Browse Articles

Beyond the Stokes shift: Quantifying excited-state symmetry breaking effects in steady-state spectra of quadrupolar molecules

We present an approach for modeling and interpreting the optical spectra of donor–acceptor aggregates, demonstrated on A–π–D–π–A/D–π–A–π–D systems with identical electron-donor (D) and electron-acceptor (A) units. The key advance is a detailed description of electronic–vibrational transitions incorporating symmetry-breaking charge transfer. Analysis of the results reveals the excited-state structural changes in the molecule caused by symmetry breaking, which manifest themselves in increasing the Huang–Rhys factors by up to a factor of 2.9. This unexpected outcome challenges the generally accepted view that normal vibrations are not significantly affected by charge transfer. Comparison of the simulated and experimental steady-state spectra demonstrates the high accuracy of the method. The model parameters are estimated using an algorithm that imitates swarm intelligence. The approach is based on a theory that addresses the interaction of the electronic subsystem of the molecule with both the intramolecular degrees of freedom and solvent polarization, which leads to an adiabatic excited-state free energy curve. The adiabatic effects on the steady-state spectra are discussed.

A chemical epigenetic tool to probe site-specific DNA-binding protein complexes

Site-specific DNA binding by proteins is critical for regulating transcriptional activity and cell fate decision. However, identifying proteins bound to specific genomic regions (e.g., promoter or enhancer regions) remains challenging. To address this, we developed a chemical epigenetic tool, named Site-specific noncanonical amino acid-mediated capture of protein (SCOPE), incorporating a photo-crosslinking amino acid into a nuclease-deficient dCas9 mutant. Human pluripotent stem cells (hPSCs) carrying SCOPE enable the capture of proteins bound to, in theory, any genomic location, facilitating the study of the cell context–dependent DNA–protein interactions. Using SCOPE, we identified the OCT4/SOX2/CARHSP1 complex binding to the NANOG promoter to maintain pluripotency in hPSCs. During ectoderm differentiation, ZIC2 acts as a competitive inhibitor, binding the same promoter region to downregulate NANOG expression and promote differentiation. Additionally, SCOPE identified that ZNF8 binds to the distal regulatory region of OCT4 to maintain naïve pluripotency. In summary, SCOPE provides a robust system for uncovering cell context–dependent, site-specific genome regulators, offering valuable insights into gene regulation networks driving cell fate transitions.

HALO: hierarchical causal modeling for single cell multi-omics data

Scrutinizing oxygen isotope effects in liquid water with coupled cluster accuracy

Nuclear quantum effects significantly affect the properties of liquid water, in particular due to the quantum delocalization of protons, and differences between normal water (H2O) and heavy water (D2O) are detectable in experiments and simulations. In addition to H/D substitution, oxygen isotope substitution (16O/18O) can be used in experiments to extract partial structure factors and to obtain structural insights. That raises the question of whether the structures of normal water and 18O-substituted water are indeed identical, as such approaches would assume. We perform converged path integral simulations with CCSD(T) accuracy of liquid H2natO and H218O, made possible by intertwining accurate machine-learned high dimensional neural network potential methodology with efficient near-linear scaling coupled cluster theory, and quantify structural differences under ambient conditions. We find statistically significant changes in the water structure upon oxygen isotope substitution—thus being manifestations of nuclear quantum effects. They lead to enhanced radial oxygen–oxygen correlations in the first shell of H218O of up to 0.5% compared to normal water, followed by less pronounced changes that extend even to the second and third shells. Interestingly, we also discover that the quantum delocalization of the hydrogen atoms is approximately 0.1% smaller in H218O than in H2natO due to oxygen isotope effects, that linear hydrogen bond configurations are favored in H218O relative to H2natO, and that hydrogen atoms in H218O are displaced slightly more toward hydrogen bond acceptors.

Soluble guanylyl cyclase, the NO receptor, drives vasorelaxation via endothelial S-nitrosation

We previously demonstrated that the NO-stimulated soluble guanylyl cyclase (GC1), which produces cGMP, also has the ability to transfer S-nitrosothiols (SNO) to other proteins in a reaction involving oxidized Thioredoxin 1 (oTrx1). This transnitrosation cascade was established in vitro and involved Cys 610 (C610) of GC1 as the major SNO-donor. To assay the relevance of GC1 transnitrosation under physiological conditions and in oxidative pathologies, we studied a knock-in mouse in which C610 was replaced with a serine (KI αC 610S ) under basal or angiotensin II (Ang II)-treated conditions. Despite similar GC1 expression and NO responsiveness, the Ang II-treated KI mice displayed exacerbated oxidative pathologies including higher mean arterial pressure and more severe cardiac dysfunctions compared to the Ang II-treated WT. These phenotypes were associated with a drastic decrease in global S-nitrosation and in levels of SNO-Trx1 in the KI mice. To investigate the mechanism underlying the dysregulation of blood pressure, pressure myography and in vivo intravital microscopy were conducted to analyze the vascular tone of resistance vessels. Both approaches indicated that, even in the absence of oxidative stress, the single mutation C610S led to a significant disruption of the endothelium-dependent, acetylcholine-induced vasorelaxation while NO-dependent smooth muscle relaxation remained unchanged. Mechanistically, the vasorelaxation defect was associated with decreased endothelial calcium influx and membrane hyperpolarization, independent of NO bioavailability. These findings indicate that the C610S mutation uncouples two NO signaling vasodilatory pathways (endothelial SNO and smooth muscle NO-cGMP) and suggest that GC1 transnitrosation activity is essential for endothelium-derived hyperpolarization.

Retraction Note: Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells

Velocity map imaging studies of the ultraviolet photodissociation of methyl chloride

We report a high resolution velocity map imaging study of the ground state and spin–orbit excited Cl atoms and of vibrationally state selected CH3(v) fragments formed in the photodissociation of jet-cooled CH3Cl molecules at three wavelengths in the range 193.3 ≤ λ ≤ 212 nm (in its A band continuum) and when exciting various vibronically resolved absorption features in the ranges 146 ≤ λ ≤ 160 and 138 ≤ λ ≤ 140.6 nm, associated with the first two predissociated Rydberg states of this molecule. Excitation in all cases results in prompt C–Cl bond fission, on timescales shorter than the parent rotational period. Most of the excess energy is partitioned into product kinetic energy, ET, but the deduced Cl/Cl* branching ratios and favored CH3 product vibrational motions are excitation wavelength/excited state dependent. So, too, are the fragment recoil anisotropies which, even within one CH3(v) + Cl/Cl* product channel, are found to be sensitive functions of ET. The trends observed at longer λ reflect the wavelength dependent partial cross sections for excitation to the 3Q1, 3Q0, and 1Q1 components of the A band continuum, but full interpretation of the present data demands a much more detailed, quantum state resolved picture of the non-adiabatic population transfer probabilities between these dissociative parent states and, at higher excitation energies, the Jahn–Teller induced distortions within the photoexcited Rydberg states and their non-adiabatic couplings with the continuum states. Additional CH3+ and Cl+ signals evident in the images at lower ET are attributed to, respectively, two pump photon induced dissociative ionizations and one probe photon induced photodissociation of CH2Cl products formed via a competing primary C–H bond fission process.

From propulsion to suction: Unraveling thrust reversal in propellers at intermediate Reynolds numbers

This study investigates propeller hydrodynamics at intermediate Reynolds numbers ( Re ), crucial for small-scale robotic systems but still uncharted. Experiments on a propeller-driven underwater vehicle and numerical simulations reveal thrust reversal—a phenomenon where clockwise propeller rotation leads to backward motion—in the approximate range 1.3 ≲ Re ≲ 150 under specific conditions. Notably, counterclockwise rotation consistently results in backward motion. Simulations reveal that this behavior arises when centrifugal suction, an inward force along the axis caused by radial outward flow from the propeller’s rotation, dominates over fluid backward acceleration, the primary thrust mechanism at high Re . These findings provide critical insights into the unique dynamics of the intermediate Re regime and inform the design of efficient propulsion systems for miniature aquatic robots.

Author Correction: Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering

Manning-type potential induced by kink scatterings with phonons in molecular chains with hyperbolic double-well substrates

A rescaled Manning potential is obtained in the analysis of scatterings of small-amplitude excitations with a kink defect. The generic model is a nonlinear Klein–Gordon Hamiltonian describing a one-dimensional chain of identical molecules subjected to a hyperbolic single-particle substrate potential. To account for isotope effects that are likely to affect characteristic equilibrium parameters of the molecular chain, including the lattice spacing (i.e., the characteristic intermolecular distance) and/or the barrier height, the hyperbolic substrate potential is endowed with a real parameter whose variation makes it suitable for the description of molecular excitations in a broad range of systems with inversion symmetry. These include hydrogen-bonded molecular crystals, α-helix proteins, long polymer chains, and two-state quantum-tunneling systems in general. Double-well models with deformable profiles are relevant in physical contexts where the equilibrium configurations are sensitive to atomic or molecular substitutions, dilution, solvation, and so on.

The intrinsic neuronal network of the central nervous system and its modular (subsystem) architecture in a mammal

The vertebrate central nervous system (CNS) has two great topographic divisions—brain and spinal cord—that together integrate the body’s internal physiology and behavioral interactions with the environment. To clarify the architecture of intra-CNS connectivity supporting this integration in a mammal (rat), network science analyses were applied at the level of gray matter regions (nodes) connected by directed and weighted axonal projections. Neuroanatomical evidence indicates a bilateral, predominantly sexually monomorphic neuronal network of 840 nodes and a projected 81,434 direct interconnections (of the 704,760 possible connections), representing a projected network density of 12%; 32% of identified connections terminate contralaterally, and 41% of identified connections participate in bidirectionally linking a pair of nodes. Local network differentiations examined with unsupervised multiresolution consensus cluster analysis revealed a nested hierarchy of interconnected modules (clusters or subsystems) that were conservatively assigned putative functional roles. This structure–function hierarchy includes only three first-order modules, indicating a tripartite systems architecture (distinct from the bipartite brain-spinal cord topographic division): a bilaterally symmetric module pair centered in the forebrain-midbrain, associated with behavior control, cognition, and affect; and a single bilateral module centered in the rhombicbrain-spinal cord, associated with behavior execution and reflex integration. This modular spatial patterning suggests possible developmental and phylogenetic correlates. Additional analyses of the CNS’s basic structural network plan included global neuronal network features—specifically, measures of centrality, rich club, and small world topology—that transcend modular boundaries.

Enhanced electrocaloric effect in ferroelectric ceramics via defect dipole engineering

Two packing pathways of Janus-like homopolymer-grafted nanoparticles at fluid–fluid interfaces

Polymer-grafted nanoparticles (PGNPs) assembled at fluid–fluid interfaces significantly reduce interfacial tension and effectively stabilize multiphase liquid systems. Understanding and actively controlling the packing of these PGNPs is of significant fundamental interest for the interfacial behavior of nanoparticles and of interest in soft matter physics. Here, we investigate the packing of Janus-like homopolymer-grafted nanoparticles at fluid–fluid interfaces using molecular dynamics simulations and umbrella sampling methods. For bare nanoparticles at interfaces, where enthalpic interactions dominate, interface-mediated attractions drive nanoparticle aggregation. This results in locally ordered hexagonal clusters with high average order parameters. As the packing fraction increases, the system evolves from small, locally hexagonal aggregates to a globally ordered hexagonal phase (path I). This pathway contrasts sharply with the behavior of purely repulsive particles in two dimensions, which undergo an entropy-driven, sharp disorder-to-order transition (path II). For Janus-like PGNPs at interfaces, the packing behavior is governed by the competition between two factors: (i) interface-mediated attractive interactions (enthalpic contribution) and (ii) steric repulsion between grafted polymer chains (entropic contribution). Increasing either grafting density or grafted chain lengths enhances the entropic contribution and repulsive interactions, causing a shift in the dominant packing mechanism from enthalpy-driven (path I) to entropy-driven (path II). This competition induces a transition between ordering pathways. Notably, at a chain length of N = 15 and grafting number Z = 8, the entropic effects completely suppress hexagonal ordering. We attribute this suppression to the significant interface deformation by the PGNPs, which maximizes the system’s entropy by disrupting the close-packing structure. Our study provides novel insights into the interfacial packing of PGNPs and reveals how competition between enthalpy and entropy drives transitions between distinct ordering pathways.

Electrostatics and viscosity are strongly linked in concentrated antibody solutions

Monoclonal antibodies are among the most promising therapeutic agents in modern medicine, yet their formulation into high-concentration solutions for subcutaneous self-administration poses a major challenge. A key obstacle is the marked increase in viscosity often observed under these conditions. To gain deeper insights into this phenomenon, coarse-grained models derived from soft matter physics have been widely employed. However, these models have yet to be fully leveraged for analyzing the rheological collective properties of such systems. In this study, using molecular dynamics simulations, we directly compute the antibody solution viscosity by starting from commonly used models in which electrostatic interactions are treated through effective screened Coulomb potentials. We demonstrate that this approach fails to reproduce experimental evidence and we show, by analyzing stress correlations in the system, that it is necessary to treat the heterogeneously charged domains with explicit Coulomb interactions, also including counterions and salt ions. By thoroughly analyzing the microscopic structure of the system, we further reveal the presence of transient strongly correlated antibodies which would not be present if charges were treated implicitly, thus pointing to a prominent role of electrostatics in determining the increase in viscosity at high concentrations. By taking advantage of our realistic treatment, new approaches can be devised to ensure that antibody solutions exhibit the desired characteristics for their intended broad use and effective deployment.

Programmable afterglow tuning in monodisperse SiO2 microparticles through spatially confined emitter doping

Spin decoherence in molecular crystals: Nuclear vs electronic spin baths

The loss of information about the relative phase between two quantum states, known as decoherence, strongly limits resolution in electron paramagnetic spectroscopy and hampers the use of molecules for quantum information processing. At low temperatures, the decoherence of an electronic molecular spin can be driven by its interaction with either other electron spins or nuclear spins. Many experimental techniques have been used to prolong the coherence time of molecular qubits, but these efforts have been hampered by the uncertainty about which of the two mechanisms is effectively limiting coherence in different experimental conditions. Here, we use the cluster-correlation expansion to simulate the decoherence of two prototypical molecular qubits and quantitatively demonstrate that nuclear spins become the leading source of decoherence only when the electron spin concentration is below ∼1 mM. Moreover, we show that deuterated samples, much easier to achieve than fully spin-free environments, could achieve record coherence times of ∼0.1 ms for an electron spin concentration of ∼0.1 mM. Alternatively, hydrogen-rich molecular crystals with electron spin concentrations below 1 mM can still achieve coherence times of 10 ms through dynamical decoupling, showing that the potential of molecular spins for quantum technologies is still untapped.

Identification of claudin-3 as an entry factor for rat hepacivirus

Approximately 58 million people worldwide are believed to be infected with hepatitis C virus (HCV), a major causative agent of chronic liver diseases. Hepacivirus ratti strain rn-1, which was discovered from Rattus norvegicus (Norway rat) and designated Norway rat hepacivirus 1 (NRHV1), shares similar properties with HCV in terms of genetic homology, target cell tropism, pathogenicity, and the immune response. In vivo infection systems for NRHV1 will help overcome the challenges in HCV research for vaccine development. However, the virological characteristics of NRHV1, such as the mechanisms of cell entry, remain largely unexplored, in part owing to a paucity of cell culture systems for NRHV1. Here, we identified the host factors that facilitate NRHV1 entry by profiling the gene expression of two cell lines with different susceptibilities to NRHV1 infection. NRHV1 employs rodent orthologues of HCV entry factors, including scavenger receptor class BI, CD81, and occludin, and utilizes claudin-3 (CLDN3) but not claudin-1. The expression of rat and mouse, but not human, CLDN3 facilitates the entry of NRHV1 into murine cell lines that are nonsusceptible to NRHV1 infection. The host-specific cell entry of CLDN3 is determined by two amino acid residues, Ile 44 and Trp 46 , in extracellular loop 1. These findings suggest that CLDN3 serves as an entry factor for rat hepacivirus.

Metal organic framework derived In2O3/ZrO2 heterojunctions with interfacial oxygen vacancies for highly selective CO2-to-methanol hydrogenation

Comparison of microscopic dynamics and continuum theory for Poiseuille and diffusioosmotic flows in a microchannel

Diffusioosmotic flows in a microchannel are investigated using microscopic coarse-grained particle-based simulations that incorporate molecular interactions between fluid particles and channel walls. The fluid–wall molecular interactions, coupled with concentration gradients, generate flows in the potential regions where the interactions are effective, thereby driving global flows in the bulk. Fluid velocities in narrow potential regions obtained from simulations are quantitatively compared with predictions from continuum theory that accounts for density and viscosity variations. While continuum theory adequately predicts enhanced flow velocities throughout the channel, it does not fully capture flow behaviors in regions of very low fluid density near the wall, revealing its limitations. Friction between the fluid and the wall can be controlled by temperature. As temperature decreases, friction is reduced, which makes the wall surface more slippery. In addition, Poiseuille flows driven by gravity are simulated using microscopic dynamics incorporating fluid–wall molecular interactions. Fluid velocity slips near the wall, and corresponding enhancements in flow velocities throughout the channel are quantitatively analyzed by comparing simulation results with theoretical predictions that account for viscosity variations in the potential region.

Molecular basis of SARS-CoV-2 proofreading enzyme–mediated resistance to remdesivir

SARS-CoV-2’s remarkable resistance to nucleotide analog antivirals such as remdesivir, which thwarts RNA synthesis by inhibiting viral polymerase (RdRp), challenges available therapies. We reveal that remdesivir incorporation destabilizes RdRp–RNA complex while enhancing RNA binding to the proofreading exoribonuclease (ExoN), facilitating remdesivir excision. Conserved ExoN determinants for remdesivir recognition and excision underpin ExoN-mediated resistance across all coronaviruses. These findings inform the design of next-generation antivirals and combination therapies capable of overcoming ExoN-mediated resistance.