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Toll/interleukin-1 receptor (TIR) domain-containing proteins play a critical role in immune responses in diverse organisms, but their function in bacterial systems remains to be fully elucidated. This study, focusing on Escherichia coli , addresses how TIR domain-containing proteins contribute to bacterial immunity against phage attack. Through an exhaustive survey of all E. coli genomes available in the NCBI database and testing of 32 representatives of the 90% of the identified TIR domain-containing proteins, we found that a significant proportion (37.5%) exhibit antiphage activities. These defense systems recognize a variety of phage components, thus providing a sophisticated mechanism for pathogen detection and defense. This study not only highlights the robustness of TIR systems in bacterial immunity, but also draws an intriguing parallel to the diversity seen in mammalian Toll-like receptors (TLRs), enriching our understanding of innate immune mechanisms across life forms and underscoring the evolutionary significance of these defense strategies in prokaryotes. Here, Wang et al survey Escherichia coli genomes to show that TIR domain-containing proteins in E. coli serve as robust anti-phage systems.

Influenza virus remains a significant global health threat because of its ability to evolve rapidly and cause both seasonal epidemics and global pandemics. Although seasonal influenza vaccines provide some protection, their effectiveness depends on accurate prediction and annual reformulation to antigenically match circulating strains. Mismatches between vaccine strains and circulating viruses can significantly reduce protective efficacy. Universal influenza vaccines aim to overcome these limitations by eliciting broad and long-lasting immunity against conserved viral components. Recent strategies have focused on targeting conserved antigens shared across diverse strains, such as the HA stem, M2e, NP, and M1, and on employing platforms, including chimeric constructs, peptide ensembles, DNA/RNA-based approaches, and virus-like particles. In parallel, mucosal delivery, particularly via the intranasal route, has gained attention for its ability to induce secretory IgA and tissue-resident memory T (TRM) cells, which provide cross-protective immunity at the respiratory barrier. This review highlights key advances and persistent challenges in the development of broadly cross-reactive influenza vaccines, with emphasis on conserved antigen design, mucosal immunity, delivery strategies, and future directions toward achieving universal protection against both seasonal and pandemic influenza strains.

In the relentless arms race between bacteria and phages, bacteria have evolved a variety of defense strategies to combat phage infection. However, no system has been previously demonstrated to specifically inhibit phage genomic DNA ejection. Here, we present a bacterial antiphage system, termed HXS, which provides broad-spectrum and robust antiphage activity by interfering with phage DNA entry. The HXS system consists of two radical S-adenosylmethionine (rSAM) enzymes (HxsB and HxsC), a small protein (HxsD), and the effector HxsA with a peptidoglycan-binding domain and five His-Xaa-Ser (HXS) repeats. HxsB/HxsC catalyze rSAM enzyme-dependent maturation of HxsA, including N-terminal processing and a site-specific +8 Da modification, thereby producing a periplasmic effector required for HXS defense. Biochemical evidence supports a model in which the matured effector likely engages incoming DNA electrostatically to arrest entry, establishing an rSAM enzyme-modified protein effector in antiphage defense.

In bone tissue engineering, repairing infected bone defects is an enduring challenge. The development of bone tissue engineering scaffolds with a local antimicrobial drug delivery system is a promising method to overcome this challenge. Thus, in this work, a sodium alginate (SA)/hydroxyapatite (HAP)/collagen (COL) multimaterial composite scaffold carrying amoxicillin (AMX) porous hydroxyapatite microspheres (mHAPs) (AMX@mHAPs) was fabricated utilizing a three-dimensional (3D) printing and freeze-drying composite process for infected bone defects. The morphology of the scaffolds was evaluated by SEM, which indicated that the prepared scaffold contained microporous structures and embedded drug-loaded microspheres into hydrogels with a diameter of 18.62 ± 2.77 μm. The drug-loaded availability of the scaffold was investigated via FTIR, which showed that AMX could be loaded successfully on mHAPs by a stirring process and hydrogen-bonding forces. Thereafter, evaluation of the physicochemical properties of the fabricated scaffold revealed that the mechanical properties of the scaffold could be enhanced by the addition of AMX@mHAPs (increased appr. 1.71-fold compared to the AMX@mHAPs-free scaffold at 15% strain), and the swelling property could also be altered. Furthermore, in vitro drug release and antibacterial tests suggested that the fabricated scaffold had excellent drug release and long-term antibacterial properties. Finally, the cytocompatibility of the composite scaffolds was assessed by seeding rabbit adipose-derived stem cells (rASCs), and the results proved that cells could attach, proliferate and migrate on the scaffold and exhibited favorable cytocompatibility. Together, these results demonstrated that the preparation process of the composite scaffold is feasible and that the fabricated SA/HAP/COL composite scaffold loaded with AMX@mHAPs has great potential for infected bone defect repair.

Developing simple, durable, and efficient photocatalysts is crucial for achieving environmentally friendly treatment of organic pollutants in water. In this study, nanoscale titanium dioxide (TiO 2 ) with a size of approximately 5 nm was synthesized using the sol-gel method, and carbon quantum dots (CQDs) with a size of around 3–5 nm were prepared via a vacuum heating process. The preparation conditions could be controlled to render the TiO 2 surface positively charged and the CQDs surface negatively charged. The combination of TiO 2 with CQDs can form a heterojunction, thereby improving light absorption and the separation efficiency of photogenerated carriers. This enables effective light harvesting and carrier transfer, enhancing the photocatalytic performance. The ζ-potentiometer and electron spin resonance (ESR) measurements confirmed the successful fabrication of high-performance TiO 2 /CQDs composites through electrostatic attraction, forming an interfacial high-speed channel for the transfer of photogenerated carriers. The results demonstrated that the degradation kinetics rate of TiO 2 /CQDs composites reached 0.1345 min − 1 and degraded 98% of tetracycline hydrochloride within 30 min, which is 6.0 and 4.9 times higher than individual TiO 2 and CQDs, respectively. Based on analytical data and experimental results, the photocatalytic mechanism was elucidated, and intermediates along with reactive species were identified to propose possible degradation pathways. Additionally, antimicrobial testing confirmed the nontoxicity of the constructed catalysts and the complete degradation of the pollutants. Graphical abstract

A biomimetic cartilage scaffold featuring a continuous hydroxyapatite (HA) concentration gradient and a spatially curved architecture was developed using a dual-channel mixing extrusion-based 3D printing approach. By dynamically regulating the feeding rates of two bioinks during printing, a continuous HA gradient decreasing from the bottom to the top of the scaffold was precisely achieved, mimicking the compositional transition from the calcified to the non-calcified cartilage region in native articular cartilage. The integration of gradient material deposition with synchronized multi-axis motion enabled accurate fabrication of curved geometries with high structural fidelity. The printed scaffolds exhibited stable swelling and degradation behavior and showed improved compressive performance compared with step-gradient counterparts. Rheological analysis confirmed that the bioinks possessed suitable shear-thinning and recovery properties, ensuring printability and shape stability during extrusion. In vitro evaluations demonstrated good cytocompatibility, supporting bone marrow mesenchymal stem cell (BMSC) adhesion and proliferation. Chondrogenic assessment based on scaffold extracts indicated that the incorporation of HA and its gradient distribution did not inhibit cartilage-related extracellular matrix synthesis, confirming the biosafety of the composite hydrogel system. Overall, this study presents a controllable and versatile fabrication strategy for constructing curved, compositionally graded cartilage scaffolds, providing a promising platform for the development of biomimetic cartilage tissue engineering constructs.

Generative drug design facilitates the creation of compounds effective against pathogenic target proteins. This opens up the potential to discover novel compounds within the vast chemical space and fosters the development of innovative therapeutic strategies. However, the practicality of generated molecules is often limited, as many designs focus on a narrow set of drug-related properties, failing to improve the success rate of subsequent drug discovery process. To overcome these challenges, we develop TamGen, a method that employs a GPT-like chemical language model and enables target-aware molecule generation and compound refinement. We demonstrate that the compounds generated by TamGen have improved molecular quality and viability. Additionally, we have integrated TamGen into a drug discovery pipeline and identified 14 compounds showing compelling inhibitory activity against the Tuberculosis ClpP protease, with the most effective compound exhibiting a half maximal inhibitory concentration (IC 50 ) of 1.9 μM. Our findings underscore the practical potential and real-world applicability of generative drug design approaches, paving the way for future advancements in the field. Generative AI holds promise for creating novel compounds. Here, authors introduce TamGen, a GPT-like model designed to generate molecules tailored to specific target proteins. TamGen identified 14 potent compounds against the Tuberculosis ClpP protease, showing its potential for drug discovery.

Drug combinations have been the hotspot of the pharmaceutical industry, but the promising applications are limited by the unmet solubility and low bioavailability. In this work, novel cocrystals, consisting of two antithrombotic drugs with poor solubility and low bioavailability in vivo, namely, apixaban (Apx) and quercetin (Que), were developed to discover a potential method to improve the poor solubility and internal absorption of the drug combination. Compared with Apx, the dissolution behavior of Apx–Que (1:1) and Apx–Que–2ACN (1:1:2) was enhanced significantly, while the physical mixture of the chemicals failed to exhibit the advantages. The dissolution improvements of Apx–Que–2ACN could be explained by the fact that the solid dispersion-like structure and column-shaped cage of Que accelerated the access of the solvent to the inner layer of Apx. The fracture of the hydrogen bonds of Apx, which was the joint of the adjacent Que chains, facilitated the break-up of the structures. Besides, the bioavailability of Apx–Que was increased compared with the physical mixture and Apx, and Apx–Que remained stable in high temperature and illumination conditions. Therefore, a drug–drug cocrystal of two antithrombotic agents with poor solubility was developed, which exhibited greatly improved solubility, bioavailability and superior stability, indicating a novel method to overcome the shortages of drug combination.

Three-dimensional (3D) bioprinting is a promising and rapidly evolving technology in the field of additive manufacturing. It enables the fabrication of living cellular constructs with complex architectures that are suitable for various biomedical applications, such as tissue engineering, disease modeling, drug screening, and precision regenerative medicine. The ultimate goal of bioprinting is to produce stable, anatomically-shaped, human-scale functional organs or tissue substitutes that can be implanted. Although various bioprinting techniques have emerged to develop customized tissue-engineering substitutes over the past decade, several challenges remain in fabricating volumetric tissue constructs with complex shapes and sizes and translating the printed products into clinical practice. Thus, it is crucial to develop a successful strategy for translating research outputs into clinical practice to address the current organ and tissue crises and improve patients’ quality of life. This review article discusses the challenges of the existing bioprinting processes in preparing clinically relevant tissue substitutes. It further reviews various strategies and technical feasibility to overcome the challenges that limit the fabrication of volumetric biological constructs and their translational implications. Additionally, the article highlights exciting technological advances in the 3D bioprinting of anatomically shaped tissue substitutes and suggests future research and development directions. This review aims to provide readers with insight into the state-of-the-art 3D bioprinting techniques as powerful tools in engineering functional tissues and organs.

The structure and composition of natural bone show gradient changes. Most bone scaffolds prepared by bone tissue engineering with single materials and structures present difficulties in meeting the needs of bone defect repair. Based on the structure and composition of natural long bones, this study proposed a new bone scaffold preparation technology, the dual-phase composite forming process. Based on the composite use of multiple biomaterials, a bionic natural long bone structure bone scaffold model with bone scaffold pore structure gradient and material concentration gradient changes along the radial direction was designed. Different from the traditional method of using multiple nozzles to achieve material concentration gradient in the scaffold, the dual-phase composite forming process in this study achieved continuous 3D printing preparation of bone scaffolds with gradual material concentration gradient by controlling the speed of extruding materials from two feed barrels into a closed mixing chamber with one nozzle. Through morphological characterization and mechanical property analysis, the results showed that BS-G (radial gradient long bone scaffolds prepared by the dual-phase composite forming process) had obvious pore structure gradient changes and material concentration gradient changes, while BS-T (radial gradient long bone scaffolds prepared by printing three concentrations of material in separate regions) had a discontinuous gradient with obvious boundaries between the parts. The compressive strength of BS-G was 1.00 ± 0.19 MPa, which was higher than the compressive strength of BS-T, and the compressive strength of BS-G also met the needs of bone defect repair. The results of in vitro cell culture tests showed that BS-G had no cytotoxicity. In a Sprague–Dawley rat experimental model, blood tests and key organ sections showed no significant difference between the experimental group and the control group. The prepared BS-G was verified to have good biocompatibility and lays a foundation for the subsequent study of the bone repair effect of radial gradient long bone scaffolds in large animals.