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...
Endothelial dysfunction is now considered an important early event in the development of atherosclerosis, which precedes gross morphological signs and clinical symptoms. The assessment of flow-mediated dilation (FMD) was introduced almost 20 years ago as a noninvasive approach to examine vasodilator function in vivo. FMD is widely believed to reflect endothelium-dependent and largely nitric oxide-mediated arterial function and has been used as a surrogate marker of vascular health. This noninvasive technique has been used to compare groups of subjects and to evaluate the impact of interventions within individuals. Despite its widespread adoption, there is considerable variability between studies with respect to the protocols applied, methods of analysis, and interpretation of results. Moreover, differences in methodological approaches have important impacts on the response magnitude, can result in spurious data interpretation, and limit the comparability of outcomes between studies. This review results from a collegial discussion between physiologists with the purpose of developing considered guidelines. The contributors represent several distinct research groups that have independently worked to advance the evidence base for improvement of the technical approaches to FMD measurement and analysis. The outcome is a series of recommendations on the basis of review and critical appraisal of recent physiological studies, pertaining to the most appropriate methods to assess FMD in humans.
The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping ≈ 10% of the sky to a white noise level of 2 µK-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of σ(r) = 0.003. The large aperture telescope will map ≈ 40% of the sky at arcminute angular resolution to an expected white noise level of 6 µK-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensorto-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources a .
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Vascular endothelial function is essential for maintenance of health of the vessel wall and for vasomotor control in both conduit and resistance vessels. These functions are due to the production of numerous autacoids, of which nitric oxide (NO) has been the most widely studied. Exercise training has been shown, in many animal and human studies, to augment endothelial, NO-dependent vasodilatation in both large and small vessels. The extent of the improvement in humans depends upon the muscle mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training can induce generalized benefit. Increased NO bioactivity with exercise training has been readily and consistently demonstrated in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. These conditions may all be associated with increased oxygen free radicals which impact on NO synthase activity and with which NO reacts; repeated exercise and shear stress stimulation of NO bioactivity redresses this radical imbalance, hence leading to greater potential for autacoid bioavailability. Recent human studies also indicate that exercise training may improve endothelial function by up-regulating eNOS protein expression and phosphorylation. While improvement in NO vasodilator function has been less frequently found in healthy subjects, a higher level of training may lead to improvement. Regarding time course, studies indicate that short-term training increases NO bioactivity, which acts to homeostatically regulate the shear stress associated with exercise. Whilst the increase in NO bioactivity dissipates within weeks of training cessation, studies also indicate that if exercise is maintained, the short-term functional adaptation is succeeded by NO-dependent structural changes, leading to arterial remodelling and structural normalization of shear. Given the strong prognostic links between vascular structure, function and cardiovascular events, the implications of these findings are obvious, yet many unanswered questions remain, not only concerning the mechanisms responsible for NO bioactivity, the nature of the cellular effect and relevance of other autacoids, but also such practical questions as the optimal intensity, modality and volume of exercise training required in different populations.
Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.
On the 400 th anniversary of Harvey's Lumleian lectures, this review focusses on the impact of physical exercise on "hemodynamic" forces associated with the movement of blood through arteries in humans and the functional and structural adaptations that result from repeated episodic exposure to such stimuli. The late 20 th century discovery that endothelial cells modify arterial tone via paracrine transduction, provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the inter-relationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions and the implications for human health.Exercise modifies blood flow, luminal shear stress, arterial pressure and tangential wall stress, all of which can transduce changes in arterial function, diameter and wall thickness.There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute substantially to the well-established decrease in cardiovascular risk attributed to physical activity.
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...
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