Browse Articles

High-fidelity Cas9-mediated targeting of KRAS driver mutations restrains lung cancer in preclinical models

Abstract Missense mutations in the 12th codon of KRAS are key drivers of lung cancer, with glycine-to-cysteine (G12C) and glycine-to-aspartic acid (G12D) substitutions being among the most prevalent. These mutations are strongly associated with poor survival outcomes. Given the critical role of KRAS in lung cancer and other cancers, it remains as a major target for the development of new and complementary treatments. We have developed a CRISPR-High Fidelity (HiFi)-Cas9-based therapy strategy that can effectively and specifically target KRAS G12C and KRAS G12D mutants, avoiding KRAS WT off-targeting and affecting KRAS downstream pathways, thereby significantly reducing tumorgenicity. The delivery of HiFiCas9 components via ribonucleoprotein particles (RNPs) and adenovirus (AdV) effectively abrogates cell viability in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) preclinical models, including 2D and 3D cell cultures, cell-derived xenografts (CDX), and patient-derived xenograft organoids (PDXO). Our in vitro studies demonstrate that HiFiCas9-based therapy achieves superior KRAS inhibition compared to Sotorasib and effectively circumvents certain resistance mechanisms associated with Sotorasib treatment. Moreover, in vivo delivery using adenoviral particles significantly suppresses tumor growth in preclinical NSCLC models. Collectively, our findings establish HiFiCas9 as an effective therapeutic strategy with promising clinical applications, especially if in vivo delivery methods are further optimized.

Transboundary conflict from surface water scarcity under climate change

Revealing Parallel Inter‐ and Intra‐Ligand Charge Transfer Dynamics in [Ru(L) ₂ (dppz)] ²⁺ Molecular Lightswitch with N K‐Edge X‐Ray Absorption Spectroscopy

Abstract In photoactive metal complexes the localization of photoexcited charges dictates the site of chemical reactivity, but few studies measure the charge redistribution in these systems with spatial precision. Herein, we track the inter‐ and intra‐ligand charge transfer processes that underpin light‐driven charge separation in the well‐studied “molecular lightswitch” [Ru(bpy) 2 dppz] 2+ (aqueous [Ruthenium II (2,2′‐bipyridine)2(dipyrido[3,2‐a:2′,3′‐c]phenazine)] 2+ [Cl − ] 2 ) by probing the electronic structure of ligand nitrogen atoms in real‐time using ultrafast X‐ray absorption spectroscopy and first principles calculations. We confirm the localization of excited electron density on the phenazine N atoms of dppz and we newly identify two parallel electron transfer pathways to populate this state. Sub‐70 fs electron transfer to the phenazine portion of dppz is observed and attributed to intra‐ligand electron transfer following Ru‐to‐dppz metal‐to‐ligand charge transfer (MLCT) excitation. This fast charge transfer was not reported in prior ultrafast studies. The slower (ca. 2 ps) charge transfer reported extensively in time‐resolved optical absorption and emission studies is reassigned here to inter‐ligand electron “hopping” between nearly isoenergetic ligand moieties following Ru‐to‐bpy MLCT excitation. The results demonstrate much faster charge separation than previously identified in this well‐studied system, highlighting how extended azaacene ligand motifs promote the competitive charge transfer processes needed to drive light‐driven electron transfer chemistry.

Coordinated active repression operates via transcription factor cooperativity and multiple inactive promoter states in a developing organism

Abstract Refining transcriptional levels via active repression in a euchromatic context represents a critical regulatory process. While the molecular players of active repression are well described, their dynamics remain obscure. Here, we used snail expression dynamics as a paradigm to uncover how repression, mediated by the Snail (Sna) repressor, can be imposed within a developing tissue. Combining live imaging and mathematical modeling, we show that Sna-mediated repression is cooperative and that cooperativity is primarily mediated by the distal enhancer. Repression shifts transcription bursting dynamics from a two-state ON/OFF regime to a three-state repressed regime with two temporally distinct OFF states. Mutating Sna binding sites suggests that repression introduces the long-lasting inactive state, which is stabilized by cooperativity. Our approach offers quantitative insights into the dynamics of repression and how transcription factor cooperativity coordinates cell fate decisions within a tissue.

Synergistic Covalently and Mechanically Interlocked Polymer

Abstract Integrating different polymer types into a unified system in a thoughtful manner leverages their complementary advantages, providing a promising strategy for developing high‐performance materials. Mechanically interlocked polymers (MIPs), characterized by their unique spatial entanglement, exhibit distinctive performance advantages, yet their potential to expand material properties through rational integration with other polymer architectures presents substantial opportunities for continued investigation. Herein, we report a coherent integration of covalent polymers (CPs) and mechanically interlocked polymers through sequential orthogonal polymerizations, developing a novel synergistic covalently and mechanically interlocked polymer (CMIP) featuring both structural stability and force‐induced dynamics. Compared to its structurally similar but noninterlocked control sample, CMIP demonstrates markedly enhanced thermomechanical stability and performance recovery, achieving a 93.4% recovery efficiency at 100% strain after just 5 min of rest, in contrast to 59.7% for the control. This remarkable stability and recovery result from the synergistic interplay between the covalent polymer framework and the interlocked structure, which work in tandem to preserve network integrity and enable rapid host−guest reformation. Notably, despite this significant improvement, CMIP retains a comparable damping capacity (91% versus 87%) and material toughness (14.8 versus 15.1 MJ m −3 ), owing to the efficient energy dissipation mechanisms enabled by host−guest dissociation and subsequent sliding motion. This strategy imparts CMIP with unique characteristics, offering a prospective pathway for the development of a diverse array of advanced synergistic materials with enhanced, multifaceted properties.

Deferral of scheduled transcatheter heart valve interventions strongly increases the risk of congestive heart failure

Abstract Deferral of non-emergency cardiac interventions is associated with worse clinical outcomes, even post-procedurally. Affected patients show signs of congestive heart failure (CHF) after the waiting time. To identify predictors of CHF with clinical progress during prolonged waiting time, and assess the impact of CHF on the actual intervention date and of the identified baseline predictors in case of deferral on subsequent outcomes. Consecutive patients whose non-emergency cardiac intervention was postponed during the first Covid-19 related lockdown between March 19th and April 30th, 2020 were included (n = 178). Binary logistic regression analysis was performed to identify predictors of clinically progredient CHF, indicated by an NT-proBNP level of > 900 pg/ml on the actual intervention date in combination with worsening of dyspnea as assessed by NYHA class, emergency heart failure hospitalization, or declining left ventricular ejection fraction (LVEF) during the waiting time. Clinical outcomes were compared to a seasonal control group undergoing such interventions in 2019 as scheduled (n = 214). 89 of 178 deferred patients (50.0%) had an NT-proBNP level of > 900 pg/ml in combination with clinical symptoms indicating CHF on the actual intervention date. Thereof, repeated data measurement was available for 72 patients, of whom 54 (75%) experienced new-onset or worsening of CHF, while 18 (25%) had stable, pre-existing CHF. Planned transcatheter heart valve intervention was the only independent predictor of CHF with clinical progress (OR 34.632, 95%-CI 3.337–359.404, p = 0.003). Risk was even higher in patients with planned mitral or tricuspid edge-to-edge-repair (M/T-TEER) than in those with transcatheter aortic valve replacement (TAVR) (82.4% vs. 40.0%; p = 0.035 after Bonferroni correction). During the post-procedural 36-month follow-up, rates of emergency hospitalization or death were significantly higher in patients with CHF and time-to event was shorter compared to those without (57.3% vs. 14.0%, p < 0.001; HR 6.432, 95%-CI 3.476–11.868; log rank p < 0.001). Higher event rates and shorter time-to-event in deferred compared to regularly treated patients after the originally planned intervention date were observed only in those with the predictor scheduled heart valve intervention (83.7% vs. 40.4%, p < 0.001; HR 4.37, 95%-CI 2.50–7.64, log rank p < 0.001). Deferral of planned transcatheter heart valve intervention, TAVR and especially M/T-TEER, leads to a highly increased risk of clinically progredient CHF during prolonged waiting time and worse clinical outcomes. Therefore, these procedures should be prioritized and postponement should be avoided.

Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling in male mice

Abstract Inflammation is increasingly recognized as a risk factor for psychiatric disorders. Animal models of stress and stress-related disorders are associated with blood neutrophilia. The mechanistic relevance of this to symptoms or behavior is unclear. We characterized the immune response to chronic social defeat (CSD) stress at brain border regions in male mice. Here we show that chronic, but not acute, stress causes neutrophil accumulation in the meninges—i.e., “meningeal neutrophilia”— but not the brain. CSD promotes neutrophil trafficking to meninges via vascular channels originating from skull bone marrow (BM). Transcriptional analysis suggests CSD increases type I interferon (IFN-I) signaling in meningeal neutrophils. Blocking this pathway via the IFN-I receptor (IFNAR) protects against the negative behavioral effects of CSD stress. Our identification of IFN-I signaling as a putative mediator of meningeal neutrophil recruitment may facilitlate development of new therapies for stress-related disorders.

Outside Front Cover: Conditional Stabilization of the Hypoxia‐Inducible Factor HIF1α: Photoswitchable Stapled Peptides Prevent Elongin BC–Mediated Degradation (Angew. Chem. Int. Ed. 36/2025)

Developing a plant based hand sanitizer using antibacterial Apium graveolens leaf extract

A quadratic paradigm describes the relationship between phenotype severity and variation

Conduction Band Convergence and Modular Nanostructures: Driving High Thermoelectric Performance in <i>n</i> ‐Type PbSe

Abstract n ‐type lead chalcogenides showing high thermoelectric performance are rare due to the larger energy offset between the two lowest energy conduction bands minima, leaving ample opportunity to modulate electronic structure for improving their thermoelectric performance. Here, we present a remarkable thermoelectric figure of merit (zT) of ∼1.8 at 873 K in n ‐type PbSe doped with MoCl 5 by modulation of the conduction bands, while simultaneously suppressing the phonon transport. Doping MoCl 5 in PbSe induces notable convergence of conduction bands and an increased density of states near the Fermi level, mainly due to the contribution of Mo 4 d orbital hybridized with the Se 4 p ‐Pb 6 p . This results in an improved Seebeck coefficient, despite maintaining a high n ‐type charge carrier concentration resulting in an excellent power factor (σS 2 ) of ∼21 µW cm −1 K −2 at 873 K for PbSe + 1 mol% MoCl 5 . When the solid solution limit of the doping exceeds, it forms unique modular nano‐heterostructures (5‐30 nm) of PbSe‐MoSe 2 misfit layered compounds embedded in PbSe matrix. These nano‐heterostructures significantly intensify phonon scattering, leading to an ultralow lattice thermal conductivity (κ lat ) of 0.20 W m −1  K −1 at ∼725 K in PbSe + 1 mol% MoCl 5 sample.

Signature of cooperativity in the stochastic fluctuations of small systems with application to the bacterial flagellar motor

Abstract The cooperative binding of molecular agents onto a substrate is pervasive in living systems. To study whether a system shows cooperativity, one can rely on a fluctuation analysis of quantities such as the number of substrate-bound units and the residence time in an occupancy state. Since the relative standard deviation from the statistical mean monotonically decreases with the number of binding sites, these techniques are only suitable for small enough systems, such as those implicated in stochastic processes inside cells. Here, we employ a general-purpose grand canonical Hamiltonian description of a small one-dimensional (1D) lattice gas with either nearest-neighbor or long-range interactions as prototypical examples of cooperativity-influenced adsorption processes. First, building upon previous work on finite-size one-dimensional Ising-type models, we elucidate how the strength and sign of the interaction potential between neighboring bound particles on the lattice determine the intensity of the fluctuations of the mean occupancy and the nature of bound particle-particle correlations. We present our theoretical results, which extend beyond standard analysis, in a novel, physically transparent form. We explore simple limiting cases of the parameter space in greater detail, examine the complete probability distribution functions for occupation, and relate these to the shape and strength of the fluctuations. Second, we leverage these relationships to compare the theoretical predictions of our model to data from single molecule experiments on bacterial flagellar motors (BFM) of Escherichia coli. In this way, we find evidence that cooperativity controls the mechano-sensitive dynamical assembly of the torque-generating units, the so-called stator units, onto the BFM and thereby arrive at an estimate of the stator-stator interaction potential from our fluctuation analysis. Furthermore, we attempt to clarify the link between occupation fluctuations and the adaptability of the BFM. Finally, we conclude that the system resides in a sweet spot of the parameter space (phase diagram) with characteristics suitable for a smoothly and widely adaptive system, while minimizing fluctuations.

Low-temperature molten-salt enabled synthesis of highly-efficient solid-state emitting carbon dots optimized using machine learning

A method for constructing digital twins of CNC machine tools feed systems based on hybrid mechanism-data

Isotope-encoded spatial biology identifies plaque-age-dependent maturation and synaptic loss in an Alzheimer’s disease mouse model

Abstract Understanding how amyloid beta (Aβ) plaques develop and lead to neurotoxicity in Alzheimer’s disease remains a major challenge, particularly given the temporal delay and weak correlation between plaque deposition and cognitive decline. This study investigates how the evolving pathology of plaques affects the surrounding tissue, using a knock-in Aβ mouse model ( App NL-F/NL-F ). We combined mass spectrometry imaging with stable isotope labeling to timestamp Aβ plaques from the moment of their initial deposition, enabling us to track their aging spatially. By integrating spatial transcriptomics, we linked changes in gene expression to the age of the plaques, independent of the mice’s chronological age or disease stage. Here we show that older plaques were associated with reduced expression of synaptic genes. Additionally, when correlated with structure-specific dyes, we show that plaque age positively correlated with structural maturation. These more compact and older plaques were linked to greater synapse loss and increased toxicity.

Photoresponsive Slide‐Ring Gels Enable Modulation of Sliding Dynamics

Abstract Cyclodextrin‐based slide‐ring gels (SRGs) have emerged as a promising class of materials owing to their unique topology. Upon mechanical loading, the slidable cross‐links of the polymer network freely translocate along the polymer backbone enabling pronounced energy dissipation in the material, which is associated with exceptional ductility and toughness. Despite the critical role of sliding dynamics in defining SRG mechanical properties, attempts to control them have primarily been limited to tuning the overall loading of macrocycles. Further, SRGs that can be triggered via an external stimulus have yet to be reported. In this work, we present light‐responsive SRGs based on azobenzene‐containing polymers. Reversible photoswitching of the azobenzenes modulates the sliding dynamics of the threaded α‐cyclodextrin (α‐CD) macrocycles. By using UV–Vis and circular dichroism spectroscopy, we show that α‐CDs readily bind to the azobenzenes along the polymer backbone in the E configuration. Upon light irradiation, and thus isomerization to the Z isomer, the macrocycles no longer interact with the azobenzenes, allowing them to freely translocate along the polymer backbone. As a result of this E to Z isomerization and difference in sliding dynamics, the mechanical properties of the SRGs reversibly alternate between a stiff and a soft state.

Harnessing remote sensing and machine learning techniques for detecting and monitoring the invasion of goldenrod invasive species

Single-molecule fluorescence microscopy reveals regulatory mechanisms of MYO7A-driven cargo transport in stereocilia of live inner ear hair cells

Abstract Stereocilia are F-actin-based cylindrical protrusions on the apical surface of inner ear hair cells that function as biological mechanosensors of sound and acceleration. During stereocilia development, specific unconventional myosins transport proteins and phospholipids as cargo and mediate elongation, differentiation and acquisition of the mechanoelectrical transduction (MET). How unconventional myosins localize themselves and cargo in stereocilia using energy from ATP hydrolysis is only partially understood. Here, we developed STELLA-SPIM microscopy to visualize movement of single myosin molecules in live hair cell stereocilia. STELLA-SPIM demonstrated that MYO7A, a component of MET machinery, shows processive movement toward stereocilia tips when chemically dimerized or constitutively activated by missense mutations disabling tail-mediated autoinhibition. Conversely, MYO7A shows step-wise but not processive movement in stereocilia when its tail is tethered to the plasma membrane or F-actin in the presence of MYO7A interacting partners. We posit that MYO7A dimerizes and moves processively in stereocilia when unleashed from autoinhibition.

Synergistic Modulation of Intermediate Adsorption and Active Hydrogen Supply Enable Pulsed Nitrate‐to‐Hydroxylamine Electroreduction with Nearly 100% Faradaic Efficiency

Abstract Electrochemical hydroxylamine (NH 2 OH) synthesis from NO x under ambient conditions presents a sustainable alternative to energy‐intensive industrial methods, but its selectivity remains limited by unbalanced active hydrogen (H*) supply and intermediate adsorption. Herein, we develop boron‐doped amorphous Bi metallene arrays for efficient nitrate‐to‐NH 2 OH electroreduction. In situ spectroscopy and theoretical calculations reveal that the amorphous structure and B‐induced p‐sp orbital hybridization modulate the electronic structure, optimizing intermediate adsorption while enhancing H* generation. These synergistic effects collectively reduce the energy barrier of the potential‐determining step, significantly improving catalytic activity and selectivity. The catalyst achieves an NH₂OH Faradaic efficiency (FE) of 85.3% at −0.4 V versus reversible hydrogen electrode (RHE). By employing a pulsed potential strategy, the FE further increases to nearly 100%, surpassing most reported counterparts. This work not only proposes a novel catalyst design leveraging amorphous engineering and orbital hybridization but also demonstrates the efficacy of pulsed electrolysis in steering reaction pathways for electrosynthesis.

Gastrointestinal tract disease classification from wireless capsule endoscopy images based on deep learning information fusion and Newton Raphson controlled marine predator algorithm