European Strategy for Particle Physics -- Accelerator R&D Roadmap

The 2020 update of the European Strategy for Particle Physics emphasised the importance of an intensified and well-coordinated programme of accelerator R&D, supporting the design and delivery of future particle accelerators in a timely, affordable and sustainable way. This report sets out a roadmap for European accelerator R&D for the next five to ten years, covering five topical areas identified in the Strategy update. The R&D objectives include: improvement of the performance and cost-performance of magnet and radio-frequency acceleration systems; investigations of the potential of laser / plasma acceleration and energy-recovery linac techniques; and development of new concepts for muon beams and muon colliders. The goal of the roadmap is to document the collective view of the field on the next steps for the R&D programme, and to provide the evidence base to support subsequent decisions on prioritisation, resourcing and implementation.Comment: 270 pages, 58 figures. Editor: N. Mounet. LDG chair: D. Newbold. Panel chairs: P. V\'edrine (HFM), S. Bousson (RF), R. Assmann (plasma), D. Schulte (muon), M. Klein (ERL). Panel editors: B. Baudouy (HFM), L. Bottura (HFM), S. Bousson (RF), G. Burt (RF), R. Assmann (plasma), E. Gschwendtner (plasma), R. Ischebeck (plasma), C. Rogers (muon), D. Schulte (muon), M. Klein (ERL

Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension.

Pulmonary arterial hypertension is associated with a decreased antioxidant capacity. However, neither the contribution of reactive oxygen species to pulmonary vasoconstrictor sensitivity, nor the therapeutic efficacy of antioxidant strategies in this setting are known. We hypothesized that reactive oxygen species play a central role in mediating both vasoconstrictor and arterial remodeling components of severe pulmonary arterial hypertension. We examined the effect of the chemical antioxidant, TEMPOL, on right ventricular systolic pressure, vascular remodeling, and enhanced vasoconstrictor reactivity in both chronic hypoxia and hypoxia/SU5416 rat models of pulmonary hypertension. SU5416 is a vascular endothelial growth factor receptor antagonist and the combination of chronic hypoxia/SU5416 produces a model of severe pulmonary arterial hypertension with vascular plexiform lesions/fibrosis that is not present with chronic hypoxia alone. The major findings from this study are: 1) compared to hypoxia alone, hypoxia/SU5416 exposure caused more severe pulmonary hypertension, right ventricular hypertrophy, adventitial lesion formation, and greater vasoconstrictor sensitivity through a superoxide and Rho kinase-dependent Ca2+ sensitization mechanism. 2) Chronic hypoxia increased medial muscularization and superoxide levels, however there was no effect of SU5416 to augment these responses. 3) Treatment with TEMPOL decreased right ventricular systolic pressure in both hypoxia and hypoxia/SU5416 groups. 4) This effect of TEMPOL was associated with normalization of vasoconstrictor responses, but not arterial remodeling. Rather, medial hypertrophy and adventitial fibrotic lesion formation were more pronounced following chronic TEMPOL treatment in hypoxia/SU5416 rats. Our findings support a major role for reactive oxygen species in mediating enhanced vasoconstrictor reactivity and pulmonary hypertension in both chronic hypoxia and hypoxia/SU5416 rat models, despite a paradoxical effect of antioxidant therapy to exacerbate arterial remodeling in animals with severe pulmonary arterial hypertension in the hypoxia/SU5416 model

A Parametrically Constrained Optimization Method for Fitting Sedimentation Velocity Experiments

AbstractA method for fitting sedimentation velocity experiments using whole boundary Lamm equation solutions is presented. The method, termed parametrically constrained spectrum analysis (PCSA), provides an optimized approach for simultaneously modeling heterogeneity in size and anisotropy of macromolecular mixtures. The solutions produced by PCSA are particularly useful for modeling polymerizing systems, where a single-valued relationship exists between the molar mass of the growing polymer chain and its corresponding anisotropy. The PCSA uses functional constraints to identify this relationship, and unlike other multidimensional grid methods, assures that only a single molar mass can be associated with a given anisotropy measurement. A description of the PCSA algorithm is presented, as well as several experimental and simulated examples that illustrate its utility and capabilities. The performance advantages of the PCSA method in comparison to other methods are documented. The method has been added to the UltraScan-III software suite, which is available for free download from http://www.ultrascan.uthscsa.edu

TEMPOL attenuates the development of pulmonary hypertension.

<p>Representative traces of right ventricular (RV) pressure measurements (mmHg) in rats treated with vehicle, SU5416, and/or TEMPOL and exposed to normoxia (A) or hypoxia (B). (C) Summary data for peak RVSP (mmHg). Dotted line equals normoxia-vehicle average. Values are means ± SE; n = 5 animals/group. *P < 0.05 vs. the normoxia group; # P < 0.05 vs. the corresponding SU5416 vehicle group; τ p < 0.05 vs. corresponding TEMPOL-vehicle group; analyzed by multiple two-way ANOVA and individual groups compared with the Student-Newman-Keuls test.</p

ET-1-induced VSM Ca²⁺ sensitization and vasoconstriction are augmented in small pulmonary arteries from animals treated with SU5614.

<p>(A) Basal tone (baseline diameter as a % of Ca²⁺-free diameter) in non-permeabilized, endothelium-disrupted, pressurized small pulmonary arteries. (B) vasoconstriction (% baseline diameter) to endothelin-1 (ET-1; 10⁻¹⁰ to 10⁻⁷ M) in Ca²⁺-permeabilized, endothelium-disrupted, pressurized small pulmonary arteries from rats treated with vehicle or SU5416 and exposed to normoxia or hypoxia. Values are means ± SE; n = 5–6 animals/group. *P ≤ 0.05 vs. normoxic group; #P <0.05 vs. corresponding vehicle treatment; analyzed by two-way ANOVA and individual groups compared with the Student-Newman-Keuls test.</p

Enhanced basal tone and ET-1-induced pulmonary VSM Ca²⁺ sensitization following hypoxia/SU5416 is mediated by Rho kinase (ROK).

<p>(A) HA-1077-mediated change in vessel diameter (% baseline diameter) in non-permeabilized, endothelium-disrupted, pressurized small pulmonary arteries. (B) Vasoconstriction (% baseline diameter) to endothelin-1 (ET-1; 10⁻¹⁰ to 10⁻⁷ M) in the presence of HA-1077 (10 μM) in Ca²⁺-permeabilized, endothelium-disrupted, pressurized small pulmonary arteries from normoxic and hypoxic rats treated with vehicle or SU5416. (C) Effect of HA-1077 on ET-1 mediated vasoconstriction in each group compared to vehicle-treated arteries (from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180455#pone.0180455.g009" target="_blank">Fig 9</a>). Values are means ± SE; n = 4–5 animals/group; * p < 0.05 vs. vehicle-treated arteries; analyzed by two-way ANOVA and individual groups compared with the Student-Newman-Keuls test.</p

Right ventricular hypertrophy is not attenuated by TEMPOL.

<p>Representative AZAN trichrome-stained whole heart sections (A) and higher magnification images of the right ventricle (B) from rats treated with vehicle, SU5416, and/or TEMPOL and exposed to normoxia or hypoxia. AZAN trichrome shows cell nuclei (dark red), collagen (blue) and orange-red in cytoplasm. C) Summary data showing Fulton’s index [ratio of RV to left ventricular plus septal (LV + S) heart weight] Values are means ± SE; n = animals/group (indicated in bars). *P < 0.05 vs. the normoxia group; # P < 0.05 vs. the corresponding SU5416 vehicle group; analyzed with multiple two-way ANOVA and individual groups compared with the Student-Newman-Keuls test.</p