Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation

Classical activation of macrophages (M(LPS+IFNγ)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1β production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Endothelial cell tetrahydrobiopterin deficiency attenuates LPS-induced vascular dysfunction and hypotension

Overproduction of nitric oxide (NO) is thought to be a key mediator of the vascular dysfunction and severe hypotension in patients with endotoxaemia and septic shock. The contribution of NO produced directly in the vasculature by endothelial cells to the hypotension seen in these conditions, vs. the broader systemic increase in NO, is unclear. To determine the specific role of endothelium derived NO in lipopolysaccharide (LPS)-induced vascular dysfunction we administered LPS to mice deficient in endothelial cell tetrahydrobiopterin (BH4), the essential co-factor for NO production by NOS enzymes. Mice deficient in endothelial BH4 production, through loss of the essential biosynthesis enzyme Gch1 (Gch1fl/flTie2cre mice) received a 24 hour challenge with LPS or saline control. In vivo LPS treatment increased vascular GTP cyclohydrolase and BH4 levels in aortas, lungs and hearts, but this increase was significantly attenuated in Gch1fl/flTie2cre mice, which were also partially protected from the LPS-induced hypotension. In isometric tension studies, in vivo LPS treatment reduced the vasoconstriction response and impaired endothelium-dependent and independent vasodilatations in mesenteric arteries from wild-type mice, but not in Gch1fl/flTie2cre mesenteric arteries. Ex vivo LPS treatment decreased vasoconstriction response to phenylephrine in aortic rings from wild-type and not in Gch1fl/flTie2cre mice, even in the context of significant eNOS and iNOS upregulation. These data provide direct evidence that endothelial cell NO has a significant contribution to LPS-induced vascular dysfunction and hypotension and may provide a novel therapeutic target for the treatment of systemic inflammation and patients with septic shock

Research Proposal: Assessing the Effectiveness of the Business on Board Program

Board performance is widely recognized as a critical ingredient in a non-profit organization’s ability to achieve impact and to meet its mission and goals. The problem for many organizations, particularly those operating in the arts and culture environment, is that it can take new board members several months and often longer before they begin to function effectively in their governance role. To speed up the learning curve, BOB provides advance training to prepare new board members to hit the ground running so that they will be able to participate in their initial meetings with confidence. BOB also provides training for current board members seeking to improve their governance and leadership competencies. As there is no one best way for any organization to operate, each board and its members must consider and develop approaches and practices that recognize the unique requirements of its environmental context, services, and their leadership/management. Assessing the overall effectiveness of the BOB program becomes important for the Arts + Business Council of Greater Philadelphia and for the Boards on which their BOB graduates serve. The proposed project, therefore, is designed to measure the effectiveness of participating in the BOB program on non-profit board behaviors and the effect of participation in the BOB program on leadership of the organization for which board members provide guidance as well as the companies for whom these individuals work

Comprehensive psychosocial screening in a pediatric diabetes clinic

The ISPAD recommends routine, comprehensive psychosocial screening for adolescents with diabetes. However, few clinics have implemented procedures consistent with these guidelines. This study describes the results of a universal, comprehensive psychosocial screening program in an integrated pediatric diabetes clinic located within an academic medical center. Participants included 232 ethnically diverse adolescents with type 1 diabetes (55.5% female; M age = 14.85; 58.5% Hispanic; 20% Black). Adolescents completed screening measures on iPads in the waiting room before their medical visit. The proportion of adolescents screening positive on each psychosocial measure was assessed, and regression analyses evaluated how psychosocial variables accounted for variance in insulin non-adherence and glycemic control (measured by A1c). Psychosocial concerns were common and ranged from 7% of adolescents screening positive for disordered eating and suicide risk to 52% screening positive for low motivation to manage diabetes. A1c and insulin non-adherence were positively correlated with suicide risk, depressive symptoms, anxiety, disordered eating, diabetes stress, blood glucose monitoring stress, family conflict, and total number of elevations, and negatively correlated with intrinsic motivation. Insulin non-adherence, disordered eating, diabetes stress, and family conflict uniquely predicted A1c. Age, motivation, and family conflict uniquely predicted insulin non-adherence. Eighty-three percent of eligible youth completed the screener. Referrals by physicians to the team psychologist increased by 25% after the screening program was implemented. Comprehensive psychosocial screening can be effectively implemented as part of routine pediatric diabetes care and can identify adolescents in need of additional supports

Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation

Classical activation of macrophages (M(LPS+IFNg)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1b production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage

Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation

Classical activation of macrophages (M(LPS+IFNg)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1b production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage