Slow wound healing in the elderly has attracted much attention recently due to the associated infection risks and decreased longevity. The “brain–skin axis” theory suggests that abnormalities in the brain and nervous system can lead to skin degeneration because abnormal mental states, like chronic stress, can have negative physiological and functional effects on the skin through a variety of processes, resulting in delayed wound healing and accelerated skin aging. However, it remains unclear whether maintaining a youthful brain has beneficial effects on aged skin healing. In light of this, we identified youthful brain-derived extracellular vesicles (YBEVs) and created a composite GelMA hydrogel material that encourages scarless wound healing in aged skin. We found that YBEVs reduce the expression of senescence, senescence-associated secretory phenotypes, and inflammation-associated proteins, and even restore dysfunction in senescent cells. Furthermore, by encouraging collagen deposition, angiogenesis, epidermal and dermal regeneration, and folliculogenesis, we demonstrated that YBEV-containing composite hydrogels accelerated scarless wound healing in skin wounds of aged rats. The pro-repairing speed and effect of this composite hydrogel even matched that of young rats. Subsequent proteomic analysis revealed the presence of numerous proteins within YBEVs, some of which may play a role in the regulation of skin energy intake, particularly through oxidative phosphorylation and mitochondrial function. In conclusion, the findings suggest that maintaining a youthful brain could potentially alleviate skin aging, and the proposed YBEVs-GelMA hydrogel emerges as a promising strategy for addressing age-related impairments in skin healing.

Fat-1, an enzyme encoded by the fat-1 gene, is responsible for the conversion of endogenous omega-6 polyunsaturated fatty acids into omega-3 polyunsaturated fatty acids in Caenorhabditis elegans. To better investigate whether the expression of Fat-1 will exert a beneficial function in dyslipidemia and metabolic dysfunction-associated fatty liver disease (MAFLD), we established an adeno-associated virus 9 expressing Fat-1. We found that adeno-associated-virus-mediated expression of Fat-1 markedly reduced the levels of plasma triglycerides and total cholesterol but increased high-density lipoprotein levels in male wild-type hamsters on both chow diet and high-fat diet as well as in chow-diet-fed male LDLR^−/− hamsters. Fat-1 ameliorated diet-induced MAFLD in wild-type hamsters by enhancing fatty acid oxidation through the hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent pathway. Mechanistically, Fat-1 increased the levels of multiple lipid derivatives as ligands for PPARα and simultaneously facilitated the nuclear localization of PPARα. Our results provide new insights into the multiple therapeutic potentials of Fat-1 to treat dyslipidemia, MAFLD, and atherosclerosis.

Spermatogonial stem cells (SSCs) are essential for initiating and maintaining normal spermatogenesis, and notably, they have important applications in both reproduction and regenerative medicine. Nevertheless, the molecular mechanisms controlling the fate determinations of human SSCs remain elusive. In this study, we identified a selective expression of APBB1 in dormant human SSCs. We demonstrated for the first time that APBB1 interacted with KAT5, which led to the suppression of GDF15 expression and consequent inhibition of human SSC proliferation. Intriguingly, Apbb1^−/− mice assumed the disrupted spermatogenesis and markedly reduced fertility. SSC transplantation assays revealed that Apbb1 silencing enhanced SSC colonization and impeded their differentiation, which resulted in the impaired spermatogenesis. Notably, 4 deleterious APBB1 mutation sites were identified in 2,047 patients with non-obstructive azoospermia (NOA), and patients with the c.1940C>G mutation had a similar testicular phenotype with Apbb1^−/− mice. Additionally, we observed lower expression levels of APBB1 in NOA patients with spermatogenic arrest than in obstructive azoospermia patients with normal spermatogenesis. Collectively, our findings highlight an essential role of APBB1/KAT5/GDF15 in governing human SSC fate decisions and maintaining normal spermatogenesis and underscore them as therapeutic targets for treating male infertility.

The stages of transcription initiation and elongation are critical in the regulation of HIV-1 gene expression. Recent single-molecule imaging in living cells has shown that HIV-1 transcription occurs across multiple time scales and plays a key role in the control of latency. However, the molecular mechanisms of HIV-1 transcription remain poorly understood due to the lack of a unified modeling framework and advanced computational methods for analyzing HIV-1 imaging data. Here, we present a general stochastic model that characterizes HIV-1 transcription dynamics and computes the distributions of initiation times and nascent RNA counts. Our results show that coordination between initiation and elongation modulates transcription dynamics and that leveraging initiation-time data enhances model identification. Meanwhile, we develop a statistical inference method that integrates initiation-time data and nascent RNA data. Our results show that incorporating initiation-time data allows for accurate inference of the initiation rate and elongation time, with these parameter estimates being independent of the models used. When applied to HIV-1 transcription data in living cells, our theory and inference methods confirm the dual role of Tat in HIV-1 transcriptional regulation. In addition, the optimal predictive model indicates that Tat induces viral reactivation and latency exit by altering the number of silent states of the promoter. Our approach may provide the potential to improve current HIV-1 cure strategies.

Accurately reconstructing the intricate structure of natural organisms is the long-standing goal of 3-dimensional (3D) bioprinting. Projection-based 3D printing boasts the highest resolution-to-manufacturing time ratio among all 3D-printing technologies, rendering it a highly promising technique in this field. However, achieving standardized, high-fidelity, and high-resolution printing of composite structures using bioinks with diverse mechanical properties remains a marked challenge. The root of this challenge lies in the long-standing neglect of multi-material printability research. Multi-material printing is far from a simple physical assembly of different materials; rather, effective control of material interfaces is a crucial factor that governs print quality. The current research gap in this area substantively hinders the widespread application and rapid development of multi-material projection-based 3D bioprinting. To bridge this critical gap, we developed a multi-material projection-based 3D bioprinter capable of simultaneous printing with 6 materials. Building upon this, we established a fundamental framework for multi-material printability research, encompassing its core logic and essential process specifications. Furthermore, we clarified several critical issues, including the cross-linking behavior of multicomponent bioinks, mechanical mismatch and interface strength in soft–hard composite structures, the penetration behavior of viscous bioinks within hydrogel polymer networks, liquid entrapment and adsorption phenomena in porous heterogeneous structures, and error source analysis along with resolution evaluation in multi-material printing. This study offers a solid theoretical foundation and guidance for the quantitative assessment of multi-material projection-based 3D bioprinting, holding promise to advance the field toward higher precision and the reconstruction of more intricate biological structures.

The emergence and prevalence of methicillin-resistant Staphylococcus aureus (MRSA) severely compromises conventional β-lactam antibiotics efficacy and poses an extensive global health challenge. Given the close relationship between docosahexaenoic acid (DHA) and metabolic alterations, this study aimed to reveal the novel function of DHA to potentiate β-lactam antibiotics activity through a lipid peroxidation mechanism. Additionally, DHA exhibited significant inhibitory effects on the catalytic function of β-lactamase through interactions with active residues. Herein, the dual-faceted mechanisms of perturbation of lipid metabolism and β-lactamase catalytic inhibition achieved the potentiated antibacterial efficacy of β-lactam antibiotics in combination with DHA against MRSA. Furthermore, to enhance the pharmacodynamic performance and stability of DHA, amoxicillin and DHA co-loaded nanoemulsions (Amo/DHA-NEs) were prepared via high-energy emulsification. Intriguingly, we found that Amo/DHA-NEs effectively rescued MRSA-induced infections in the murine infection models, as evidenced by the superior bacterial clearance and mitigated inflammation. Collectively, this work reveals a potentially exploitable link between DHA-driven metabolic reprogramming and β-lactams resistance, and we propose combination therapies of DHA and β-lactams targeting the emerging threat of MRSA infections.

Acute respiratory distress syndrome (ARDS) survivors often suffer from long-term psychiatric disorders such as depression, but the underlying mechanisms remain unclear. Here, we found marked alterations in the composition of gut microbiota in both ARDS patients and mouse models. We investigated the role of one of the dramatically changed bacteria—Akkermansia muciniphila (AKK), whose abundance was negatively correlated with depression phenotypes in both ARDS patients and ARDS mouse models. Specifically, while fecal transplantation from ARDS patients into naive mice led to depressive-like behaviors, microglial activation, and intestinal barrier destruction, colonization of AKK or oral administration of its metabolite—propionic acid—alleviated these deficits in ARDS mice. Mechanistically, AKK and propionic acid decreased microglial activation and neuronal inflammation through inhibiting the Toll-like receptor 4/nuclear factor κB signaling pathway. Together, these results reveal a microbiota-dependent mechanism for ARDS-related depression and provide insight for developing a novel preventative strategy for ARDS-related psychiatric symptoms.

Room-temperature (RT) terahertz (THz) detection finds widespread applications in security inspection, communication, biomedical imaging, and scientific research. However, the state-of-the-art detection strategies are still limited by issues such as low sensitivity, narrow response range, slow response speed, complex fabrication techniques, and difficulties in scaling up to large arrays. Here, we present a high-sensitivity, broadband-response, and high-speed RT THz detection strategy by utilizing a deep subwavelength metal–semiconductor–metal (MSM) structure. The spontaneously formed 2-dimensional electron gas (2DEG) at the CdTe/PbTe interface provides a superior transport channel characterized by high carrier concentration, low scattering, and high mobility. The synergy of the electromagnetic induced well effect formed in the MSM structure, and the efficient and rapid transport capabilities of the 2DEG channel give rise to an impressive performance improvement. The proposed 2DEG photodetector exhibits a broad frequency range from 22 to 519 GHz, an ultralow noise equivalent power of 3.0 × 10⁻¹⁴ W Hz^−1/2 at 166 GHz, and a short response time of 6.7 μs. This work provides an effective route for the development of high-performance RT THz detection strategies, paving the way for enhanced THz technology applications.

Twisted nylon actuators (TNAs) are widely recognized in soft robotics for their excellent load-to-weight ratio and cost-effectiveness. However, their limitations in deformation and output force restrict their ability to support more advanced applications. Here, we report 3 performance-enhancing strategies inspired by the construction process of chromosome, which are validated through 3 novel types of TNAs. First, we design a dual-level helical structure, demonstrating remarkable improvements in the deformation (60.2% vertically and approximately 100% horizontally) and energy storage capability (launching a miniature basketball to 131 cm in height). Second, we present a parallel-twisted method, where the output force of TNAs reaches 11.0 N, achieving 12.1% contraction under a load of 15 N (10,000 times its weight). Additionally, we construct the dual-level helical structure based on parallel-twisted TNAs, resulting in a 439.7% improvement in load capability. We have adopted TNAs for several applications: (a) two bionic elbows capable of rotating and shooting a miniature basketball over 130 cm; (b) a robot that can rapidly jump over 30 cm; and (c) a soft finger that achieves contracting (15.3% contraction under 2 kg load), precise bending (tracking errors less than 2.0%), and twisting motions. This work presents approaches for fabricating high-performance soft actuators and explores the potential applications of these actuators for driving soft robots with multifunctional capabilities.