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Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model
Abstract MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing therapies for MDS is challenging due to the variability in MECP2 expression among patients and the risk of inducing Rett syndrome through excessive pharmacological intervention. Reducing dosage to optimize silencing often compromises durability and necessitates increased dosing frequency. We present here a series of fully chemically modified small interfering RNAs (siRNAs) designed for isoform-selective and total Mecp2 silencing. Among these, we identify six lead siRNA candidates across two chemical scaffolds, achieving targeted total Mecp2 expression reductions ranging from 25% to 75%, sustained for at least four months following a single administration. The efficacy and safety of human ortholog silencing are evaluated using a mouse model with ~8-fold human Mecp2 transgene expression. In this severe duplication model, a single dose of the total isoform-silencing siRNA rescues early mortality and select behavioral impairments. Overall, this study introduces preclinical candidates for the treatment of MDS. Furthermore, it establishes a target selection strategy applicable to other dosage-sensitive gene imbalances.
Dynamic catalytic interface driven three-step synergistic mechanism for boosting ammonia and hydroxylamine synthesis
Hardware acceleration of simulated annealing for constraint satisfaction problems
Abstract Simulated annealing (SA), a metaheuristic algorithm inspired by physical annealing processes, attempts to solve combinatorial optimization problems by performing a stochastic search that iteratively explores the solution space. Probabilistic solution evaluation allows the algorithm to escape local minima and progressively converge toward a global optimum, even within complex solution landscapes. In this work, we present the hardware acceleration of SA for spatial optimization within constrained environments, specifically targeting drone placement that maximizes area coverage while avoiding no-fly zones. Stochasticity is introduced through a true random number generator (TRNG) based on two-dimensional (2D) materials. The system energy is evaluated using a 2D logic circuit and the acceptance of candidate solutions is governed by a programmable 2D circuit with tunable threshold behavior. For a representative drone placement task, our hardware-based annealing accelerator circuit modules consume 43 nJ of energy per iteration and achieve an 1800-fold search acceleration relative to brute-force exploration of the solution space. This work also underscores the potential of 2D-material-enabled stochastic and programmable hardware for real-time constrained optimization.
Analysis of 14q12 microdeletions reveals novel regulatory loci for the neurodevelopmental disorder-related gene FOXG1
Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies
Abstract Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer’s disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.
Quantum adiabatic transport in a quantum anomalous Hall insulator
Abstract An exceptional trait of the quantum Hall effect is quantum adiabatic transport, dissipationless quantized edge transport that is robust to bias voltages multiple orders of magnitude larger than any known relevant energy scale. This enables stable and highly sensitive measurements in quantum metrology at temperatures above 1 K. In contrast, prior experiments have shown that an electrical bias of the same order applied to the quantum anomalous Hall edge modes in magnetic topological insulators causes a breakdown of quantization, resulting from material limitations (electric field activates bulk transport). In this paper, to mitigate the effects of this electric field and study edge transport at a large electrical bias, we utilize electrochemical potential balancing. We find that electrical transport along the edge of a quantum anomalous Hall insulator is ubiquitously of dissipationless quantum adiabatic nature. In fact, we can verify that the adiabaticity holds at least up to an applied bias voltage of some 600 mV at 4.2 K, multiple orders of magnitude larger than any known energy scale associated with the quantum anomalous Hall state. This is a level of robustness on par with the conventional quantum Hall modes used in mainstream metrology.
Computational methods toward ultrastable glasses
Ultrastable glasses, amorphous solids with exceptionally low-energy states and enhanced kinetic, thermodynamic, and mechanical stability, have long been a subject of intense experimental interest. Over the past decade, their computational realization has emerged as a major goal in condensed matter physics, as numerical methods can exploit unphysical moves to access deeply supercooled and nonequilibrium glassy states far beyond the reach of conventional cooling protocols, thereby providing key insights into the nature of the glass transition and amorphous states and enabling the design of mechanically robust glassy materials. In this review, we outline the key steps underlying the most effective algorithms developed across the field. For each approach, we discuss its efficiency, limitations, and physical interpretation. We finally present a comparative analysis of the stability achieved across these methods, with the aim of equipping both newcomers and experts with an intuitive and comprehensive understanding of the field’s current state and the opportunities it presents.
The Cahn–Hilliard residuum and its implications for critical-point wetting at solid solution surfaces
As part of their seminal 1958 analysis of nonuniform solutions, Cahn and Hilliard [J. Chem. Phys. 28, 258–267 (1958)] identified the Laplacian of the composition field as the key contribution to the excess free energy in solids with a conserved network of discrete atomic sites. Integration by parts converted to the now familiar gradient-square form underlying phase-field simulations and studies of critical-point wetting. The residuum from the integration by parts has since been ignored. Here, we examine its implications using critical-point wetting at the surface of an Ising-type solid solution for a representative case. As a benchmark, atomistic Monte Carlo simulation shows a continuous increase in wetting-layer thickness up to the bulk critical temperature. In contrast, the classical gradient-square continuum model predicts a first-order wetting transition. A more realistic Laplacian-based continuum formulation does not readily admit physically meaningful minimization by standard variational methods. As a discrete approach, a plane-by-plane model with an excess energy based on a second-difference (curvature) operator yields solutions consistent with the benchmark. Summation by parts transforms this operator into a first-difference- (gradient-) square form, and neglect of the residual term again leads to an incorrect first-order transition. Thus, the choice between curvature and gradient-square formulations alters the predicted character—first-order transition or continuous evolution in layer thickness—of the wetting, underscoring the fundamental importance of this choice.
Benchmarking semiempirical quantum chemical methods on liquid water
Stimulated by the renewed interest and recent developments in semiempirical quantum chemical (SQC) methods for noncovalent interactions, we examine the properties of liquid water under ambient conditions by means of molecular dynamics (MD) simulations, both with the conventional neglect of diatomic differential overlap-type methods, e.g., AM1 and PM6, and with DFTB-type (density-functional tight-binding) methods, e.g., DFTB2 and GFN-xTB (Geometry-Frequency-Noncovalent eXtended Tight-Binding). Besides the original parameter sets, some specifically reparameterized SQC methods (denoted as AM1-W, PM6-fm, and DFTB2-iBi) targeting various smaller water systems ranging from molecular clusters to bulk are considered as well. The quality of these different SQC methods for describing liquid water properties under ambient conditions is assessed by comparison with well-established experimental data and also with BLYP-D3 density functional theory-based ab initio MD simulations. Our analyses reveal that static and dynamic properties of bulk water are poorly described by all considered SQC methods with the original parameters, regardless of the underlying theoretical models, with most of the methods suffering from too weak hydrogen bonds and hence predicting a far too fluid water with highly distorted hydrogen bond kinetics. Meanwhile, the reparameterized force-matched PM6-fm method is shown to be able to quantitatively reproduce the static and dynamic features of liquid water and thus can be used as a computationally efficient alternative to electronic structure-based MD simulations for liquid water that requires extended length and time scales. DFTB2-iBi predicts a slightly overstructured water with reduced fluidity, whereas AM1-W gives an amorphous ice-like structure for water under ambient conditions.
Phase fluctuations in a confined fluid
Fluid phase equilibrium depends on the external constraints imposed on a system. In a closed system with fixed volume, depending on the average density, a vapor bubble may be stable, metastable, or unstable, with respect to the homogeneous liquid phase. In the case where the bubble is metastable, we study its lifetime, i.e., the average waiting time needed to observe bubble collapse, and the corresponding lifetime of the homogeneous liquid. For the smallest systems, we predict the possibility to observe phase flipping, when the fluid oscillates between states with and without bubble. We provide an example of phase flipping in a simulation of a Lennard-Jones fluid.
Elasticity of a polymer chain with deformable bonds under fixed extension and constant force
The force–extension response of a polymer chain provides a direct link between molecular conformations and mechanical behavior. Motivated by directional control conditions commonly encountered in single-molecule stretching, we investigate the elasticity of a polymer chain with deformable bond lengths and bond angles in fixed-extension (FE) and constant-force (CF) ensembles, where the extension is defined as the chain’s end-to-end distance projected along the pulling direction. We formulate both ensembles in terms of this projected extension and express their partition functions in transfer-matrix form. Exploiting the resulting structural similarity, we develop a unified computational framework that enables a direct comparison of their finite-chain responses. We show that the FE–CF difference is a finite-chain effect that decreases with increasing force and chain length. We further establish quantitative criteria for the onset of practical ensemble equivalence over finite force ranges and examine their dependence on bond stretching and bond-angle coupling. Applied to realistic carbon-backbone chains, we show that FE-like and CF-like responses become practically equivalent at experimentally relevant chain lengths in the higher-force regime probed by atomic force microscopy, whereas finite-chain ensemble differences remain appreciable in the lower-force regimes accessed by optical and magnetic tweezers. In the long-chain regime of practical equivalence, the semianalytical deformable freely rotating chain (dFRC) model proposed in our previous work [J. Zhu and L. Brassart, Phys. Rev. Lett. 134, 218101 (2025)] provides an accurate reduced description of the full statistical-mechanical response. These results clarify how ensemble choice, finite-chain effects, and local bond deformations jointly shape single-chain elasticity and provide a framework for interpreting and modeling single-chain stretching experiments.
Ensemble density functional theory of excited states: Exact <i>N</i> -centered formalism and practical opportunities
Ground-state electronic structure calculations using Kohn–Sham density functional theory (KS-DFT) offer an unprecedented balance between efficiency and accuracy, now paradigmatic to the fields of quantum chemistry and condensed matter physics. KS-DFT can be extended to model electronic excitations through density mapping onto a non-interacting ensemble state in which, unlike in thermal theories, the weights assigned to the excited states vary independently. Ensemble DFT (eDFT) has lately become a vibrant area of research thanks to its numerous appeals, such as the adequate treatment of multiple excitations for which the widely used time-dependent extension of DFT struggles. Recently, an enlarged type of ensemble, referred to as a N-centered (Nc) ensemble, has been introduced to describe within the same unified formalism both neutral and charged electronic excitations. This perspective paper provides a detailed exposition of exact Nc-eDFT, with a comprehensive review of its formal developments. To cut practical computational tools out of the exact theory, three original strategies are presented, complementing existing approaches. The first one, related to the design of ensemble density-functional approximations, consists in recycling regular ground-state functionals by dressing them with a weight-dependent scaling function deduced from exact properties of eDFT. We then explore quasi-degenerate formulations of ensemble density-functional perturbation theory, suggesting alternative definitions for the ensemble Hartree, exchange, and correlation energies, individually, and paving the way toward robust orbital-dependent eDFAs. Finally, we revisit and generalize the concept of quantum bath for an ensemble of non-interacting states, laying the foundations of an in-principle exact (in the sense of lattice eDFT) quantum embedding theory of excited states.
Quantifying pressure effects on the THF hydrate–water interfacial free energy at coexistence conditions: A computer simulation study
In this study, the tetrahydrofuran (THF) hydrate–aqueous interfacial free energy, γhw, is determined along the univariant two-phase coexistence line of the THF hydrate from molecular dynamic simulations. In particular, we determine γhw at 100, 250, and 1000 bar and at the corresponding coexistence temperatures. γhw is directly evaluated from simulations using the mold integration–host methodology, which is an extension of the original mold integration method. Water and THF molecules are described using the well-known TIP4P/ice model and a rigid version of the TraPPE model, respectively. This study is a natural extension of our previous studies, where the same model combination was used to describe the univariant two-phase dissociation line of the THF hydrate in a wide range of pressures [J. Algaba et al., J. Chem. Phys. 160, 164718 (2024)] and to calculate the THF hydrate–water γhw value at 500 bar and the corresponding coexistence temperature [M. J. Torrejón et al., J. Chem. Phys. 161, 064701 (2024)]. The results obtained in this study show excellent agreement with the only experimental data reported in the literature, 24(8) mJ/m2. This is the first time that the THF hydrate–water γhw is predicted along the univariant two-phase dissociation line of the THF hydrate. Our results suggest that there exists a minimum of energy at intermediate-low pressures and, in general, the γhw does not change significantly with the pressure in the range considered in this study. Once again, it is confirmed that the mold integration–host technique can be used to predict directly and accurately the hydrate–water γhw for hydrates with a sII crystallographic structure.
Capturing electron correlation at mean-field cost: Assessment of i-DMFT and the underlying correlation conjecture
Accurately treating strong electron correlation in quantum chemistry typically requires multireference wave function methods with steep computational scaling. The recently proposed i-DMFT method promises near configuration–interaction accuracy at mean-field cost by invoking an empirical linear relation between correlation energy and entropy (Collins’ conjecture), whose validity remains unclear. We systematically assess this relation across a range of di- and polyatomic molecules, including diverse bond types, third-row elements, different types of geometric distortions, and excited states. We find that the conjectured linearity holds for bond-breaking processes dominated by electron redistribution within orbital pairs but breaks down for heterolytic dissociation and excited states. In simple molecules, i-DMFT provides a reasonable description of total energies but does not reliably reproduce reduced density matrices or individual energy components. It further degrades in more complex cases, such as ethylene. Based on these results, we formulate criteria for the validity of the conjecture and outline implications for entropy-based reduced density matrix functionals.
Voltage-tunable nonequilibrium dispersion interactions
We develop a nonequilibrium Green’s function theory for dispersion interactions between two nanostructures, each an open quantum system driven into a nonequilibrium steady state by an applied bias voltage. Starting from the two-particle nonequilibrium Green’s function, we derive a general expression for the interaction energy in terms of the polarization propagators of the individual systems. The interaction energy admits a physically transparent decomposition into charge noise and charge dissipation contributions, providing a fluctuation–dissipation interpretation that generalizes the equilibrium London picture. Model calculations for coupled molecular junctions demonstrate that the applied voltage can enhance the attractive dispersion interaction by nearly an order of magnitude relative to equilibrium. In thermal equilibrium, the dispersion interaction is universally attractive, irrespective of the specific form of the nanostructure Hamiltonians or their coupling to reservoirs. Out of equilibrium, we introduce a generalized Kubo–Martin–Schwinger ratio that parameterizes the departure from detailed balance. We show that, in contrast to equilibrium, nonequilibrium conditions can lead to a repulsive dispersion interaction. Finally, we discuss the conditions under which population inversion in the electronic leads can drive a sign reversal of the dispersion interaction.
Improving NMR cryoporometry with octamethylcyclotetrasiloxane: From network models to accurate thermodynamic parameters
Nuclear magnetic resonance cryoporometry is capable of probing large-pore materials with pore sizes ranging from tens to thousands of nanometers. Achieving higher spatial sensitivity requires probe liquids with large solid–liquid interfacial energies, which are often poorly known. A representative example is octamethylcyclotetrasiloxane, which has attracted considerable interest for thermoporometry applications despite the wide scatter in the thermodynamic properties reported in the literature. In this work, we present an experimental approach for accurately determining these properties by exploiting recent advances in the description of solid–liquid equilibria in confined systems. The two proposed strategies provide highly consistent results and can be readily extended to other liquids with unknown thermodynamic properties.
Electron-ionization-dissociation dynamics of laser-excited SO2B̃B11/ÃA21 studied using velocity map imaging
It is well known that electron-driven chemistry for electronically excited molecules is markedly different from that for their ground-state counterparts, yet in most cases, reaction mechanisms and electron scattering cross sections are determined by theory alone due to experimental challenges. We report the development of a pump–probe velocity map imaging (VMI) apparatus, where laser-excited molecules in a molecular beam subsequently interact with a dissociating electron beam. The product ions are probed using a calibrated VMI mass spectrometer to report absolute cross sections and information on the dynamics of the dissociation reactions. We demonstrate the apparatus on the electron-ionization-dissociation (EID) process of SO2 molecules excited to the electronically mixed Clements’ manifold B̃B11/ÃA21. Compared to ground-state SO2 molecules, we observed that for the state-selective EID formation of SO+ cations: (a) the thermodynamic threshold is lowered by the energy of the electronic excitation and (b) the partial cross sections with equivalent total energy are enhanced by factors of 2–4 for two distinct vibrational bands of the Clements’ manifold. Finally, the VMI images reveal that the SO+ fragments from the electronic excited states of SO2 are formed with kinetic energies up to 0.5 eV, whereas those from the ground state are predominantly below 0.2 eV. The change in the kinetic energy distribution is attributed to intramolecular vibrational relaxation and molecular geometry changes on the lower adiabatic surface of the Clements’ manifold, which shift the Franck–Condon region of the dissociative cationic state.