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Mechanism of SARS-CoV-2 resistance to nucleotide analog-based antivirals
Abstract The remarkable ability of SARS-CoV-2 to resist many nucleotide analog (NA)-based antivirals represents a formidable challenge to therapeutic efforts. Here, we reveal fundamental insights into how its unique proofreading exoribonuclease (ExoN) counteracts two representative NA antivirals, bemnifosbuvir and sofosbuvir, which are designed to inhibit the viral RNA polymerase (RdRp). Our findings unveil that NA incorporation alters RNA-binding dynamics, significantly increasing the affinity of RNA to ExoN while weakening its interaction with RdRp. This shift likely facilitates RNA dissociation from RdRp, subsequent recognition by ExoN, and excision of NAs. Strikingly, we elucidate the mechanism underlying varied levels of resilience of different NAs to ExoN excision. Our cryo-EM structures of ExoN in complex with either of the two NA-incorporated RNAs reveal previously unknown ExoN-NA interactions mediated by the functional groups on the modified ribose rings of NAs, illuminating the key determinants of their recognition and excision. Furthermore, we identify an allosteric regulatory loop of ExoN that promotes the full activation of ExoN but is displaced by the binding of NAs exhibiting resilience to ExoN excision. These discoveries provide a molecular framework for understanding SARS-CoV-2 resistance to NA-based antivirals and highlight mechanisms that could be exploited to improve anti-coronavirus drug design.
Delineating homogeneous zones for rock joint wall mechanical properties in open-pit mine slope based on a multi-indicator stacked generalization model
Magneto-ionic control of magnetism through voltage-driven carbon transport
Optomechanical vector sensing of new forces at 6 micron separation
Abstract The search for new gravity-like interactions at the sub-millimeter scale is a compelling area of research, with important implications for the understanding of classical gravity and its connections with quantum physics. We report improved constraints on Yukawa-type interactions in the $$10\,\mathrm {\mu m}$$ regime using optically levitated dielectric microspheres as test masses. The search is performed, for the first time, sensing multiple spatial components of the force vector, and with sensitivity improved by a factor of $$\sim 100$$ with respect to previous measurements using the same technique. The resulting upper limit on the strength of a hypothetical new force is $$10^7$$ at a Yukawa range $$\lambda \simeq 5\;\mu$$ m and close to $$10^6$$ for $$\lambda \gtrsim 10\;\mu$$ m. This result also advances our efforts to measure gravitational effects using micrometer-size objects, with important implications for embryonic ideas to investigate the quantum nature of gravity.
Genomics reveal Staphylococcus aureus persists during long-term urinary catheterization despite antimicrobial therapy and catheter exchanges
Contrastive learning enhanced MobileMamba for real time industrial defect detection on edge devices
Historical deforestation drives strong rainfall decline across the southern Amazon basin
Abstract The Amazon forest has recently experienced substantial human-induced loss of forest cover. However, the extent to which such historical deforestation has altered regional observed precipitation through inter-regional atmospheric moisture transport remains unclear. Here, we combine satellite observations and an atmospheric moisture tracking model to quantify these feedbacks over the past four decades (1980-2019). We identify a contrasting northern increase and southern decrease dipole trend in observed precipitation across the Amazon basin. The pronounced reduction in precipitation for the southern Amazon basin reaches up to 3.9-5.4 mm yr -1 per year, resulting in an 8-11% decline in annual precipitation across the observation period. We discover that this reduction in precipitation is primarily (52-72%) related to widespread deforestation in the southern basin and upwind regions over South America. Deforestation substantially suppresses forest-sourced moisture, increases atmospheric stability and moisture outflow, leading to precipitation reduction. We also find that climate models substantially underestimate the sensitivity of precipitation to deforestation, implying that the Amazon forest is at risk of major loss much sooner than previously projected.
Fluid–structure interaction in underwater blasting demolition of cofferdam structures: a case study of three gorges phase III RCC cofferdam
Weak mantle wedge causes mantle exhumation punctuated with discrete oceanic crust in the Tyrrhenian basin
Therapeutic efficacy of Annona muricata in counteracting nephrolithiasis-induced electrolyte imbalance and antioxidant disruption in ethylene glycol-treated rats
Climate and traits drive bark decomposition patterns at global scale
Non-invasive screening of alzheimer’s disease via label-free tri-spectral retinal imaging
Superelastic Tellurium Thermoelectric Coatings for Advanced Trimodal Microsensing
Abstract Tactile endoscopes can provide physicians with rich sensory information, enabling fast and accurate medical diagnoses. However, existing tactile endoscopy sensors do not consider temperature perception, which is a very important diagnostic indicator in medicine. Here, we report for the first time a tellurium-based superelastic thermoelectric visual-tactile sensor. This platform achieves a breakthrough by combining tellurium thermocouples designed based on crystal structures with viscoelastic silicone encapsulation, enabling simultaneous microscale visual, thermal, and force measurements in a single device. By employing a morphologically optimized tellurium-polymer heterointerface and advanced deep neural network algorithms, we address the inherent trade-off between transparency and responsiveness, achieving artifact-free imaging, real-time thermal mapping, and microstructure force feedback. We conduct clinical endoscopic palpation experiments on live rabbits and successfully achieve tactile diagnosis of inflamed tissue including temperature distribution, especially in cases where visual distinction is difficult, pointing out possible development directions for intelligent endoscopy systems.
Improving rectal tumor segmentation with anomaly fusion derived from anatomical inpainting: a multicenter study
Host-guest strategy for full-visible-spectrum piezochromism in halogen-bonded organic frameworks
Optimizing design parameters for slotted blade Savonius hydrokinetic turbine: A multi-fidelity approach
Intranasal replicon vaccine establishes mucosal immunity and protects against H5N1 and H7N9 influenza
Radiological Hazard Assessment of Soil at North Oil Company Using Spatial Distribution and Monte Carlo Simulation in Kirkuk Governorate, Iraq
Structural basis of outer membrane biogenesis by the TamAB translocase
Abstract The outer membrane is vital for Gram-negative bacteria, playing crucial roles in colonization, pathogenesis and drug resistance. The translocation and assembly module A and B (TamAB) nanomachinery has been reported to be involved in transport of phospholipids from the inner membrane to the outer membrane, as well as insertion of critical outer membrane proteins. However, the underlying mechanisms remain poorly understood. Here we report cryogenic electron microscopy structures of TamAB in two conformations at resolutions of 3.69 and 3.82 Å. We reveal a hybrid barrel structure formed between the first β-strand of the TamA barrel and the last β-strand of the TamB C-terminal domain, which is folded inside the β-barrel. By integrating structural analysis with functional data, biochemical assays, and molecular dynamics simulations, we identify key residues involved in TamAB interactions and characterize the mechanisms of anterograde phospholipid transport within the continuously beta-helical hydrophobic cavity of TamB. Through disulfide bond crosslinking and functional assays, we reveal that TamA crosslinks with both TamB and Ag43. Additionally, we confirm that the two cryo-EM conformational states of TamAB exist in vivo. While BAM overexpression can compensate for TamAB deletion in Ag43 insertion, it does not rescue phospholipid transport. Given that TamA and TamB orthologs are widely distributed in among bacterial and eukaryotic organisms, our findings have broad implications in cell envelope biogenesis and offer potential avenues for therapeutic development through inhibition.