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...

Aims Excessive lipid accumulation in Bruch’s membrane (BrM) is a hallmark of ageing, the major risk factor for age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells may utilise reverse cholesterol transport (RCT) activity to move lipid into BrM, mediated through ATP-binding cassette A1 (ABCA1) and scavenger receptor BI (SR-BI). Methods ABCA1 expression was assessed by reverse transcription polymerase chain reaction (RT-PCR) and western blotting of human RPE cell extracts. Lipid transport assays were performed using radiolabelled photoreceptor outer segments (POS). ABCA1 and SR-BI expression was examined in normal mouse eyes by immunofluorescence staining. BrMs of ABCA1 and SR-BI heterozygous mice were examined microscopically. Results Human RPE cells expressed ABCA1 mRNA and protein. The ABCA1 and SR-BI inhibitor glyburide (also known as glibenclamide) abolished basal transport of POS-derived lipids in RPE cells in the presence of high-density lipoprotein. Mouse retina and RPE expressed ABCA1 and SR-BI. SR-BI was highly expressed in RPE. BrMs were significantly thickened in SR-BI heterozygous mice, but not in ABCA1 heterozygous mice. Conclusion RPE cells express ABCA1 and SR-BI. This implies a significant role for SR-BI and ABCA1 in lipid transport and RCT in the retina and RPE.

In early age-related macular degeneration (AMD), lipid-containing deposits (drusen) accumulate in Bruch's membrane underlying the retinal pigment epithelium (RPE).Recent studies indicate that apolipoprotein E (apoE) may play a role in lipid trafficking in AMD. Compared with the apoE3 allele, the apoE4 and apoE2 alleles are associated with decreased and increased risk for AMD, respectively; drusen contain high levels of apoE, and apoE null mice develop lipid deposits in Bruch's membrane similar to those observed in AMD. Primary cultures of human RPE cells expressing the apoE3 allele were grown on Transwell ® culture plates. Western blotting, ELISA assay, and mass spectrometry confirmed that apoE3 was secreted into the apical and basal chambers and that secretion was upregulated by thyroid hormone, 9-cis -retinoic acid, and 22( R )-hydroxycholesterol. In addition, basally secreted apoE associated with exogenously added HDL. These results indicate that apoE secretion can be regulated by specific hormones and that apoE associates with HDL. The findings are consistent with a role for apoE in lipid trafficking through Bruch's membrane and may be relevant to AMD. Age-related macular degeneration (AMD) is the leading cause of severe visual loss in the developed world (1, 2). In the early stages of the disease, before visual loss occurs from choroidal neovascularization, there is progressive accumulation of lipids in Bruch's membrane (3-6). Bruch's membrane lies at the critical juncture between the outer retina and its blood supply, the choriocapillaris. Lipid deposition causes reduced hydraulic conductivity and macromolecular permeability in Bruch's membrane and is thought to impair retinal metabolism (7-9). Interestingly, lipid accumulation in Bruch's membrane similar to that in AMD has been observed in apolipoprotein E (apoE) null mice (10, 11). Because of the additional association between apoE alleles and other age-related degenerations, such as Alzheimer's disease and atherosclerosis, there has been recent investigation into a potential role for apoE in AMD.Several studies of apoE polymorphism in AMD have been conducted (12)(13)(14). In contrast to Alzheimer's disease, the apoE4 allele has been associated with a reduced prevalence of AMD. The apoE2 allele is slightly increased in patients with AMD. Further supporting a role in AMD pathogenesis, apoE has been detected in drusen, the Bruch's membrane deposits that are the hallmark of AMD (13,15). Immunohistochemical studies of postmortem eyes have demonstrated apoE in the basal aspect of the retinal pigment epithelium (RPE) (15). Cultured RPE cells synthesize high levels of apoE mRNA, comparable to the levels found in brain (15).Although the role of apoE in AMD is not established, this apolipoprotein has several functions that may affect the course of this disease. ApoE has anti-angiogenic (16), anti-inflammatory (17), and anti-oxidative (18) effects. These are all considered atheroprotective attributes of apoE, but they may also be important in protecting a...

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