore data relevant to ABA practitioner perspectives and result in useful information about the community’s perception about the importance of TIC in ABA practice and feasible ways to move forward implementing TIC components in ABA practice using guidance from an implementation science model.

Computational modelling of the heart tube during development reveals the interplay between tissue asymmetry and growth that helps our hearts take shape.Computational modelling of the heart tube during development reveals the interplay between tissue asymmetry and growth that helps our hearts take shape.

The relationship between elitism and corruption in the United States has become problematic for the prosperity of our democracy. Throughout United States history, this relationship has continually evolved and allowed for elites to be able to pursue personal interests and abuse their positions. The pursuit of corrupt actions to achieve personal gain results in a widening gap between the elites and the masses. A thorough analysis of the history of the United States (with special emphasis on scandals and events within each block of time) shows that this is, in fact, the case; the evolutionary relationship has resulted in an imbalance of power between the elites and the masses, and this imbalance of power is tipped unfairly towards the elite class. This is detrimental for the masses as they are losing their promised freedoms while the elites are continually gaining power. The prosperity of the nation is no longer a priority. These issues must be analyzed and addressed in order to ensure that the nation will continue to prosper and to come up with effective solutions for returning power to the people and keeping the elites checked.