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At least 847 records · Page 47

Subdomain cryo-EM structure of nodaviral replication protein A crown complex provides mechanistic insights into RNA genome replication

For positive-strand RNA [(+)RNA] viruses, the major target for antiviral therapies is genomic RNA replication, which occurs at poorly understood membrane-bound viral RNA replication complexes. Recent cryoelectron microscopy (cryo-EM) of nodavirus RNA replication complexes revealed that the viral double-stranded RNA replication template is coiled inside a 30- to 90-nm invagination of the outer mitochondrial membrane, whose necked aperture to the cytoplasm is gated by a 12-fold symmetric, 35-nm diameter “crown” complex that contains multifunctional viral RNA replication protein A. Here we report optimizing cryo-EM tomography and image processing to improve crown resolution from 33 to 8.5 Å. This resolves the crown into 12 distinct vertical segments, each with 3 major subdomains: A membrane-connected basal lobe and an apical lobe that together comprise the ~19-nm-diameter central turret, and a leg emerging from the basal lobe that connects to the membrane at ~35-nm diameter. Despite widely varying replication vesicle diameters, the resulting two rings of membrane interaction sites constrain the vesicle neck to a highly uniform shape. Labeling protein A with a His-tag that binds 5-nm Ni-nanogold allowed cryo-EM tomography mapping of the C terminus of protein A to the apical lobe, which correlates well with the predicted structure of the C-proximal polymerase domain of protein A. These and other results indicate that the crown contains 12 copies of protein A arranged basally to apically in an N-to-C orientation. Moreover, the apical polymerase localization has significant mechanistic implications for template RNA recruitment and (-) and (+)RNA synthesis.

59 BASIC BIOLOGICAL SCIENCES↗

Development of MOSCATO: A CFD-Level Electrochemistry and Corrosion Simulator for Molten Salt Systems

For both coolant and fueled variants of molten salt reactors (MSRs), the corrosion of structural materials is a significant challenge. The corrosion stems from chemical and electrochemical reactions initiated by fissile material, fission products, and impurities in the salt. Lower-fidelity models rely on empirical correlations for mass transfer, simplified lumped temperature profiles, and similar assumptions. They do not capture detailed spatial variations in complex geometries, creating the need for high-fidelity modeling to bridge this gap.As we approach the demonstration and possible deployment of MSRs in this decade, the development of a high-fidelity, high-performance simulator becomes imperative. To simulate the complex electrochemical environment and corrosion within molten salt systems, we have developed the Molten Salt Chemistry And TranspOrt (MOSCATO) code. This endeavor is comprised of three essential components. First, mass transfer equations are coupled with the Navier-Stokes equations in order to account for the transport of species in the salt. Second, the diffusion of alloy constituents, such as Cr, Fe, Ni, etc. is simulated within the structural metals. Third, the alloy and salt domains are coupled to account for the heterogeneous chemical and electrochemical reactions that occur at the salt-alloy interface.MOSCATO manages all three components within the framework of the highly scalable, open-source spectral element method computational fluid dynamics code Nek5000/NekRS. This integration enables MOSCATO to harness the immense computational power of modern high-performance computing resources, ensuring both high fidelity and computational speed.In addition to code development, we have initiated a comprehensive verification and validation campaign, utilizing data from diverse sources. First, MOSCATO's electrochemical solver was verified with reference numerical data. Then validation occurred against experiments: one of a thermal galvanic cell and the other for corrosion in flowing molten salt of FLiNaK (LiF-NaF-KF). This campaign verified and validated MOSCATO as a reliable tool for simulating electrochemical environments and corrosion in molten salt systems.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

Topological superconductivity induced by a triple- q magnetic structure

Here we demonstrate that the recently discovered triple- q (3 q ) magnetic structure, when embedded in a magnet-superconductor hybrid (MSH) system, gives rise to the emergence of topological superconductivity. We investigate the structure of chiral Majorana edge modes at domain walls, and show that they can be distinguished from trivial in-gap modes through the spatial distribution of the induced supercurrents. Finally, we show that topological superconductivity in 3 q MSH systems is a robust phenomenon that does not depend on the relative alignment of the magnetic and superconducting layers, or on the presence of electronic degrees of freedom in the magnetic layer.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Evolution of magnetism, valence, and crystal lattice in EuCd 2 As 2 under pressure

EuCd 2 As 2 has been proposed to be one of the ideal platforms as an intrinsic topological magnetic system, potentially hosting a single pair of Weyl points when it is tuned into the ferromagnetic state with spins aligned out of plane by either external pressure or chemical doping. To investigate the possible realization of an ideal topological state, we have systematically investigated pressure control of the magnetic state, valence, and crystal structure using synchrotron-based time-domain Mössbauer spectroscopy, x-ray absorption spectroscopy, and powder x-ray diffraction. Our experimental results show that the magnetic configuration remains mostly in plane under pressure up to 42.8 GPa and pressure effectively enhances the magnetic ordering temperature. Meanwhile, Eu ions remain divalent when subjected to pressure up to 35.9 GPa, and the trigonal crystal lattice is maintained up to 34.6 GPa. Our work provides valuable experimental data to benchmark future theoretical studies in magnetic topological materials.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

A design of resonant inelastic X-ray scattering (RIXS) spectrometer for spatial- and time-resolved spectroscopy

The optical design of a Hettrick–Underwood-style soft X-ray spectrometer with Wolter type 1 mirrors is presented. The spectrometer with a nominal length of 3.1 m can achieve a high resolving power (resolving power higher than 10000) in the soft X-ray regime when a small source beam (<3 µm in the grating dispersion direction) and small pixel detector (5 µm effective pixel size) are used. Adding Wolter mirrors to the spectrometer before its dispersive elements can realize the spatial imaging capability, which finds applications in the spectroscopic studies of spatially dependent electronic structures in tandem catalysts, heterostructures, etc . In the pump–probe experiments where the pump beam perturbs the materials followed by the time-delayed probe beam to reveal the transient evolution of electronic structures, the imaging capability of the Wolter mirrors can offer the pixel-equivalent femtosecond time delay between the pump and probe beams when their wavefronts are not collinear. In combination with some special sample handing systems, such as liquid jets and droplets, the imaging capability can also be used to study the time-dependent electronic structure of chemical transformation spanning multiple time domains from microseconds to nanoseconds. The proposed Wolter mirrors can also be adopted to the existing soft X-ray spectrometers that use the Hettrick–Underwood optical scheme, expanding their capabilities in materials research.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗

A Performance-Portable MultiGPU Implementation of 3D Euler Equations using ProtoX and IRIS

Computational scientists often face challenges when developing and optimizing code for high-performance computing (HPC), especially when trying to leverage GPUs. Given the heterogeneity of the nodes that comprise many modern HPC facilities, considerable demand exists for performance portable solutions for the core computational kernels used in many scientific computing libraries. In this work, we demonstrate a fourth-order finite volume method–based implementation of the Euler equations, which are an integral part of computational fluid dynamics. Our performance-portable multiGPU implementation for Euler equations uses ProtoX to generate kernels and IRIS for portability. ProtoX is a domain-specific language that uses a structured-grid partial differential equation library called Proto as its front end and the SPIRAL code generation system as its back end to generate optimized kernels for different architectures. Optimized kernels generated by ProtoX are orchestrated through the IRIS intelligent runtime system to provide portability. Two levels of optimizations within the IRIS runtime— directed acyclic graph fusion and task fusion—are explored to efficiently utilize computing resources in a multiGPU environment. Performance improvement through these optimizations is showcased by comparing the base ProtoX-IRIS implementation on AMD GPUs (Frontier node) and on NVIDIA GPUs (NVIDIA DGX-1).

Mankad, Het↗

Mechanism of structural colors in binary mixtures of nanoparticle-based supraballs

Inspired by structural colors in avian species, various synthetic strategies have been developed to produce noniridescent, saturated colors using nanoparticle assemblies. Nanoparticle mixtures varying in particle chemistry and size have additional emergent properties that affect the color produced. For complex multicomponent systems, understanding the assembled structure and a robust optical modeling tool can empower scientists to identify structure-color relationships and fabricate designer materials with tailored color. Here, we demonstrate how we can reconstruct the assembled structure from small-angle scattering measurements using the computational reverse-engineering analysis for scattering experiments method and use the reconstructed structure in finite-difference time-domain calculations to predict color. We successfully, quantitatively predict experimentally observed color in mixtures containing strongly absorbing nanoparticles and demonstrate the influence of a single layer of segregated nanoparticles on color produced. The versatile computational approach that we present is useful for engineering synthetic materials with desired colors without laborious trial-and-error experiments.

36 MATERIALS SCIENCE↗

Antibiotic that inhibits trans -translation blocks binding of EF-Tu to tmRNA but not to tRNA

trans-Translation is conserved throughout bacteria and is essential in many species. High-throughput screening identified a tetrazole-based trans-translation inhibitor, KKL-55, that has broad-spectrum antibiotic activity. A biotinylated version of KKL-55 pulled down elongation factor thermo-unstable (EF-Tu) from bacterial lysates. Purified EF-Tu bound KKL-55 in vitro with a K d = 2 µM, confirming a high-affinity interaction. An X-ray crystal structure showed that KKL-55 binds in domain 3 of EF-Tu, and mutation of residues in the binding pocket abolished KKL-55 binding. RNA-binding assays in vitro showed that KKL-55 inhibits binding between EF-Tu and transfer-messenger RNA (tmRNA) but not between EF-Tu and tRNA. These data demonstrate a new mechanism for the inhibition of EF-Tu function and suggest that this specific inhibition of EF-Tu•tmRNA binding is a viable target for antibiotic development.

59 BASIC BIOLOGICAL SCIENCES↗

CAHS: Context-Aware Homology Search

Protein homology search is foundational to bioinformatics: it supports annotation transfer, structure/function inference, and evolutionary analysis over rapidly expanding sequence repositories (e.g., UniProtKB). Profile hidden Markov models (pHMMs), as implemented in HMMER, remain the most widely trusted approach because they provide statistically calibrated E-values; however, their gap behavior is fixed once a profile is trained, despite biological evidence that insertion/deletion tolerance varies across flexible loops and intrinsically disordered regions. We present CAHS (Context-Aware Homology Search), a lightweight query-time adapter for pHMM search that incorporates learned and biologically motivated signals without changing HMMER's downstream search pipeline or its calibrated E-value reporting. Given a query sequence, CAHS computes per-residue representations from a protein language model and a disorder predictor, maps these to profile coordinates, and modulates only match-state transition rows (gap-open and gap-extension probabilities) while preserving Plan7 constraints. We comprehensively evaluate CAHS across six structurally diverse protein families and multi-domain architectures against a 570k-sequence target corpus. CAHS expands detection capability, retrieving thousands of additional remote homologs at relaxed thresholds by maintaining alignment quality through flexible regions. For multi-domain proteins, context-aware modulation resolves 94% of fragmented alignments. Crucially, CAHS preserves hit-set invariance at stringent operating points (E<10-10), demonstrating increased statistical confidence without inflating false positives. Furthermore, sharper statistical distinction between homologs and background noise during early filter stages yields up to a 3.87× acceleration in end-to-end wall-clock time on high-performance computing clusters. Overall, CAHS illustrates a practical AI-for-science design pattern: augmenting a trusted probabilistic model with query-specific learned signals to improve interpretable, reproducible inference in data-rich biology.

Bhattaram, Swethasree [Georgia Institute of Techno↗

Impedance and wakefield studies of the EIC RCS 591 MHz five-cell cavity

The Electron-Ion Collider (EIC) is a next-generation accelerator complex designed to enable high-luminosity collisions between highly polarized electrons and light ions (e.g., He-3). A central component of its Electron Injection System (EIS) is the Rapid Cycling Synchrotron (RCS), which accelerates a single 28 nC electron bunch from 750 MeV to 5, 10, or 18 GeV using an array of 591 MHz five-cell superconducting RF (SRF) cavities—eight at the current design stage. To ensure stable acceleration of high-charge bunches, we conducted detailed impedance and wakefield studies of the SRF cavity structure using both frequency- and time-domain methods. Wakefield solvers (ECHO3D, ECHO1D, CST), eigenmode analysis, and multi-particle tracking with ELEGANT were employed to evaluate longitudinal and transverse impedance effects and to determine instability thresholds. These studies provide critical input for the cavity design and operating parameters required to preserve beam quality and stability in the RCS.

Accelerator Physics↗

First Sagittarius A* Event Horizon Telescope Results. IV. Variability, Morphology, and Black Hole Mass

In this paper we quantify the temporal variability and image morphology of the horizon-scale emission from Sgr A*, as observed by the EHT in 2017 April at a wavelength of 1.3 mm. We find that the Sgr A* data exhibit variability that exceeds what can be explained by the uncertainties in the data or by the effects of interstellar scattering. The magnitude of this variability can be a substantial fraction of the correlated flux density, reaching ~100% on some baselines. Through an exploration of simple geometric source models, we demonstrate that ring-like morphologies provide better fits to the Sgr A* data than do other morphologies with comparable complexity. We develop two strategies for fitting static geometric ring models to the time-variable Sgr A* data; one strategy fits models to short segments of data over which the source is static and averages these independent fits, while the other fits models to the full data set using a parametric model for the structural variability power spectrum around the average source structure. Both geometric modeling and image-domain feature extraction techniques determine the ring diameter to be 51.8 ± 2.3 μas (68% credible intervals), with the ring thickness constrained to have an FWHM between ~30% and 50% of the ring diameter. To bring the diameter measurements to a common physical scale, we calibrate them using synthetic data generated from GRMHD simulations. This calibration constrains the angular size of the gravitational radius to be ${4.8}_{-0.7}^{+1.4}$ μas, which we combine with an independent distance measurement from maser parallaxes to determine the mass of Sgr A* to be ${4.0}_{-0.6}^{+1.1}\times {10}^{6}$ M⊙.

79 ASTRONOMY AND ASTROPHYSICS↗

Allosteric inhibition of the IZUMO1–JUNO fertilization complex by the naturally occurring antisperm antibody OBF13

Sperm IZUMO1 binds to egg JUNO, and this interaction is essential for mammalian fertilization. Isolated from a female mouse immunized with syngeneic sperm, the antisperm antibody OBF13 recognizes IZUMO1 and inhibits murine fertilization. How OBF13 interferes with sperm–egg interactions was unknown. Here, we present the X-ray crystal structure of IZUMO1 in complex with OBF13. OBF13 binds to the apex of the four-helix domain of IZUMO1, distant from the JUNO-binding site. Our crystal structure of OBF13-bound IZUMO1 resembles apo-IZUMO1 and differs from the structure of IZUMO1 in complex with JUNO. We identify that OBF13 carries a low level of somatic hypermutation, and through deep mutational scanning, we engineer an affinity-enhanced OBF13 variant. This OBF13 variant single-chain fragment variable decreases the apparent affinity of IZUMO1 for membrane-bound murine JUNO and blocks the binding of acrosome-reacted sperm to eggs, thereby preventing fertilization. We propose allostery between the OBF13 epitope and the JUNO-binding site. OBF13 inhibits a conformational change in IZUMO1, preventing fusion-competent sperm from adhering to murine eggs during fertilization. Surprisingly, murine IZUMO1 binds to hamster JUNO with an affinity ~20-fold higher than to murine JUNO. The decreased affinity caused by OBF13 of murine IZUMO1 for hamster JUNO is sufficient for murine sperm to bind to and fuse with hamster eggs. Our studies provide a structural and mechanistic framework for species-specific, allosteric inhibition of IZUMO1 by a naturally occurring antisperm antibody and offer insights into the development of immunocontraceptives.

Science & Technology - Other Topics↗

The CRISPR effector Cam1 mediates membrane depolarization for phage defence

Prokaryotic type III CRISPR–Cas systems provide immunity against viruses and plasmids using CRISPR-associated Rossman fold (CARF) protein effectors. Recognition of transcripts of these invaders with sequences that are complementary to CRISPR RNA guides leads to the production of cyclic oligoadenylate second messengers, which bind CARF domains and trigger the activity of an effector domain. Whereas most effectors degrade host and invader nucleic acids, some are predicted to contain transmembrane helices without an enzymatic function. Whether and how these CARF–transmembrane helix fusion proteins facilitate the type III CRISPR–Cas immune response remains unknown. Here we investigate the role of cyclic oligoadenylate-activated membrane protein 1 (Cam1) during type III CRISPR immunity. Structural and biochemical analyses reveal that the CARF domains of a Cam1 dimer bind cyclic tetra-adenylate second messengers. In vivo, Cam1 localizes to the membrane, is predicted to form a tetrameric transmembrane pore, and provides defence against viral infection through the induction of membrane depolarization and growth arrest. These results reveal that CRISPR immunity does not always operate through the degradation of nucleic acids, but is instead mediated via a wider range of cellular responses.

59 BASIC BIOLOGICAL SCIENCES↗

A Graph Dynamical neural network approach for decoding dynamical states in ferroelectrics.

Ferroelectric materials such as BaTiO 3 show tremendous potential for emerging advances in memory devices, particular neuromorphic type devices. High density of memory can be obtained by stabilising polar domain walls at the nanoscale, regions of discontinuity between the well-defined polarization order parameter, but little is known about what controls their structure and dynamics in real nanoscale materials. Indeed, chiral polar domain walls have been observed in heterogeneous ferroelectrics, such as oxygen-deficient BaTiO 3 , but very little is known about how such polar-domains walls interact with defects. Indeed, a critical understanding of how dynamics of domain-walls depend on point-defects is crucial to create engineered ferroelectric memory devices. For this work, we perform large-scale simulations of nansocale domain-wall dynamics in pristine and defective BaTiO 3 using reactive force-field developed by us earlier (Phys. Chem. Chem. Phys., 2019, 21, 18240–18249), and capture their dynamical dependence on point defects using a graph dynamical neural-network approach, which we adapted to interrogate solids with well-defined order-parameters, and implemented using Pytorch based libraries. Our machine learning (ML) approach goes beyond the traditional post-processing methods to capture both spatial and temporal heterogeneities of large-scale molecular dynamics simulations of complex defective ferroelectric oxide materials. We crucially find that isolated oxygen vacancies introduce very localized spatial regions (~1–2 unit-cell in length) that show slow dipole relaxation due to formation of defect-dipoles, and that these defect-dipoles in turn slow the intrinsic dynamics of domain walls. Further, the roughness of domain walls, also influenced by vacancies, introduce dynamic heterogeneity along the domain-wall. As such we find a novel mechanism by which quenched disorder due to defects introduce dynamic heterogeneity thereby influencing response to external fields (particularly time varying fields) in a ferroelectric. Our study also emphasizes the need for creating digital twins of dynamical quantities to achieve autonomous in operando control of nanoscale switching.

42 ENGINEERING↗

Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1

UHRF1 is an important epigenetic regulator associated with apoptosis and tumour development. It is a multidomain protein that integrates readout of different histone modification states and DNA methylation with enzymatic histone ubiquitylation activity. Emerging evidence indicates that the chromatin-binding and enzymatic modules of UHRF1 do not act in isolation but interplay in a coordinated and regulated manner. Here, we compared two splicing variants (V1, V2) of murine UHRF1 (mUHRF1) with human UHRF1 (hUHRF1). We show that insertion of nine amino acids in a linker region connecting the different TTD and PHD histone modification-binding domains causes distinct H3K9me3-binding behaviour of mUHRF1 V1. Structural analysis suggests that in mUHRF1 V1, in contrast to V2 and hUHRF1, the linker is anchored in a surface groove of the TTD domain, resulting in creation of a coupled TTD-PHD module. This establishes multivalent, synergistic H3-tail binding causing distinct cellular localization and enhanced H3K9me3-nucleosome ubiquitylation activity. In contrast to hUHRF1, H3K9me3-binding of the murine proteins is not allosterically regulated by phosphatidylinositol 5-phosphate that interacts with a separate less-conserved polybasic linker region of the protein. Our results highlight the importance of flexible linkers in regulating multidomain chromatin binding proteins and point to divergent evolution of their regulation.

60 APPLIED LIFE SCIENCES↗

CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism

CLC-2 is a voltage-gated chloride channel that contributes to electrical excitability and ion homeostasis in many different tissues. Among the nine mammalian CLC homologs, CLC-2 is uniquely activated by hyperpolarization, rather than depolarization, of the plasma membrane. The molecular basis for the divergence in polarity of voltage gating among closely related homologs has been a long-standing mystery, in part because few CLC channel structures are available. Here, we report cryoEM structures of human CLC-2 at 2.46 – 2.76 Å, in the presence and absence of the selective inhibitor AK-42. AK-42 binds within the extracellular entryway of the Cl – -permeation pathway, occupying a pocket previously proposed through computational docking studies. In the apo structure, we observed two distinct conformations involving rotation of one of the cytoplasmic C-terminal domains (CTDs). In the absence of CTD rotation, an intracellular N-terminal 15-residue hairpin peptide nestles against the TM domain to physically occlude the Cl – -permeation pathway. This peptide is highly conserved among species variants of CLC-2 but is not present in other CLC homologs. Previous studies suggested that the N-terminal domain of CLC-2 influences channel properties via a “ball-and-chain” gating mechanism, but conflicting data cast doubt on such a mechanism, and thus the structure of the N-terminal domain and its interaction with the channel has been uncertain. Through electrophysiological studies of an N-terminal deletion mutant lacking the 15-residue hairpin peptide, we support a model in which the N-terminal hairpin of CLC-2 stabilizes a closed state of the channel by blocking the cytoplasmic Cl – -permeation pathway.

59 BASIC BIOLOGICAL SCIENCES↗

Origin of High Activity and Durability of Twisty Nanowire Alloy Catalysts under Oxygen Reduction and Fuel Cell Operating Conditions

The ability to control the surface composition and morphology of alloy catalysts is critical for achieving high activity and durability of catalysts for oxygen reduction reaction (ORR) and fuel cells. Here, this report describes an efficient surfactant-free synthesis route for producing a twisty nanowire (TNW) shaped platinum–iron (PtFe) alloy catalyst (denoted as PtFe TNWs) with controllable bimetallic compositions. PtFe TNWs with an optimal initial composition of ~24% Pt are shown to exhibit the highest mass activity (3.4 A/mg Pt , ~20 times higher than that of commercial Pt catalyst) and the highest durability (<2% loss of activity after 40000 cycles and <30% loss after 120000 cycles) among all PtFe-based nanocatalysts under ORR or fuel cell operating conditions reported so far. Using ex situ and in situ synchrotron X-ray diffraction coupled with atomic pair distribution function (PDF) analysis and 3D modeling, the PtFe TNWs are shown to exhibit mixed face-centered cubic (fcc)-body-centered cubic (bcc) alloy structure and a significant lattice strain. A striking finding is that the activity strongly depends on the composition of the as-synthesized catalysts and this dependence remains unchanged despite the evolution of the composition of the different catalysts and their lattice constants under ORR or fuel cell operating conditions. Notably, dealloying under fuel cell operating condition starts at phase-segregated domain sites leading to a final fcc alloy structure with subtle differences in surface morphology. Due to a subsequent realloying and the morphology of TNWs, the surface lattice strain observed with the as-synthesized catalysts is largely preserved. This strain and the particular facets exhibited by the TNWs are believed to be responsible for the observed activity and durability enhancements. These findings provide new insights into the correlation between the structure, activity, and durability of nanoalloy catalysts and are expected to energize the ongoing effort to develop highly active and durable low-Pt-content nanowire catalysts by controlling their alloy structure and morphology.

25 ENERGY STORAGE↗

An Open-Source Frequency-Domain Model for Floating Wind Turbine Design Optimization

A new frequency-domain dynamics model has been developed that uses open-source components to efficiently represent a complete floating wind turbine system. The model, called RAFT (Response Amplitudes of Floating Turbines), incorporates quasi-static mooring reactions, strip-theory and potential-flow hydrodynamics, blade-element-momentum aerodynamics, and linear turbine control. The formulation is compatible with a wide variety of support structure configurations and no manual or time-domain preprocessing steps are required, making RAFT very practical in design and optimization workflows. The model is applied to three reference floating wind turbine designs and its predictions are compared with results from time-domain OpenFAST simulations. There is good agreement in mean offsets as well the statistics and spectra of the dynamic response, verifying RAFT’s general suitability for floating wind analysis. Follow-on work will include verification of potential-flow and turbine-control features and application to optimization problems.

17 WIND ENERGY↗