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An engineered viral RNA degrader on mitochondrial surface that mitigates RNA virus infection
Effects of blue light and blue-light protection eyeglass lenses on the oxidative status of mouse corneas
Mapping the canine gut microbiome: insights from the Dog Aging Project
Human cathelicidin peptide LL-37 compacts nucleic acids and alters neutrophil extracellular trap structure
Cross-resistance patterns in SARS-CoV-2 against 3CL protease inhibitors
Abstract SARS-CoV-2 is now endemic, with infections commonplace. While much of the population now has immunity, some subsets remain at risk. For such individuals, small-molecule antivirals are the frontline treatment. However, studies have identified resistance-conferring mutations to these compounds, and there are now cases of resistant viruses emerging during treatment. These occurrences make clear the need to understand the resistance mechanisms for SARS-CoV-2 antivirals. Here, we report the pathways to resistance for atilotrelvir and simnotrelvir, two 3CL protease inhibitors used for COVID-19 treatment, and ibuzatrelvir, a compound in late-stage clinical development. Through high-throughput passaging, we reveal that resistance can readily arise, and that there is a large degree of overlap in the mutations which emerge. Moreover, viral inhibition assays demonstrate that there is not only strong cross-resistance between the emerged viruses against these three molecules, but also against two additional widely used antivirals, nirmatrelvir and ensitrelvir, as well. Cellular assays highlight S144A, E166A, and E166V as mediating broad resistance, with E166V having the strongest effects. These results have important clinical implications, including the need to carefully consider cross-resistance properties in salvage therapy and combination treatment, as well as emphasizing the need for the further development of SARS-CoV-2 antivirals with differing modalities.
A multi-class framework for face mask compliance detection using lightweight deep learning models
Non-lytic viral immunotherapy induces long-term glioblastoma survival and tumor-specific immunity without eliciting an antiviral response
Abstract Glioblastoma is a lethal brain tumor that is resistant to conventional therapies. Here we present a non-lytic replicating retrovirus (RRV) that delivers an IL-15-receptor-linked fusion protein (RLI) superagonist directly into glioblastoma cells, creating localized immunotherapy biofactories. In orthotopic mouse models, RRV-RLI dramatically suppresses tumor growth, prolongs survival, and induces lasting remission with immunologic memory. Mechanistically, we observe increased CD8⁺ T cell and natural killer cell infiltration and activation, alongside elevated antigen presentation pathways. Combining RRV-RLI with temozolomide, which is standard-of-care chemotherapy for glioblastoma, enhances antitumor immunity. T cell receptor sequencing reveals a polyclonal repertoire of T cells, enhanced by combining RRV-RLI with temozolomide. Analysis of the T-cell repertoire suggests it to be directed against tumor rather than viral antigens, supporting the specificity and re-applicability of our approach. These findings illustrate that RRV-RLI reprograms glioblastoma into an immunostimulatory hub, offering a viral immunotherapy against glioblastoma and potentially other therapy-resistant solid tumors.
Research on improved nonlinear viscoelastic-plastic damage model of rock and parameter identification
Olfactory tubercle mediates adaptive social behavior by controlling threat assessment and the expression of social threat memories during recall in male mice
Abstract The ability to dynamically assess and update threat responses based on changing environmental contexts is fundamental for survival. Here, we developed an odor-based paradigm where male mice encounter a restrained conspecific that subsequently becomes aggressive, allowing us to study how mice assess threats and update memories upon recall. Using calcium imaging, chemogenetics, and electrophysiology, we identified the olfactory tubercle (OT) as a key mediator of social threat assessment. While OT activity was not required during the initial aggressive encounter, it proved to be essential during recall, where its inhibition prevented the expression of avoidance behavior. Notably, recall induces persistent synaptic plasticity at basolateral amygdala (BLA)-to-OT synapses that persists after behavioral extinction. We identified a neuromodulatory switch in the OT: serotonin facilitates avoidance during recall, whereas its blockade triggers dopamine release and approach behavior. Our findings demonstrate that the OT orchestrates social threat assessment through synaptic plasticity and neuromodulatory control.
Comprehensive macroscopic living anatomy of the swine heart: comparative visual approach with virtual dissection
Abstract Swine is one of the major large animal species used in translational research. Extensive knowledge has been accumulated on the normal anatomy of the swine heart, highlighting its similarities with the human heart, including its size and coronary arterial system. However, when these hearts are compared three-dimensionally as they lie on each thorax without distortion, remarkable differences are recognized beyond already known similarities. Those differences include, but are not limited to, the cardiac axis, aortic axis, aortic arch plane, aortic arch/pulmonary trunk relationship, atrial appendages extent, pulmonary arteries/veins/trachea/bronchi relationship, left azygos vein drainage, coronary arterial orifices relationship, fossa ovalis/aortic root relationship, and ventricular trabeculations features. In addition to conventional and rough recognition of similarities between the swine and human hearts, detailed knowledge of differences in the living anatomy of the swine and human hearts is especially fundamental for conducting effective in vivo experiments, including fluoroscopic procedures and survival studies with surgical intervention. Also, this knowledge is useful for discussing the feasibility and limitations of applying the insights obtained from the swine heart study to the human heart. Thus, we herein demonstrate comprehensive macroscopic living anatomy of the swine heart compared with that of the human heart using cardiac computed tomographic datasets obtained from live swine, as well as datasets from recovered swine hearts after pressure-perfusion and fixation to maintain their physiological, non-distorted anatomy.
Ultra-long-range spin coupling in graphene revealed by atomically resolved spin excitations
Abstract Magnetic interactions between localized spins-½ play a central role in quantum magnetism, spin-based quantum computing, and quantum simulation. The range and strength of these interactions are key figures of merit. Here, we probe exchange interactions in pairs of spins-½ introduced by chemisorption of individual hydrogen atoms on graphene. Using scanning tunneling microscopy and inelastic electron tunneling spectroscopy, supported by large-scale mean-field Hubbard calculations, we demonstrate 3 meV exchange couplings at separations beyond 10 nm, surpassing all prior systems. The couplings can be ferro- or antiferromagnetic depending on the relative sublattice arrangement. Real-space mapping of spin excitation amplitudes enables characterization with atomic-resolution. Through atomic manipulation we extend this control to spin trimers, revealing collective spin excitations when pairwise exchange couplings are comparable.
Triboelectrically-induced non-contact polypropylene/polyvinylidene fluoride sensor with low permittivity supporting layers affecting its interfacial charge dynamics
Abstract This work presents a simple and low-cost approach to triboelectric sensing based on commercially available nonwoven polypropylene (PP) membranes paired with electrospun polyvinylidene fluoride (PVDF) to form a triboelectric nanogenerator (TENG), which is further utilized as a sensor operating predominantly in a non-contact regime. The initial contact electrification creates an interfacial charge state that is retained after contact, allowing subsequent separation changes to generate electrical signals via electrostatic induction without requiring continuous contact. The introduction low-permittivity sublayers (polyvinyl chloride (PVC), biaxially oriented polyethylene terephthalate (BOPET), and low-density polyethylene (LDPE)) beneath the tribonegative PVDF membrane significantly enhances the TENG’s mechano-electric performance by modifying the electric field distribution in the multilayer dielectric structure. The PP/PVDF+LDPE layer achieves a peak open-circuit voltage of 689 V and a maximum power density of 5.46 mWcm⁻² in comparison to 376 V and 2.05 mWcm⁻², respectively, for PP/PVDF. This confirms that the dielectric permittivity of the supporting layer is a key parameter controlling the electrical output of the PP/PVDF triboelectric system. The device was validated under various pressure stimuli and vibrations demonstrating its ability to simultaneously sense motion and harvest energy.
Organic carbon oxidation state shapes fermentative methanogenic microbiomes and controls greenhouse gas fluxes
Improved quantum long short-term memory with successive variational mode decomposition for solar irradiance prediction
TGFβ-mediated dural progenitor cell migration into the coronal suture is crucial for preventing craniosynostosis
Antifungal-induced DNA dynamics and chitin remodelling across Cryptococcus spp. and the novel broad-spectrum anti-cryptococcal candidate CPTH2
Abstract Antifungal drug resistance is a growing global health concern, yet treatment options remain limited to just four classes: polyenes, azoles, allylamines, and echinocandins. Cryptococcus species are responsible for life-threatening meningoencephalitis and pulmonary infections, which cause over 140,000 deaths annually. The high mortality of Cryptococcus is driven by limited drug access, toxicity, persistence, and emerging resistance. To better understand antifungal resistance and identify novel therapeutics, we profiled a genetically diverse panel of Cryptococcus isolates spanning all major lineages (VNI, VNIII, VNIV, VGI–VGVI). Phenotypic assays were used to assess susceptibility to fluconazole (FLZ), 5-fluorocytosine (5-FC), and amphotericin B (AmpB), as well as the epigenetic inhibitors CPTH2 (a histone acetyltransferase inhibitor) and SAHA (a histone deacetylase inhibitor). We found lineage- and strain-specific variation in antifungal susceptibility, with disc-diffusion and microdilution assays yielding consistent patterns. Pharmacodynamic modelling revealed potent fungicidal activity of CPTH2 across all tested lineages. DNA content and chitin levels varied significantly by lineage and treatment: FLZ and CPTH2 induced DNA content increases in susceptible strains, suggesting a stress response, while 5-FC-induced chitin remodelling was most pronounced in resistant strains. Multivariate analysis identified chitin induction as a principal driver of phenotypic variance under antifungal stress. Our findings reveal lineage-specific antifungal responses in Cryptococcus , highlight the antifungal potential of epigenetic inhibitors such as CPTH2, and underscore the utility of phenotypic profiling to inform drug development and resistance surveillance.
Soluble uric acid suppresses neutrophil-mediated host defense in sepsis
Abstract Neutrophils are essential for host defense and inflammation, yet their dysfunction is a hallmark of acquired immunodeficiency in kidney disease, contributing to increased susceptibility to infections such as peritonitis, sepsis, and pneumonia. We speculated that impaired renal clearance of the metabolite soluble uric acid (sUA) accounts for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9–14 mg/dL) related or unrelated to kidney disease significantly exacerbates the inflammatory immune response in mice with endotoxemia and bacterial sepsis. Despite promoting hyperinflammation, HU simultaneously impairs host defense, an effect that is partially reversible by lowering UA levels with febuxostat. We validated these findings in vitro using neutrophils or serum from healthy individuals or hyperuricemic patients with chronic kidney disease. Depleting UA partially restores neutrophil function. Mechanistically, sUA promotes neutrophil activation and degranulation but impairs phagocytosis, leading to reduced NOX2 expression independent of intracellular MPO levels. This results in diminished ROS production and defective bacterial clearance in human neutrophils. In contrast, sUA has no impact on neutrophil extracellular trap formation following exposure to LPS or E.coli . Together, our findings identify HU as an immunometabolic regulator that amplifies hyperinflammation, while simultaneously impairing effective host defense, suggesting that targeting UA may help to overcome acquired immunodeficiency in kidney disease.