Parameterized Computational Framework for the Description and Design of Genetic Circuits of Morphogenesis Based on Contact-Dependent Signaling and Changes in Cell-Cell Adhesion.

Synthetic development is a nascent field of research that uses the tools of synthetic biology to design genetic programs directing cellular patterning and morphogenesis in higher eukaryotic cells, such as mammalian cells. One specific example of such synthetic genetic programs was based on cell-cell contact-dependent signaling using synthetic Notch pathways and was shown to drive the formation of multilayered spheroids by modulating cell-cell adhesion via differential expression of cadherin family proteins in a mouse fibroblast cell line (L929). The design method for these genetic programs relied on trial and error, which limited the number of possible circuits and parameter ranges that could be explored. Here, we build a parameterized computational framework that, given a cell-cell communication network driving changes in cell adhesion and initial conditions as inputs, predicts developmental trajectories. We first built a general computational framework where contact-dependent cell-cell signaling networks and changes in cell-cell adhesion could be designed in a modular fashion. We then used a set of available in vitro results (that we call the "training set" in analogy to similar pipelines in the machine learning field) to parameterize the computational model with values for adhesion and signaling. We then show that this parameterized model can qualitatively predict experimental results from a "testing set" of available in vitro data that varied the genetic network in terms of adhesion combinations, initial number of cells, and even changes to the network architecture. Finally, this parameterized model is used to recommend novel network implementation for the formation of a four-layered structure that has not been reported previously. The framework that we develop here could function as a testing ground to identify the reachable space of morphologies that can be obtained by controlling contact-dependent cell-cell communications and adhesion with these molecular tools and in this cellular system. Additionally, we discuss how the model could be expanded to include other forms of communication or effectors for the computational design of the next generation of synthetic developmental trajectories.

Cardiovascular Complications of Marijuana and Related Substances: A Review.

The recreational use of cannabis has sharply increased in recent years in parallel with its legalization and decriminalization in several countries. Commonly, the traditional cannabis has been replaced by potent synthetic cannabinoids and cannabimimetics in various forms. Despite overwhelming public perception of the safety of these substances, an increasing number of serious cardiovascular adverse events have been reported in temporal relation to recreational cannabis use. These have included sudden cardiac death, vascular (coronary, cerebral and peripheral) events, arrhythmias and stress cardiomyopathy among others. Many of the victims of these events are relatively young men with few if any cardiovascular risk factors. However, there are reasons to believe that older individuals and those with risk factors for or established cardiovascular disease are at even higher danger of such events following exposure to cannabis. The pathophysiological basis of these events is not fully understood and likely encompasses a complex interaction between the active ingredients (particularly the major cannabinoid, Δ9-tetrahydrocannabinol), and the endo-cannabinoid system, autonomic nervous system, as well as other receptor and non-receptor mediated pathways. Other complicating factors include opposing physiologic effects of other cannabinoids (predominantly cannabidiol), presence of regulatory proteins that act as metabolizing enzymes, binding molecules, or ligands, as well as functional polymorphisms of target receptors. Tolerance to the effects of cannabis may also develop on repeated exposures at least in part due to receptor downregulation or desensitization. Moreover, effects of cannabis may be enhanced or altered by concomitant use of other illicit drugs or medications used for treatment of established cardiovascular diseases. Regardless of these considerations, it is expected that the current cannabis epidemic would add significantly to the universal burden of cardiovascular diseases.

Posttraumatic stress disorder after myocardial infarction and coronary artery bypass grafting.

Post traumatic stress disorder is a psychiatric disease that is usually precipitated by life threatening stressors. Myocardial infarction, especially in the young can count as one such event. The development of post traumatic stress after a coronary event not only adversely effects psychiatric health, but leads to increased cardiovascular morbidity and mortality. There is increasing evidence that like major depression, post traumatic stress disorder is also a strong coronary risk factor. Early diagnosis and treatment of this disease in patients with acute manifestations of coronary artery disease can improve patient outcomes.