Browse Articles

High-diversity base mutagenesis via simultaneous adenine, cytosine and guanine editing

Obesity-driven microbial GABA depletion promotes metabolic rewiring and colorectal cancer progression

Cross-species comparative spatial transcriptomics of hair follicle-T cell interactions identifies conserved drivers of cutaneous lupus erythematosus skin disease and associated hair loss

Large language model driven multicenter prediction and explainable risk attribution of acute kidney injury

Harnessing chloride to drive catalyst reconstruction for durable and efficient seawater electrolysis

Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2

Abstract Enzymatically active macrodomains of (+)ss-RNA viruses mediate immune evasion by countering ADP-ribosylation and are therefore promising druggable targets. Here we report testing of ADP / ADP-ribose analogues for their ability to inhibit Mac1 of SARS-CoV-2, measurement of the affinity of active compounds and characterization of their binding mode by cocrystallization, uncovering critical molecular determinants of protein-ligand interaction. Key findings of the resulting structure-activity relationship (SAR) include that inhibitory potency is improved by either replacing the distal ribose of ADP-ribose by a small alkyl group or the adenine N7 by carbon. Based on insights from the SAR, we show β-methyl-GS-441524-diphosphate as nanomolar inhibitor that exhibits >1000-fold selectivity over human MacroD1 and MacroD2. Addition of C 11 -acyloxybenzyl (AB)-masking groups yields a membrane permeable, lipophilic prodrug that inhibits SARS-CoV-2 in cell culture (EC 50 0.06 µM) while exhibiting low cytotoxicity (CC 50  > 50 µM). Replacement of the terminal methyl phosphate with an ethyl phosphonate increases stability of the prodrug with little effect on toxicity and antiviral potency (EC 50  = 0.03 µM), making it a membrane-permeable nucleotide-based prodrug against viral macrodomains.

Structural and functional studies of inward rectifier Kir7.1 and its regulation by the Melanocortin-4 receptor

An agent-guided peptide hydrogel bio-stabilizer clamps pericellular viscoelastic drift

An ingestible origami-inspired metamaterial for prolonged oral delivery of therapeutics

Abstract Poor adherence to oral drug regimens adversely affects treatment outcomes and contributes substantially to preventable healthcare costs, underscoring the need for long-acting drug delivery systems that sustain therapeutic levels over extended periods. To address this, we developed an origami-inspired, oral drug delivery dosage form capable of prolonged residence in the gastric cavity. This system achieves ease of administration and extended gastric residency through geometric design and shape optimization, allowing the dosage form to fold inside a standard ingestible capsule. Upon the capsule’s dissolution in the stomach, the dosage form rapidly transforms into its deployed configuration. Our formulation and manufacturing techniques enable the development of a long-acting dosage form with up to 40% weight loading capacity of sample drugs, such as moxifloxacin. The high surface-area-to-volume ratio of the origami design enables approximately linear release kinetics over the observed time window of candidate drugs. We incorporated pH-sensitive elements that dissolve in the neutral portions of the GI tract into the dosage form to promote its dissociation and safe transit in the intestine. In vitro and in vivo studies using swine models demonstrated extended gastric residency of up to three weeks (with a minimum of one week) and an approximately constant release rate for three days. Endoscopic and radiographic evaluations of the animal models confirmed that the dosage forms safely pass through the intestine without causing gastrointestinal obstruction or injury.

Reversible control of post-Golgi transport by brefeldin A reveals recycling endosome maturation during glycosylphosphatidylinositol-anchored protein transport

Abstract Post-Golgi transport plays a crucial role in establishing and maintaining cellular function; however, its mechanism of action remains unclear. Therefore, a system to manipulate post-Golgi transport is highly desirable. In this study, we developed a brefeldin A (BFA)-controlled system to block and restart post-Golgi transport freely, allowing the detailed observation of cargo exit from Golgi stacks using live-cell imaging, electron microscopy, and biochemical analysis. Using this system, glycosylphosphatidylinositol-anchored protein (GPI-AP) transport from the trans -Golgi network (TGN) to Golgi-associated recycling endosomes (GA-REs) was visualized. GA-REs expanded during GPI-AP uptake, indicating maturation from the TGN into REs, which later detached as free REs released from the Golgi stacks. Tubular and pearled GPI-AP-positive structures formed on the TGN, which were likely GA-REs transporting GPI-AP from the TGN. REs matured in AP-1-deficient cells, whereas GA-RE detachment was impaired, and long-tubules were observed, thereby delaying GPI-AP delivery to the plasma membrane.

Dissociable roles of prefrontal plasticity in decision-making strategy and execution of habitual behavior

Artificial Transmembrane Channels for Selective Ascorbic Acid Transport and Bioorthogonal Signal Transduction

ABSTRACT Ascorbic acid (AA), an essential bioactive molecule, plays a pivotal part in maintaining physiological functions in cells and organisms, and its intracellular homeostasis is regulated by specific natural transporter proteins. Here we report a class of artificial transmembrane channels constructed from discrete covalent organic nanotubes that mediate the selective transmembrane transport of AA. X‐ray structural analysis and vesicle‐based fluorescence assays confirmed that these molecules adopt a rigid tubular architecture with a near‐nanometer pore size, enabling their insertion into lipid bilayers to form stable transmembrane channels that mediate efficient AA transport. Importantly, AA transport mediated by these molecules can initiate bioorthogonal reactions, thereby converting an external chemical stimulus into a fluorescent signal within a biomimetic system.

A decoupled transcription platform enables tunable and predictable gene expression in yeast

Enantioselective synthesis of ring-constrained biaryls via a twist-expand-seal strategy

The saline groundwater legacy of a large buried coastal paleo-estuary

Abstract Elevated groundwater salinity in coastal regions threatens the beneficial use of fresh groundwater. Coastal groundwater management typically focuses on preventing intrusion from modern sources of seawater; however, past geological processes can also leave a legacy of saline groundwater now hidden in the subsurface. Here, multiple extensive airborne electromagnetic surveys provide detailed evidence of residual salinity from a paleo-estuary filling a late Pleistocene incised valley impacting more than 10,000 km 2 that is now hidden beneath coastal Louisiana’s deltaic plain. Our results show that the three-dimensional pattern of saline groundwater beneath Louisiana mimics that of near-surface aquifers surrounding the modern Delaware Bay estuary, fingerprinting the signature of the past drowning of a large, incised valley of the Mississippi River following post-glacial sea-level rise. These findings demonstrate a new framework for understanding legacy sources of saltwater critical for managing stressed water resources along global coastlines.

Achieving enhanced and robust propane selective oxidative dehydrogenation via electrically-driven continuous chemical looping

The VgrG2 effector of Acinetobacter baumannii mediates immune evasion by repressing Csu pilus assembly and triggering phagocyte methuosis

Hydroxy acid conjugation to lipids increases structural and hydrolytic stability

Abstract Contemporary life requires functional polymers and phospholipid-derived compartmentalization. Mutualistic relationships between compartmentalization and polymerization have never been demonstrated in an abiotic scenario. As both the polymerization of hydroxy acids and the primitive cell-like aggregation of short-chain fatty acids are well known, we study cooperative interactions between compartmentalization and polymerization using these two classes of molecules as a model system. To that end, we explore the formation of various hydroxy acid-fatty acid conjugates. All reactions produce two types of condensation products: hydroxy acid oligoesters and lipid-conjugated oligoesters. We find that conjugation of hydroxy acids to fatty acids leads to the reduction of fatty acid critical aggregation concentration by an order of magnitude. Furthermore, hydroxy acid oligomers are protected against hydrolysis only upon conjugation to fatty acids. Our work offers meaningful insights into the role of self-assembly and cooperative chemistry as selective driving forces in lipid-polymer co-evolution.

Quasi‐Closed‐Loop Crystal–Amorphous Solid–Wet Gel Transformation in Copper MOFs for Exceptional Cycling Stability in Cascade Reactions

Abstract Quasi‐closed‐loop transformations between crystals, amorphous solids, and wet gels are rarely explored in metal–organic frameworks (MOFs). We report a stimuli‐responsive Cu(I)‐MOF (Cu‐cMOF) constructed from relatively stable 1D Cu(I) secondary building units (s‐SBUs) and unstable trigonal Cu(I) SBUs (us‐SBUs). This unique architecture enables quasi‐closed‐loop crystal‐amorphous solid‐wet gel transformations through the following steps: i) The crystalline framework first undergoes oxidative amorphization via Cu(I)‐to‐Cu(II) conversion at us‐SBUs, forming amorphous Cu‐aMOF; ii) Cu‐aMOF subsequently reorganizes into wet gel (Cu‐MOG) in preheated DMAc via oxygen‐ and dimethylamine‐assisted framework fragmentation and colloidal assembly; and iii) Cu‐MOG transforms back to Cu‐cMOF via a solvent‐mediated phase transition. The relative structural persistence of the s‐SBUs—in contrast to the labile us‐SBUs—confers a degree of reversibility to the system. Remarkably, mutual regulation between reaction conditions and catalyst structure is achieved in the azidation‐click cascade reaction. The azidation step drives the transformation of Cu‐aMOF into Cu‐cMOF, while the click reaction reverses this process. Each catalyst phase exhibits step‐specific catalytic selectivity, forming a self‐sustaining structural transformation cycle that maintains over 98% efficiency after at least 20 cycles. Additionally, used catalysts can be repurposed as Cu‐MOGs for large‐sized molecule adsorption. This work establishes a cooperative switchable system with adaptive multifunctionality.

Experimental realization of a bidirectional quantum analog-to-digital converter between photonic wavefront and qubits