Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as ROR[gamma]t Allosteric Inhibitors for
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β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt β-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and β-arrestin-dependent physiological functions while sparing G protein–receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin–receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.
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We report heat mitigation for large-scale solar photovoltaic (PV) arrays is crucial to extend lifetime and energy harvesting capacity. PV module temperature is dependent on site-specific farm geometry, yet common predictions consider panel-scale and environmental factors only. Here, we characterize convective cooling in diverse PV array designs, capturing combined effects of spatial and atmospheric variation on panel temperature and production. Parameters, including row spacing, panel inclination, module height, and wind velocity, are explored through wind tunnel experiments, high-resolution numerical simulations, and operating field data. A length scale based on fractal lacunarity encapsulates all aspects of arrangement (angle, height, etc.) in a single value. When applied to the Reynolds number Re within the canonical Nusselt number heat transfer correlation, lacunarity reveals a relationship between convection and farm-specific geometry. This correlation can be applied to existing and forthcoming array designs to optimize convective cooling, ultimately increasing production and PV cell life.
We report that when the temperature of solar photovoltaic modules rises, efficiency drops and module degradation accelerates. The spatial arrangement of solar modules can affect convective cooling and, consequently, module temperatures. However, the impact of row spacing on convective cooling in realistic solar farms has not yet been studied. Here, we develop six solar farm arrangements consisting of a fixed number of rows with varying streamwise row spacing. We model the flow and heat transfer of each solar farm using high-resolution large-eddy simulations. Results indicate that increasing row spacing can enhance convective cooling by 14.8%, which reduces module temperature by 6.6 °C and increases power output by 4.0% on average.
When the temperature of solar photovoltaic (PV) modules rises, efficiency drops and module degradation accelerates. Thus, it is beneficial to reduce module operating temperatures. Previous studies of solar power plants have illustrated that incoming flow characteristics, turbulent mixing, and array geometry can strongly impact convective cooling, as measured by the convective heat transfer coefficient h. In the fields of heat transfer and plant canopy flow, previous work has shown that system-scale arrangement modifications—e.g., variable spacing, barriers, or windbreaks—can passively alter the flow, enhance turbulent mixing, and influence convection. However, researchers have not yet explored how variable spacing or barriers might enhance convective cooling in solar power plants. Here, high-resolution large-eddy simulations model the air flow and heat transfer through solar power plant arrangements modified with missing modules and barrier walls. We then perform a control volume analysis to evaluate the net heat flux and compute h, which quantifies the influence of these spatial modifications on convective cooling and, thus, module temperature and power output. Installing barrier walls yields the greatest improvements, increasing h by 3.4%, reducing module temperature by an estimated 2.5 °C, and boosting power output by an estimated 1.4% on average. These findings indicate that incorporating variable spacing or barrier-type elements into PV plant designs can reduce module temperature and, thus, improve PV performance and service life.
Particle-laden flows in solar photovoltaic (PV) systems are inevitable, where wind-swept debris in open environments are carried by high winds and turbulence, coating panel surfaces or damaging structures. Particle deposition, or soiling, is a well-known issue for large-scale plants which rely on uninhibited solar rays for optimal production. But understanding the mechanisms leading to soiling requires a physical and fluid dynamics-centered focus, since turbulence dominates PV panel wakes and is also known to alter particle concentration and trajectories. This study presents an experimental campaign toward consequences of particle-laden flow between two model PV panels using time-resolved particle image velocimetry. The model array was subjected to varied particle volume fractions, including a tracer particle case and a water droplet case. Characterization of mean velocity, turbulence statistics, and mean kinetic energy within the single phase and, separately, particle phase flows showed modified features due to particle inertia. Images captured at a frequency of 1 kHz in the near wake of the upstream panel allow for a first experimental look at vorticity and convective velocity of vortex structures for single-phase and particle-phase flows which are crucial to debris transport and soiling in PV environments.
Wind plants generate large-scale wakes, which can affect the performance of neighboring installations. Such wakes are challenging to estimate due to the inherent complexity in modeling wake interactions between large quantities of turbines at various distances. Weighted directed graph networks can inform complex models by linking turbine pairs into chains of upstream and downstream neighbors for a given wind direction. A novel interpretation of the graph network adjacency matrix is proposed where each element of the matrix represents the cumulative impact of upstream turbines on an individual. In this study, wake losses were estimated with an engineering wake model across a range of inflow conditions for nine parametric variations of a system containing two neighboring wind plants. The parametric nature of the study isolates turbine spacing within the plant, separation distance between plants, and wind direction as the main drivers of wake losses. Spatial heterogeneity is computed from the weighted average adjacency matrix of each plant arrangement. The proposed method is orders of magnitude faster than wake modeling and does not require detailed turbine information or atmospheric conditions. Furthermore, the weighted average adjacency matrix provides insight on the spatial organization of wake losses at various scales. Plant heterogeneity is correlated with wake losses within and among plants. Framing wind plant wake interaction in terms of graph network spatial heterogeneity provides an efficient approach for predicting wake losses within and among neighboring wind plants with applications to other complex systems where wake interactions are key factor.
TJ-II stellarator results on modelling and validation of plasma flow asymmetries due to on-surface potential variations, plasma fuelling physics, Alfvén eigenmodes (AEs) control and stability, the interplay between turbulence and neoclassical (NC) mechanisms and liquid metals are reported. Regarding the validation of the neoclassically predicted potential asymmetries, its impact on the radial electric field along the flux surface has been successfully validated against Doppler reflectometry measurements. Research on the physics and modelling of plasma core fuelling with pellets and tracer encapsulated solid pellet injection has shown that, although post-injection particle radial redistributions can be understood qualitatively from NC mechanisms, turbulence and fluctuations are strongly affected during the ablation process. Advanced analysis tools based on transfer entropy have shown that radial electric fields do not only affect the radial turbulence correlation length but are also capable of reducing the propagation of turbulence from the edge into the scrape-off layer. Direct experimental observation of long range correlated structures show that zonal flow structures are ubiquitous in the whole plasma cross-section in the TJ-II stellarator. Alfvénic activity control strategies using ECRH and ECCD as well as the relation between zonal structures and AEs are reported. Finally, the behaviour of liquid metals exposed to hot and cold plasmas in a capillary porous system container was investigated.
We present recent highlights from the most recent operation phases of Wendelstein 7-X, the most advanced stellarator in the world. Stable detachment with good particle exhaust, low impurity content, and energy confinement times exceeding 100 ms, have been maintained for tens of seconds. Pellet fueling allows for plasma phases with reduced ion-temperature-gradient turbulence, and during such phases, the overall confinement is so good (energy confinement times often exceeding 200 ms) that the attained density and temperature profiles would not have been possible in less optimized devices, since they would have had neoclassical transport losses exceeding the heating applied in W7-X. This provides proof that the reduction of neoclassical transport through magnetic field optimization is successful. W7-X plasmas generally show good impurity screening and high plasma purity, but there is evidence of longer impurity confinement times during turbulence-suppressed phases.
The recent deuterium–tritium campaign in JET-ILW (DTE2) has provided a unique opportunity to study the isotope dependence of the L-H power threshold in an ITER-like wall environment (Be wall and W divertor). Here we present results from dedicated L-H transition experiments at JET-ILW, documenting the power threshold in tritium and deuterium–tritium plasmas, comparing them with the matching deuterium and hydrogen datasets. From earlier experiments in JET-ILW it is known that as plasma isotopic composition changes from deuterium, through varying deuterium/hydrogen concentrations, to pure hydrogen, the value of the line averaged density at which the threshold is minimum, ${\bar n_{{\text{e}},{\text{min}}}}$, increases, leading us to expect that ${\bar n_{{\text{e}},{\text{min}}}}$(T) < ${\bar n_{{\text{e}},{\text{min}}}}$(DT) < ${\bar n_{{\text{e}},{\text{min}}}}$(D) < ${\bar n_{{\text{e}},{\text{min}}}}$(H). The new power threshold data confirms these expectations in most cases, with the corresponding ordering of the minimum power thresholds. We present a comparison of this data to power threshold scalings, used for extrapolation to future devices such as ITER and DEMO.
We provide an overview of activities carried out at the TJ-II stellarator for improving our understanding of- and developing plasma physics models for particle density profiles in stellarators. Namely, we report on recent progress in turbulent particle transport simulation, validation of pellet deposition models, density profile shaping for performance control and new experimental techniques for edge turbulence and plasma-neutral interaction.
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Attosecond photoemission or photoionization delays are a unique probe of the structure and the electronic dynamics of matter. However, the spectral congestion of valence photoelectron spectra sets fundamental limits to the complexity of systems that can be studied, and the delocalization of valence electron wave functions blurs the spatial origin of the photoelectron wave packet. Using attosecond x-ray pulses from LCLS, we demonstrate the key advantages of measuring core-level delays: The photoelectron spectra remain atomlike, the measurements become element specific, and the observed scattering dynamics originate from a pointlike source when multicenter interference effects are negligible. We exploit these unique features to reveal the effects of changing functional groups (C-H vs N) and symmetry on attosecond scattering dynamics by measuring and calculating the photoionization delays between N−1𝑠 and C−1𝑠 core shells of a series of aromatic azabenzene molecules. Remarkably, the delays increase with the number of nitrogen atoms in the molecule and reveal multiple resonances. We identify two previously unknown mechanisms regulating the associated attosecond dynamics, namely the enhanced confinement of the trapped wave function with the replacement of C-H groups by N atoms and the decrease of the coupling strength among the photoemitted partial waves with increasing symmetry. This study demonstrates the unique opportunities opened by measurements of core-level photoionization delays for unraveling attosecond electron dynamics in complex matter.
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The goal of this work is to develop new solar photovoltaic (PV) modules and solar system-scale designs that promote an increase of the convective heat transfer coefficient of at least 40%, reducing the operating temperature of the solar PV panels, and leading to a boost on the annual energy yield by at least 5%. By achieving this goal, we further foresee decreasing solar panel degradation by +0.3%/year, reducing the LCOE by 2.9-4.5¢/kWh. Currently, this question and/or approach is not considered though it is a relevant factor in performance/efficiency. The technology proposed will be at a mature stage by the end of the project and could be aligned to be proven on a full-field test. PV users, installers and manufacturers will be interested in the technology due to the aforementioned benefits. The work was conducted through a suite of wind tunnel experiments, numerical simulations and field experiments. These were then evaluated through a correlation encompassing the entire data set and implementing findings into NREL SAM. The work resulted in eight peer reviewed publications with three others in preparation. The key results of the project are 1.) Showing the capability of increasing the solar farm power production by increasing the heat transfer coefficient; 2.) Providing strategies for achieving this through large scale arrangement manipulation (heights, spacings, angles), flow deflectors and vortex generators; 3.) Demonstrating scalability of results by comparing numerical simulations, wind tunnel experiments and field experiments; 4.) Providing a correlation to be able to capture the various arrangements while exploiting the heat transfer coefficient; and 5.) Proving the feasibility of such strategies and their capacity through a comprehensive techno-economic analysis. For the heat transfer coefficients, gains of 40% were attained and increases in power in the excess of 5% were observed. For heat mitigation strategies, consideration at the PV array scale were inter-panel spacing, panel height and panel angles while at the module level, wind breaks such as solid walls and selected gaps were evaluated as well as vortex generators on the panel. All proposed strategies saw an increase in heat transfer coefficient. For scalability, results were compared against field experiments and a correlation for the heat transfer quantity was attained leading to a parametric understanding of the variations and impact in the heat transfer coefficient independent of tools implemented (wind tunnel/numerical simulations). The strategies were also further assessed by a technoeconomic analysis finding improvements based on LCOE with respect to location (several states with varies atmospheric conditions/geographic locations) yielded different results. Improvements on this end were also observed especially towards the colder climates and when considering bi-facial modules. The quantitative demonstrations of such conclusions are provided in the main portion of this document with complementary results and their narration. Milestones and go/no-go points were successfully met in the project.
The eddy viscosity hypothesis is a popular method in wind turbine wake modeling for estimating turbulent Reynolds stresses. We document the downstream evolution of eddy viscosity in the wake of a wind turbine from experimental and large-eddy-simulation data. Wake eddy viscosity is isolated from its surroundings by subtracting the inflow profile, and the driving forces are identified in each wake region. Eddy viscosity varies in response to changes in turbine geometry and nacelle misalignment with larger turbines generating stronger velocity gradients and shear stresses. We propose a model for eddy viscosity based on a Rayleigh distribution. Model parameters are obtained from scaling the eddy viscosity hypothesis and demonstrate satisfactory agreement with the reference data. The model is implemented in the curled wake formulation in the FLOw Redirection and Induction in Steady State (FLORIS) framework and assessed through comparisons with the previous formulation. Our approach produced more accurate flow field estimates with lower total error for the majority of cases.
Heat transfer modeling that accounts for how convective cooling changes with PV array layout has been found to improve system LCOE in certain climates conditions. Analysis of fixed tilt systems performed using the System Advisor Model reveals that reducing system ground coverage ratio from 0.46 to 0.35 can lead to as much as a 1.7% increase in module annual energy output in Phoenix. Depending on climate conditions, these energy increases due to changing convective cooling flow can lead to LCOE improvements for systems with increased row spacing despite the increased wiring and land costs associated with increased module row spacing. While the energy gain from decreasing system ground coverage ratio can be largely attributed to increased plane of array irradiance, the convection cooling considerations presented here can have a non-negligible impact on PV power plant energy output and economic viability depending on climate conditions and array spacing parameters.