Browse Articles

Catalytic Asymmetric Synthesis of Chiral Caged Hydrocarbons as Arenes Bioisosteres

Abstract The utilization of caged hydrocarbons as bioisosteres for arenes, especially the phenyl ring, in bioactive compounds has resulted in significant enhancements in potency, solubility, and metabolic stability. These improvements highlight the potential of C(sp 3 )‐rich polycyclic scaffolds as a promising motif for the development of drug candidates. However, this strategy has also increased the structural complexity of these molecules, posing synthetic challenges in controlling the chirality of caged and highly decorated bioactive scaffolds. Over the past two years, remarkable progress has been achieved in catalytic asymmetric methodologies for the synthesis of caged hydrocarbons, significantly advancing their utility in chiral drug discovery and development. This minireview provides a comprehensive summary of recent breakthroughs in the catalytic asymmetric synthesis of chiral caged hydrocarbons, encompassing bicyclo[n.1.1]alkanes, cubanes, and related three‐dimensional scaffolds. Additionally, we highlight the intriguing applications of enantiomerically pure caged hydrocarbons in biological studies. It is anticipated that this minireview will inspire further advancements in the enantioselective synthesis of these pharmaceutically valuable caged hydrocarbons.

Direct sensing of host ferric iron by an archetype histidine kinase mediates virulence of an enteric pathogen

Two-component system (TCS) histidine kinases enable bacterial pathogens to sense environmental signals and regulate adaptive responses during infection. The EnvZ/OmpR TCS, known for its role in osmolarity/pH-dependent regulation of outer membrane porins across bacterial species, is also a central virulence regulator. However, the environmental cues that activate EnvZ/OmpR to trigger pathogenicity have remained unclear, limiting our understanding of host–pathogen interactions. Here, we demonstrate that in Vibrio parahaemolyticus , a major etiological agent of seafood-associated gastroenteritis, EnvZ functions as a direct ferric iron (Fe 3+ ) sensor governing virulence programs. Fe 3+ -EnvZ interaction triggers kinase phosphorylation and activation, enabling transcriptional control of biofilm formation, swarming motility, and type 3/6 secretion systems. An iron-binding-deficient EnvZ mutant (EnvZ Q103A ) abrogated Fe 3+ responsiveness and downstream signaling pathways. In an infant rabbit infection model, Fe 3+ enhanced V. parahaemolyticus intestinal colonization and virulence through EnvZ/OmpR signaling. This study identifies Fe 3+ as the physiological ligand activating the EnvZ/OmpR virulence regulon and provides insight into how enteric pathogens exploit host-derived iron cues to promote infection.

Multiphasic size-dependent growth dynamics of nanoparticle ensembles

Colloidal nanoparticles are of great interest in modern science and industry. However, the thermodynamic mechanism and dynamics of nanoparticle growth have yet to be understood. Addressing these issues, we tracked hundreds of in-situ growth trajectories of a nanoparticle ensemble using liquid-phase TEM and found that the nanoparticle growth, including coalescence, exhibits nanoparticle size-dependent multiphasic dynamics, unexplainable by current theories. Motivated by this finding, we developed a model and theory for an ensemble of growing nanoparticles, providing a unified, quantitative understanding of the time-dependent mean and fluctuation of nanoparticle size and size-dependent growth rate profiles across various nanoparticle systems and experimental conditions. Our work reveals that the chemical potential in a small nanoparticle strongly deviates from the Gibbs–Thomson equation, shedding light on how it governs the size-dependent growth dynamics of nanoparticles.

The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels

Paracetamol has been used for decades to relieve mild-to-moderate pain. Its analgesic effect is mainly attributed to its metabolite, AM404, acting on cannabinoid receptors or TRPV1 channels in central nervous system (CNS) neurons. Here, we show that AM404 is produced by primary sensory neurons. It inhibits sodium current in nociceptor neurons, blocking action potential (AP) generation and reducing nocifensive behavior in naïve and inflamed rats. We demonstrated that this analgesic effect of AM404 is mediated by its direct inhibition of nociceptive voltage-gated sodium channels (Na V ) 1.8 and 1.7 via the local anesthetic binding site. The Na V 1.8 and 1.7 inhibition was specific for AM404 and not observed with other metabolites of paracetamol. Our findings suggest that the analgesic effect of paracetamol is mediated mainly by direct AM404-induced inhibition of nociceptive sodium channels at the peripheral nociceptor neurons. Our findings lay a foundation for the potential development of AM404 as a selective local analgesic.

Spatially resolved DNP-assisted NMR illuminates the conformational ensemble of α-synuclein in intact viable cells

The protein α-syn adopts a wide variety of conformations including an intrinsically disordered monomeric form and an α-helical-rich membrane-associated form that is thought to play an important role in cellular membrane processes. However, despite the high affinity of α-syn for membranes, evidence that the α-helical form is adopted inside cells has been indirect. DNP-assisted solid-state NMR on frozen cellular samples can report directly on the entire conformational ensemble. By controlling the distribution of the DNP agent throughout the cellular biomass, such experiments can provide quantitative information upon the entire structural ensemble or provide information about spatially resolved subpopulations. When the polarization agent is dispersed homogeneously throughout the cell, a minority of the α-syn inside HEK293 cells adopts a highly α-helical-rich conformation. When the polarization agent is peripherally localized, the α-helical-rich conformation predominates, indicating that it is preferentially adopted near the cellular periphery. This demonstrates how selectively altering the spatial distribution of the DNP agent can be a powerful tool to observe spatially distinct structural ensembles. This approach paves the way for more nuanced investigations into the conformations that proteins adopt in different areas of the cell.

Outside Front Cover: A Bench‐stable Fluorophosphine Nickel(0) Complex and Its Catalytic Application (Angew. Chem. Int. Ed. 24/2025)

Transcranial direct current stimulation neuromodulates intracranial cognitive evoked activity in humans

Transcranial direct current stimulation (tDCS) is an easy to use, noninvasive brain stimulation technique that gained prominence for its potential in cognitive rehabilitation. Electroencephalography (EEG), which records electrical brain activity with a high temporal resolution, is well suited to quantify tDCS-induced neuromodulation in humans. However, most studies relying on scalp EEG recordings or event-related potentials showed low reliability and only indirect correlations. Here, we combined intracranial EEG (iEEG) recordings with a sham-controlled tDCS experiment during fast periodic visual stimulation. Anodal (+2 mA) tDCS was applied over the right occipito-temporal cortex for 20 min using two small ring high-definition electrodes. Through the analysis of iEEG signals of 947 intracerebral contacts in 11 drug-resistant epileptic patients, we quantified the neuromodulation of iEEG cognitive evoked responses during (P2 phase) and after (P3 phase) tDCS by comparison to a control phase before tDCS (P1 phase). Significant neuromodulations of face-selective iEEG activity in anterior & posterior temporal lobe and in the occipital lobe were found, with amplitude increases of 3% and 4%, 16% and 13%, and 36% and 33%, during and after tDCS, respectively. Interestingly, despite a unique tDCS session, the face-selective neuromodulation in the right visual occipito-temporal cortex remained significant ( P = 0.015) after tDCS (P3 vs. P1). This iEEG study demonstrates that using low intensity tDCS and small ring electrodes can induce significant electrophysiological effects on a selective cognitive function in humans.

High-throughput metabolic engineering of <i>Yarrowia lipolytica</i> through gene expression tuning

The challenge of accurately predicting which genetic alternations lead to the desired phenotype necessitates high-throughput metabolic engineering approaches where numerous hypotheses can be tested simultaneously. We describe the CRISPR-Cas9-based method TUNE YALI that enables high-throughput tuning of gene expression in the common industrial yeast Yarrowia lipolytica . The method is based on replacing the promoters of the target genes with native Y. lipolytica promoters of varying strengths or removing the promoters entirely. To demonstrate the method’s capabilities, we created a plasmid library that targets 56 transcription factors (TFs) and changes the expression of each TF to seven different levels. We transformed this library into reference and betanin-producing strains of Y. lipolytica and screened the resulting clones for changes in morphology, thermotolerance, or improved betanin production. The genetic markup of the yeast clones with the desired phenotypic changes was determined by sequencing the inserted plasmids. We identified multiple TFs whose regulatory changes increased thermotolerance, two TFs that eliminated pseudohyphal growth, and several TFs that increased betanin production. Analogous libraries can be designed to target any chosen group of genes and even all the genes. The libraries can be shared and reused, accelerating applied strain development projects and fundamental functional genomics research (TUNE YALI -TF kit and TUNE YALI -TF library are available via AddGene under catalog numbers #1000000255 and #217744).

Magnetically Induced Catalysis: Definition, Advances, and Potential

Abstract The rapidly growing importance of electrification in the chemical industry opens room for disruptive innovations regarding energy input into catalytic processes. Energy efficiency and dynamics of renewable energy supplies represent important challenges, but the design of catalytic systems to cope with such new frameworks may also stimulate the discovery of new catalyst materials and reaction pathways. In this context, many opportunities arise when catalysts are activated in a rapid, localized, and energy‐efficient manner. Among the various concepts to achieve adaptivity in catalysis, magnetic induction heating applied directly at the catalyst or in vicinity of the active site has gained increasing attention recently. In this Scientific Perspective, we provide a coherent framework to the emerging field of catalysis using magnetic fields—and in particular alternating current magnetic fields—to activate catalytic materials and define it as magnetically induced catalysis . Promising approaches and selected examples are described to illustrate the scientific concept and to highlight its broad potential for innovation in catalysis from laboratory to industrial scale.

Parallel sensory compensation following independent subterranean colonization by groundwater salamanders ( <i>Eurycea</i> )

Lineages that have invaded subterranean environments have repeatedly evolved remarkable adaptations to life in darkness. However, observational and experimental studies in additional natural systems are needed to further our understanding of repeated evolution and convergence. In Texas, a radiation of groundwater salamanders (genus Eurycea ), with independent invasions of subterranean karstic environments, offers an opportunity to investigate phenotypic convergence, parallel evolution, and the enhancement and regression of sensory systems. Adaptations to a troglobitic life in this clade include morphological, behavioral, and physiological changes within and among species. Intraspecific and interspecific variation in morphology in response to the selective pressures of life underground allows for detailed examination of physical, behavioral, and physiological changes associated with subterranean adaptation within a comparative phylogenetic framework. We find a correlated change between two sensory systems repeated across multiple subterranean Eurycea lineages: the degeneration of the eye and the expansion of the mechanosensory lateral line. The increase in anterior neuromast organs in subterranean lineages was positively correlated with the expression of pax6 (Paired-box 6), a conserved transcription factor important for vertebrate neurogenesis. Our results show a decreasing trend of PAX6 labeling in the neuromasts of adult surface salamanders ( Eurycea nana ) relative to the maintained labeling in subterranean species ( Eurycea rathbuni ). These lateral line enhancements are correlated with reductions in the development of optic systems in subterranean salamander lineages. Altogether, our findings provide a starting point for future evolutionary developmental investigations examining the genetic underpinnings of adaptive, repeated evolution in a novel system.

Interfacial H‐bond Network/Concentration Fields/Electric Fields Regulation Achieved by D‐Valine Anions Realizes the Highly Efficient Aqueous Zinc Ion Batteries

Abstract Uncontrolled mobile anions and proton transport result in many issues, including interfacial anion depletion, irregular multiphysics fields fluctuations, space charge layer‐induced interfacial Zn dendrites, and hydrogen evolution reaction (HER), which seriously exacerbates the cycling stability of zinc‐ion batteries. Herein, this work constructs an efficient D‐valine anion interface structure to reversely regulate the Zn 2+ /H + dynamic chemistry and unlocks the multiple regulation effects of this anionic interface by investigating interfacial proton transport and complex concentration/electric fields distribution of Zn anode through dynamic in‐situ spectroscopy analysis, static energy calculations, and molecular dynamics simulation. We unravel core factors affecting complicated interfacial HER processes and the generation of the space charge layer. This anionic interfacial layer severs proton hopping transport by rupturing the initial water–water hydrogen bond, which effectively restrains uncontrolled HER processes. Further, the anion‐immobilized interfacial layer accelerates Zn 2+ transfer to optimize the interfacial concentration fields. Also, the anionic interface restrains the formation of the anion depletion layer by relieving rapid Zn 2+ ions exhaustion and strengthening the uniformity of interfacial electrical field distribution, which suppresses space charges‐induced Zn dendrite growth. Consequently, Zn||Zn symmetric cells deliver an ultralong cycle life of 4150 h. Importantly, the multiple regulation effects enable Zn||I 2 cells exhibit long‐term stable life.

Polaron catastrophe within quantum acoustics

The quantum acoustic framework has recently emerged as a nonperturbative, coherent approach to electron–lattice interactions, uncovering rich physics often obscured by perturbative methods with incoherent scattering events. Here, we model the strongly coupled dynamics of electrons and acoustic lattice vibrations within this framework, representing lattice vibrations as coherent states and electrons as quantum wave packets, in a manner distinctively different from tight-binding or discrete hopping-based approaches. We derive and numerically implement electron backaction on the lattice, providing both visual and quantitative insights into electron wave packet evolution and the formation of acoustic polarons. We investigate polaron binding energies across varying material parameters and compute key observables—including mean square displacement, kinetic energy, potential energy, and vibrational energy—over time. Our findings reveal the conditions that favor polaron formation, which is enhanced by low temperatures, high deformation potential constants, slow sound velocities, and high effective masses. Additionally, we explore the impact of external electric and magnetic fields, showing that while polaron formation remains robust under moderate fields, it is weakly suppressed at higher field strengths. These results deepen our understanding of polaron dynamics and pave the way for future studies into nontrivial transport behavior in quantum materials.

Efficient Semitransparent Organic Solar Modules with Exceptional Diurnal Stability Through Asymmetric Interaction Induced by Symmetric Molecular Structure

Abstract The symmetry‐breaking design strategy of nonfullerene acceptor can improve the performance of semitransparent organic solar cells (ST‐OSCs). However, no report exists on the “asymmetric molecular interaction” induced by symmetric molecular structure in nonfullerene acceptors. Herein, we showcase that 2D fluorophenyl outer groups in symmetric 4FY promote dipole‐driven self‐assembly through asymmetric molecular interactions, resulting in a tighter packed structure than Y6 with the same symmetric geometry. Such unique properties lead to high‐performance layer‐by‐layer OSCs, accompanied by simultaneously reduced energy and recombination losses and improved charge‐related characteristics. ST‐OSCs based on PCE10‐2F/4FY achieve notable power conversion efficiency (PCE) of 10.81%, average visible transmittance of 45.43%, and light utilization efficiency (LUE) of 4.91%. Moreover, exceptional diurnal cycling stability is observed in the ST‐OSCs based on PCE10‐2F/4FY with much prolonged T 80 up to 134 h, which is about 17 times greater than the reference PCE10‐2F/Y6. Lastly, we fabricate highly efficient semitransparent organic solar modules based on PCE10‐2F/4FY (active area of 18 cm 2 ), which shows PCE of 6.78% and the highest LUE of 3.10% to date for all‐narrow bandgap semitransparent organic solar modules. This work demonstrates that asymmetry‐driven molecular interactions can be leveraged to fabricate large‐area ST‐OSCs that are efficient and stable under realistic operating conditions.

The prevalence of functional limitations in the US workforce

This research paper investigates the prevalence of functional limitations among employed adults in the United States and the association between these limitations and medical conditions. The authors administered a survey adapted from the Dutch Functional Abilities List to a nationally representative sample of US adults ages 22 and older, finding that nearly three-quarters of working adults report at least one functional limitation, with an average of nearly six functional limitations per working adult. The most common limitations were in upper body strength and torso range of motion, and with respect to the ambient environment. The study also found that mental illness, arthritis, and substance use disorder are associated with the greatest number of functional limitations in working adults. The findings have implications for economic performance, workforce planning, and social policies to support displaced and vulnerable workers with significant functional limitations. Identifying the occupations and industries with large numbers of workers with functional limitations is critical to addressing short-term labor supply disruptions (e.g., public health crises) and preparing for longer-term workforce needs (e.g., long-term care workers for an aging population).

Oxidative Rearrangements of the Alkaloid Intermediate Geissoschizine

Abstract Plants can generate structural diversity by enzymatic rearrangement of a central intermediate. 19 E ‐geissoschizine is one such chemically versatile intermediate that plays a central role in the biosynthesis of monoterpene indole alkaloids such as strychnine, ibogaine, and vinblastine. Here we report how 19 E ‐geissoschizine undergoes oxidative transformations to generate four distinct alkaloid scaffolds through the action of three biosynthetic enzymes. Using in vitro enzymatic assays and gene silencing, we demonstrate how these three cytochrome P450 enzymes in the medicinal plant Catharanthus roseus transform 19 E ‐geissoschizine into strychnos , sarpagan , akuammiline ‐type, and mavacurane‐ type alkaloids. We use mutational analysis to show how minimal changes to the active site of these similar enzymes modulate product specificity. This work highlights how substrate reactivity and enzyme mutations work synergistically to generate chemical diversity.

Detection of the knee point in lithium-ion battery degradation using a state-of-charge-dependent parameter

The rapidly expanding lithium-ion battery (LIB) market has heightened the demand for efficient diagnostics for in-use cells and the reliable grading of used cells. Various purpose-built analysis tools and statistical algorithms have been developed, but often rely on redundant instrumentation and computationally intensive procedures. Here, we propose using the variance of the capacity difference between 0.2C and 1C, Var(Δ Q 0.2C-1C (V) ), based on the strong correlation between the interfacial state of the anode and mode of capacity degradation, as a measure of the health state of individual cells. A single-point “off-board” measurement of Var(Δ Q 0.2C-1C (V) ) indicates whether a particular cell is experiencing self-limiting or accelerating degradation and is thus near a knee point in its cycle life. This assessment additionally provides a quantitative criterion for differentiating used cells for reuse or recycling. Our findings suggest that utilizing state-of-charge-dependent key electrochemical properties enables the cell health to be accurately monitored, thereby promoting sustainability in the expanding battery market.

Natural dispersal is better than translocation for reducing risks of inbreeding depression in eastern black rhinoceros ( <i>Diceros bicornis michaeli</i> )

Due to increasing anthropogenic impacts, many species survive only in small and isolated populations. Active conservation management to reduce extinction risk includes increasing habitat connectivity, translocations from captive populations, or intensive surveillance of highly protected closed populations. Advances in sequencing technology mean that it is now possible to consider the genomic impacts of such strategies, as a proxy for variation in individual fitness. Using whole genome sequences from critically endangered eastern black rhinoceros ( Diceros bicornis michaeli ), we compare the consequences of different types of conservation efforts, based on cohorts of offspring resulting from parents from different sources. Based on the fraction of the genome in runs of homozygosity (ROH) of different lengths, we found lower inbreeding in offspring of individuals that had either been translocated from ex-situ populations (F ROH&gt;1Mb = 0.047) or dispersed between proximate native populations (F ROH&gt;1Mb = 0.065) compared to the intensively managed closed population from which the migrant moved (F ROH&gt;1Mb = 0.112). However, the benefit of such movement was removed after only a few generations of closed breeding (F ROH&gt;1Mb = 0.149). Although sample size restricted power to detect significance of differences, the relative abundance of highly deleterious mutations was higher for offspring resulting from translocation compared to the other cohorts and this load was sheltered by higher heterozygosity, which could increase risks of inbreeding depression if inbreeding subsequently occurs. In contrast, native dispersers reduced the negative effects of inbreeding without compromising the benefits of past purging of deleterious mutations. Our study highlights the importance of natural dispersal and reiterates the importance of maintaining habitat corridors between populations.

A Bench‐Stable Fluorophosphine Nickel(0) Complex and Its Catalytic Application

Abstract We herein present a fluorophosphine‐based nickel(0) complex [Ni(PFPh 2 ) 4 ] ( 1 ), which is highly stable in air and water. [Ni(PFPh 2 ) 4 ] can be obtained from a one‐pot reaction of [Ni(MeCN) 4 ](BF 4 ) 2 with Ph 2 P(═O)–PPh 2 , involving a unique in situ reduction of Ni(II) to Ni(0) and a simultaneous fluorination by the BF 4 − anion. This complex does not only incorporate a nickel center in the zero‐oxidation state, resulting from a Ni(II) precursor, but also includes fluorophosphine ligands, which typically disproportionate immediately in solution. The application of [Ni(PFPh 2 ) 4 ] as highly stable Ni(0) pre‐catalyst in combination with additional phosphine ligands, such as dppf (1,1′‐bis(diphenylphosphino)ferrocene), in various coupling reactions uncovers its high catalytic activity and versatility, which is superior to [Ni(COD) 2 ] (COD═cycloocta‐1,5‐diene) as conventional Ni(0) source.

Epithelial Regnase-1 inhibits colorectal tumor growth by regulating IL-17 signaling via degradation of <i>NFKBIZ</i> mRNA

Regnase-1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA. Regnase-1 was identified as one of the frequently mutated genes in the inflamed colorectal epithelium of patients with ulcerative colitis; however, its significance in intestinal epithelial cells during the tumorigenic process remains unknown. Therefore, we developed an Apc Min/+ mouse model lacking Regnase-1 in intestinal epithelia. Regnase-1 deletion significantly enhanced colon tumor growth accompanied by elevated levels of extracellular signal-regulated kinase (ERK) phosphorylation in tumor tissues. Transcriptome analysis of the tumor tissues revealed that Nfkbiz , a mediator of the interleukin (IL)-17 signaling pathway, was the primary degradative target of Regnase-1 in enterocytes and that Regnase-1 deficiency enhanced IL-17 signaling. The treatment with antibiotics or IL-17-neutralizing antibody canceled the proliferative effect of colon tumors due to Regnase-1 deletion, suggesting the protective role of Regnase-1 against colon tumor growth was dependent on IL-17 signaling triggered by gut microbes. Analysis of the Nfkbiz knockout mouse model demonstrated that the tumor-suppressive effect of Regnase-1 depended on Nfkbiz expression. Remarkably, oral treatment of dimethyl fumarate, a potential inhibitor of Regnase-1 protein inactivation, suppressed tumor growth, downregulated Nfkbiz , and suppressed ERK activation. Furthermore, TCGA data analysis revealed that low Regnase-1 expression in colorectal cancer tissue was related to poor prognosis. Therefore, Regnase-1 represses colon tumor growth by regulating IL-17 signaling via Nfkbiz mRNA degradation. Regnase-1 could be a potential therapeutic target in colon tumors.

Plastic from CO ₂ , Water, and Electricity: Tandem Electrochemical CO ₂ Reduction and Thermochemical Ethylene‐CO Copolymerization

Abstract Converting CO 2 into industrially useful products is an appealing strategy for utilization of an abundant chemical resource. Electrochemical CO 2 reduction (eCO 2 R) offers a pathway to convert CO 2 into CO and ethylene, using renewable electricity. These products can be efficiently copolymerized by organometallic catalysts to generate polyketones. However, the conditions for these reactions are very different, presenting the challenge of coupling microenvironments typically encountered for the transformation of CO 2 into highly complex but desirable multicarbon products. Herein, we present a system to produce polyketone plastics entirely derived from CO 2 and water, where both the CO and C 2 H 4 intermediates are produced by eCO 2 R. In this system, a combination of Cu and Ag gas diffusion electrodes is used to generate a gas mixture with nearly equal concentrations of CO and C 2 H 4 , and a recirculatory CO 2 reduction loop is used to reach concentrations of above 11% each, leading to a current‐to‐polymer efficiency of up to 51% and CO 2 utilization of 14%.