De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue. We show that PAO treatment evokes an overall lipidomic remodeling of the endoplasmic reticulum (ER) membranes in macrophages and mouse tissues, which is associated with resistance of the ER to hyperlipidemic stress. By preventing ER stress, PAO blocks lipid-induced inflammasome activation in mouse and human macrophages. Chronic PAO supplementation also lowers systemic interleukin-1β (IL-1β) and IL-18 concentrations in vivo in hyperlipidemic mice. Moreover, PAO prevents macrophage ER stress and IL-1β production in atherosclerotic plaques in vivo, resulting in a marked reduction in plaque macrophages and protection against atherosclerosis in mice. These findings demonstrate that oral supplementation with a product of DNL such as PAO can promote membrane remodeling associated with metabolic resilience of intracellular organelles to lipid stress and limit the progression of atherosclerosis. These findings support therapeutic PAO supplementation as a potential preventive approach against complex metabolic and inflammatory diseases such as atherosclerosis, which warrants further studies in humans.

Aims Dysregulated immune response contributes to inefficiency of treatment strategies to control hypertension and reduce the risk of end-organ damage. Uncovering the immune pathways driving the transition from the onset of hypertensive stimulus to the manifestation of multi-organ dysfunction are much-needed insights for immune targeted therapy. Methods and Results To aid visualization of cellular events orchestrating multi-organ pathogenesis, we modeled hypertensive cardiovascular remodeling in zebrafish. Zebrafish larvae exposed to ion-poor environment exhibited rapid angiotensinogen upregulation, followed by manifestation of arterial hypertension and cardiac remodeling that recapitulates key characteristics of incipient Heart Failure with preserved Ejection Fraction. In the brain, time-lapse imaging revealed the occurrence of cerebrovascular regression through endothelial retraction and migration in response to the ion-poor treatment. This phenomenon is associated with macrophage/microglia-endothelial contacts and endothelial junctional retraction. Cytokine and transcriptomic profiling identified systemic upregulation of interferon-γ and interleukin 1β, and revealed altered macrophage/microglia transcriptional program characterized by suppression of innate immunity and vasculo/neuroprotective gene expression. Both zebrafish and a murine model of pressure overload-induced brain damage demonstrated that the brain pathology and macrophage/microglia phenotypic alteration are dependent on interferon-γ signaling. In zebrafish, interferon-γ receptor 1 mutation prevents cerebrovascular remodeling and dysregulation of macrophage/microglia transcriptomic profile. Supplementation of bone morphogenetic protein 5, identified from the transcriptomic approach as a downregulated gene in ion-poor-treated macrophages/microglia that is rescued by interferon-γ blockage, mitigated cerebral microvessel loss. In mice subjected to transverse aortic constriction-induced pressure overload, typically developing cerebrovascular injury, neuroinflammation and cognitive dysfunction, interferon-γ neutralization protected them from blood-brain-barrier disruption, cerebrovascular rarefaction, and cognitive decline. Conclusions These findings uncover cellular and molecular players of an immune pathway communicating hypertensive stimulus to structural and functional remodeling of the brain and identify anti-interferon-γ treatment as a promising intervention strategy capable of preventing pressure overload-induced damage of the cerebrovascular and nervous systems. Translational Perspective Hypertension is a major risk factor for damages of the vasculature, heart, and brain, and thereby a major healthcare burden. Inadequate cerebral blood supply due to altered cerebrovascular structure and vasoregulatory disruption upon hypertension render the brain highly susceptible to stroke and cognitive decline. We envision that the cellular and molecular mechanisms uncovered here linking immune dysregulation to cerebrovascular remodeling and functional impairment of the brain will inform future development of immunomodulatory therapeutic strategies for counteracting derangement of macrophage/microglia activation and their vasculo/neuroprotective function in response to systemic inflammation in hypertension.

A genetic logic‐gate‐based operation can activate a cellular biocatalyst. The biocatalyst needs two different inputs to be activated. Two different approaches were employed to build the AND genetic logic gate, the first approach uses a recombinase‐based gate; the other approach uses a toehold‐switch‐based approach. The Boolean logic gate enables the formation of a biofilm‐supported biocatalyst. The first circuit triggers the cell to express alkaline phosphatase and an additional circuit provides the secretion of a biofilm matrix composed of proteins that are called functional amyloids. The biofilm matrix protects the cellular biocatalyst against the negative effects of elevated temperatures. More information can be found in the full paper by U. O. S. Seker et al. on page 1799 in Issue 14, 2019 (DOI: 10.1002/cbic.201800767).

Cellular biocatalysts hold great promise for the synthesis of difficult to achieve compounds, such as complex active molecules. Whole‐cell biocatalysts can be programmed through genetic circuits to be more efficient, but they suffer from low stability. The catalytic activity of whole cells decays under stressful conditions, such as prolonged incubation times or high temperatures. In nature, microbial communities cope with these conditions by forming biofilm structures. In this study, it is shown that the use of biofilm structures can enhance the stability of whole‐cell biocatalysts. We employed two different strategies to increase the stability of whole‐cell catalysts and decrease their susceptibility to high temperature. In the first approach, the formation of a biofilm structure is induced by controlling the expression of one of the curli component, CsgA. The alkaline phosphatase (ALP) enzyme was used to monitor the catalytic activity of cells in the biofilm structure. In the second approach, the ALP enzyme was fused to the CsgA curli fiber subunit to utilize the protective properties of the biofilm on enzyme biofilms. Furthermore, an AND logic gate is introduced between the expression of CsgA and ALP by toehold RNA switches and recombinases to enable logical programming of the whole‐cell catalyst for biofilm formation and catalytic action with different tools. The study presents viable approaches to engineer a platform for biocatalysis processes.