The next generation "Stage-4" ground-based cosmic microwave background (CMB) experiment, CMB-S4, consisting of dedicated telescopes equipped with highly sensitive superconducting cameras operating at the South Pole, the high Chilean Atacama plateau, and possibly northern hemisphere sites, will provide a dramatic leap forward in our understanding of the fundamental nature of space and time and the evolution of the Universe. CMB-S4 will be designed to cross critical thresholds in testing inflation, determining the number and masses of the neutrinos, constraining possible new light relic particles, providing precise constraints on the nature of dark energy, and testing general relativity on large scales.CMB-S4 is intended to be the definitive ground-based CMB project. It will deliver a highly constraining data set with which any model for the origin of the primordial fluctuations-be it inflation or an alternative theory-and their evolution to the structure seen in the Universe today must be consistent. While we have learned a great deal from CMB measurements, including discoveries that have pointed the way to new physics, we have only begun to tap the information encoded in CMB polarization, CMB lensing and other secondary effects. The discovery space from these and other yet to be imagined effects will be maximized by designing CMB-S4 to produce high-fidelity maps, which will also ensure enormous legacy value for CMB-S4. CMB-S4 is the logical successor to the Stage-3 CMB projects which will operate over the next few years. For maximum impact, CMB-S4 should be implemented on a schedule that allows a transition from Stage 3 to Stage 4 that is as seamless and as timely as possible, preserving the expertise in the community and ensuring a continued stream of CMB science results. This timing is also necessary to ensure the optimum synergistic enhancement of the science return from contemporaneous optical surveys (e.g., LSST, DESI, Euclid and WFIRST). Information learned from the ongoing Stage-3 experiments can be easily incorporated into CMB-S4 with little or no impact on its design. In particular, additional information on the properties of Galactic foregrounds would inform the detailed distribution of detectors among frequency bands in CMB-S4. The sensitivity and fidelity of the multiple band foreground measurements needed to realize the goals of CMB-S4 will be provided by CMB-S4 itself, at frequencies just below and above those of the main CMB channels. This timeline is possible because CMB-S4 will use proven existing technology that has been developed and demonstrated by the CMB experimental groups over the last decade. There are, to be sure, considerable technical challenges presented by the required scaling-up of the instrumentation and by the scope and complexity of the data analysis and interpretation. CMB-S4 will require: scaled-up superconducting detector arrays with well-understood and robust material properties and processing techniques; high-throughput mmwave telescopes and optics with unprecedented precisi...

This document on the CMB-S4 Science Case, Reference Design, and Project Plan is the product of a global community of scientists who are united in support of advancing CMB-S4 to cross key thresholds in our understanding of the fundamental nature of space and time and the evolution of the Universe. CMB-S4 is planned to be a joint National Science Foundation (NSF) and Department of Energy (DOE) project, with the construction phase to be funded as an NSF Major Research Equipment and Facilities Construction (MREFC) project and a DOE High Energy Physics (HEP) Major Item of Equipment (MIE) project. At the time of this writing, an interim project office has been constituted and tasked with advancing the CMB-S4 project in the NSF MREFC Preliminary Design Phase and toward DOE Critical Decision CD-1. DOE CD-0 is expected imminently.CMB-S4 has been in development for six years. Through the Snowmass Cosmic Frontier planning process, experimental groups in the cosmic microwave background (CMB) and broader cosmology communities came together to produce two influential CMB planning papers, endorsed by over 90 scientists, that outlined the science case as well as the CMB-S4 instrumental concept [1, 2]. It immediately became clear that an enormous increase in the scale of ground-based CMB experiments would be needed to achieve the exciting thresholdcrossing scientific goals, necessitating a phase change in the ground-based CMB experimental program. To realize CMB-S4, a partnership of the university-based CMB groups, the broader cosmology community, and the national laboratories would be needed.The community proposed CMB-S4 to the 2014 Particle Physics Project Prioritization Process (P5) as a single, community-wide experiment, jointly supported by DOE and NSF. Following P5's recommendation of CMB-S4 under all budget scenarios, the CMB community started in early 2015 to hold biannual workshops -open to CMB scientists from around the world -to develop and refine the concept. Nine workshops have been held to date, typically with 150 to 200 participants. The workshops have focused on developing the unique and vital role of the future ground-based CMB program. This growing CMB-S4 community produced a detailed and influential CMB-S4 Science Book [3] and a CMB-S4 Technology Book [4]. Over 200 scientists contributed to these documents. These and numerous other reports, workshop and working group wiki pages, email lists, and much more may be found at the website http://CMB-S4.org.Soon after the CMB-S4 Science Book was completed in August 2016, DOE and NSF requested the Astronomy and Astrophysics Advisory Committee (AAAC) to convene a Concept Definition Taskforce (CDT) to conduct a CMB-S4 concept study. The resulting report was unanimously accepted in late 2017. 1 One recommendation of the CDT report was that the community should organize itself into a formal collaboration. An Interim Collaboration Coordination Committee was elected by the community to coordinate this process. The resulting draft bylaws were refined at the Spring 2018 CMB-S4...

Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

Abstract-Increases in arginase activity have been reported in a variety of disease conditions characterized by vascular dysfunction. Arginase competes with NO synthase for their common substrate arginine, suggesting a cause and effect relationship. We tested this concept by experiments with streptozotocin diabetic rats and high glucose (HG)-treated bovine coronary endothelial cells (BCECs). Our studies showed that diabetes-induced impairment of vasorelaxation to acetylcholine was correlated with increases in reactive oxygen species and arginase activity and arginase I expression in aorta and liver. Treatment of diabetic rats with simvastatin (5 mg/kg per day, subcutaneously) or L-citrulline (50 mg/kg per day, orally) blunted these effects. Acute treatment of diabetic coronary arteries with arginase inhibitors also reversed the impaired vasodilation to acetylcholine. Treatment of BCECs with HG (25 mmol/L, 24 hours) also increased arginase activity. This effect was blocked by treatment with simvastatin (0.1 mol/L), the Rho kinase inhibitor Y-27632 (10 mol/L), or L-citrulline (1 mmol/L). Superoxide and active RhoA levels also were elevated in HG-treated BCECs. Furthermore, HG significantly diminished NO production in BCECs. Transfection of BCECs with arginase I small interfering RNA prevented the rise in arginase activity in HG-treated cells and normalized NO production, suggesting a role for arginase I in reduced NO production with HG. These results indicate that increased arginase activity in diabetes contributes to vascular endothelial dysfunction by decreasing L-arginine availability to NO synthase. (Circ Res. 2008;102:95-102.)Key Words: arginine Ⅲ coronary arteries Ⅲ diabetes Ⅲ endothelial nitric oxide synthase Ⅲ oxidative stress Ⅲ vascular endothelial function Ⅲ vasodilation V ascular dysfunction is a major cause of morbidity and mortality in diabetic patients. 1 The pathological process is characterized by impaired endothelial cell production of the vasodilator and antiplatelet adhesion factor NO and/or decreased NO bioavailability. NO is a major regulator of vascular tone and integrity. In endothelial cells, NO is produced by activity of endothelial NO synthase (eNOS) on its substrate L-arginine. Reduced availability of L-arginine to eNOS has been implicated in vascular dysfunction in diabetes and a variety of other disease conditions. Arginase, which metabolizes L-arginine to urea and ornithine, competes directly with NOS for L-arginine. Hence increases in arginase activity can decrease tissue and cellular arginine levels, reducing its availability to eNOS. 2 This may lead to decreased NO production and increased production of superoxide by eNOS. 3 Enhanced arginase activity has been implicated in a number of conditions characterized by vascular dysfunction, including diabetic erectile dysfunction, pulmonary hypertension, ischemia/reperfusion, atherosclerosis, and agingassociated endothelial dysfunction. 4 -9 During diabetes, impaired vascular function is closely associated with oxidative stress and v...