Browse Articles

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

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.

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

The influence of structural variants from 2445 pigs on gene expression and complex traits

Balancing energy, water, and ecology through renewable energy transitions in the Yellow River Basin

Synthetic ion channel inhibitors enhance plant drought tolerance

Abstract Drought stress significantly threatens global food security. According to the FAO2024, agriculture absorbs up to 80% of drought impacts. Stomata are vital pores for gas exchange and transpiration in plants. Stomatal closure, which is crucial for drought tolerance, is regulated by ion transport systems. Here, we identify two inhibitors of plasma membrane voltage-dependent potassium (K + ) channels, NS5806 and UA49, that induce stomatal closure, reduce guard cell K + levels, and increase drought resistance in Arabidopsis plants. This chemical-induced stomatal closure pathway is distinct from the abscisic acid (ABA). Notably, K + channel inhibition led to increased cytosolic Ca 2+ , which was absent in K + inward channel mutants, highlighting the link between K + channel activity and cytosolic Ca 2+ elevation. These findings suggest that the chemical regulation of K + channels represents a strategy to induce stomatal closure, potentially improving plant drought tolerance through targeted interventions.

Single-fraction or multi-fraction stereotactic ablative body radiotherapy followed by atezolizumab in advanced triple-negative breast cancer: a randomized phase II trial

Nonvolatile nematic order manipulated by strain and magnetic field in a layered antiferromagnet

Flexible organic thin-film transistors for all-in-one retinomorphic acceleration enabled by inorganic-organic heterogeneous dielectrics

Abstract Organic neuromorphic visual sensors promise to overcome the limitations of conventional image sensors, but a trade-off between efficient charge transport and charge trapping has hindered the development of interfaces that combine efficient optical sensing and non-volatile memory. Here we show that an inorganic-organic heterogeneous dielectric (Al 2 O 3 /PAA), fabricated by low-temperature plasma-enhanced atomic layer deposition and spin-coating, enables flexible thin-film transistors with integrated sensing-memory-processing functions. The devices exhibit an average mobility of 22.65 cm 2  V −1 s −1 , a 30 µs optical response to 450 nm light, charge retention exceeding ten years, write/erase endurance over 10 4 cycles, an electrical response down to 130 ns, and stable multilevel programming at 10 µs. They emulate synaptic plasticity and achieve recognition accuracies of 99.49% (gesture), 94.78% (digit) and 92.56% (face). When integrated with a convolutional neural network accelerator, the system demonstrates real-time, interference-resistant face detection, highlighting the potential of this dielectric architecture for flexible neuromorphic vision systems.

Probing entanglement scaling across a quantum phase transition on a quantum computer

Abstract The investigation of strongly-correlated quantum matter is difficult due to the curse of dimensionality and intricate entanglement structures. These challenges are particularly pronounced in the vicinity of continuous quantum phase transitions, where quantum fluctuations manifest across all length scales. While quantum simulators give controlled access to a number of strongly correlated systems, the study of critical phenomena has been hampered by finite-size effects arising from diverging correlation lengths. Moreover, the experimental investigation of entanglement in many-body systems has been hindered by limitations in measurement protocols. To address these challenges, we employ the multiscale entanglement renormalization ansatz (MERA) and implement a holographic scheme for subsystem tomography on a fully-connected trapped-ion quantum computer. Our method accurately represents infinite systems and long-range correlations with few qubits, facilitating the efficient extraction of observables and entanglement properties, even at criticality. We observe a quantum phase transition with spontaneous symmetry breaking and reveal the evolution of entanglement properties across the critical point. For the first time, we demonstrate log-law scaling of subsystem entanglement entropies at criticality on a digital quantum computer. This achievement highlights the potential of MERA for the investigation of strongly-correlated many-body systems on quantum computers.