Liver fibrosis is a severe global health problem. However, no effective antifibrotic drugs have been approved. Surf4 is primarily located in the endoplasmic reticulum (ER) and mediates the transport of secreted proteins from the ER to the Golgi apparatus. Knockout of hepatic Surf4 (Surf4^LKO) in mice impairs very-low-density lipoprotein secretion without causing overt liver damage. Here, we found that collagen levels are significantly reduced in the liver of Surf4^LKO mice compared with control Surf4^flox mice, as demonstrated by proteomics, Western blot, and quantitative reverse transcription polymerase chain reaction. Therefore, this study aims to investigate whether and how hepatic Surf4 affects liver fibrosis. We observed that CCl₄-induced liver fibrosis is significantly lower in Surf4^LKO mice than in Surf4^flox mice. Mechanistically, hepatic Surf4 deficiency reduces serum amyloid A1 (SAA1) secretion and hepatic stellate cell (HSC) activation. Surf4 coimmunoprecipitates and colocalizes with SAA1. Lack of hepatic Surf4 significantly reduces SAA1 secretion from hepatocytes, and SAA1 activates cultured human HSCs (LX-2 cells). Conditioned medium (CM) from Surf4-deficient primary hepatocytes activates LX-2 cells to a much lesser extent than CM from Surf4^flox primary hepatocytes, and this reduced effect is restored by the addition of recombinant SAA1 to CM from Surf4-deficient hepatocytes. Knockdown of SAA1 in primary hepatocytes or TLR2 in LX-2 cells significantly reduces LX-2 activation induced by CM from Surf4^flox hepatocytes but not from Surf4^LKO hepatocytes. Furthermore, knockdown of SAA1 significantly ameliorates liver fibrosis in Surf4^flox mice but does not further reduce liver fibrosis in Surf4^LKO mice. We also observe substantial expression of Surf4 and SAA1 in human fibrotic livers. Therefore, hepatic Surf4 facilitates SAA1 secretion, activates HSCs, and aggravates liver fibrosis, suggesting that hepatic Surf4 and SAA1 may serve as treatment targets for liver fibrosis.

Hyperproliferative keratinocytes and subcutaneous inflammation contribute to the characteristic symptoms of psoriasis, including erythema, scales, or scaly plaques on the skin. These symptoms significantly affect patients' quality of life and cause severe physical and psychological distress. However, current treatment strategies have limited therapeutic effect and may lead to adverse side effects. In this study, we present the novel organic photosensitizer TBTDC [5-(((5-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)methylene)amino)-3-methylthiophene-2,4-dicarbonitrile] nanoparticles (NPs) with aggregation-induced emission (AIE) characteristics to mediate photodynamic therapy (TBTDC NP-PDT) for psoriasis treatment. We demonstrate that TBTDC NPs effectively generate reactive oxygen species upon light irradiation and lead to significant apoptosis of psoriatic keratinocytes. Furthermore, TBTDC NPs exhibit high cellular uptake in diseased keratinocytes and induce endoplasmic reticulum stress (ERS)-mediated autophagy, which can also enhance apoptosis. Importantly, TBTDC NPs show no cytotoxicity toward keratinocytes. These unique properties of TBTDC NPs enable remarkable therapeutic effects against psoriasis-like skin lesions and related inflammation in vivo. Overall, our AIE-active TBTDC NP-PDT represents a promising strategy for treating psoriasis in clinical settings.

Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to actin molecules. Consequently, this leads to a reduction in actin polymerization. Mechanistically, Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin, diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels. These alterations in actin dynamics result in inhibited cell cycle progression, increased apoptosis, and decreased proliferation of colonic epithelial cells, thereby exacerbating colitis development and progression. In contrast, the silencing of circNlgn or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization, enhanced cell survival, and reduced apoptosis and ultimately improves the outcome of colitis in vivo. Interestingly, nuclear actin polymerization is highly related with expression of PIAS3, which modulates signal transducer and activator of transcription 3 and NF-κB activity in colitis. Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerative colitis clinical intervention.

Hydrogel hemostatic sponges have been recognized for its effectiveness in wound treatment due to its excellent biocompatibility, degradability, as well as multi-facet functionalities. Current research focuses on optimizing the composition and structure of the sponge to enhance its therapeutic effectiveness. Here, we propose an adhesive hydrogel made from purely natural substances extracted from okra and Panax notoginseng. We utilize 3-dimensional (3D) printing technology to fabricate the hemostatic hydrogel scaffold, incorporating gelatin into the hydrogel and refining the mixing ratio. The interaction between gelatin and okra polyphenols contributes to successful injectability as well as stability of the printed scaffold. The okra in the scaffold exhibits favorable adhesion and hemostatic effects, and the total saponins of Panax notoginseng facilitate angiogenesis. Through in vitro experiments, we have substantiated the scaffold's excellent stability, adhesion, biocompatibility, and angiogenesis-promoting ability. Furthermore, in vivo experiments have demonstrated its dual functionality in rapid hemostasis and wound repair. These features suggest that the 3D-printed, natural substance-derived hydrogel scaffolds have valuable potential in wound healing and related applications.

Vibration is a common strategy for aquatic organisms to achieve their life activities, especially at the air–water interface. For the locomotion of small creatures, the organs with plate features are often used on water surfaces, which inspires relevant studies about using thin plates for robot propulsions. However, the influence of the general deformations of thin plates on the generated flow fields has not been considered. Here, a comprehensive investigation is conducted about the flow fields that arose by vibrations of thin plates and the potential as locomotion strategies are explored. It is discovered that as thin plates are subjected to vibration excitations on the water surface, the produced flow fields are mainly determined by the vibration shapes, and the influence rules of plate deformations on the flow fields are identified. The main factors producing asymmetric flow fields are analyzed to realize the morphology control of the flow fields. Then, to determine effective locomotion strategies on the water surface, the flow fields stimulated by integrated vibration exciters are explored, and 2 water surface robots are developed consequentially, which exhibit superior motion performance. This work reveals the basic rules of the vibration-induced-flow mechanism by thin plates and establishes new locomotion strategies for aquatic robots.

Can a robotic gripper only operate when attached to a robotic arm? The application space of the traditional gripper is limited by the robotic arm. Giving robot grippers the ability to move will expand their range of applications. Inspired by rich behavioral repertoire observed in octopus, we implement an integrated multifunctional soft robotic gripper with 6 independently controlled Arms. It can execute 8 different gripping actions for different objects, such as irregular rigid/soft objects, elongated objects with arbitrary orientation, and plane/curved objects with larger sizes than the grippers. Moreover, the soft gripper can realize omnidirectional crawling and swimming by itself. The soft gripper can perform highly integrated tasks of releasing, crawling, swimming, grasping, and retrieving objects in a confined underwater environment. Experimental results demonstrate that the integrated capabilities of multimodal adaptive grasping and omnidirectional motions enable dexterous manipulations that traditional robotic arms cannot achieve. The soft gripper may apply to highly integrated and labor-intensive tasks in unstructured underwater environments, including ocean litter collecting, capture fishery, and archeological exploration.

The integration of sensing and communication can achieve ubiquitous sensing while enabling ubiquitous communication. Within the gradually improving global communication, the integrated sensing and communication system based on optical fibers can accomplish various functionalities, such as urban structure imaging, seismic wave detection, and pipeline safety monitoring. With the development of quantum communication, quantum networks based on optical fiber are gradually being established. In this paper, we propose an integrated sensing and quantum network (ISAQN) scheme, which can achieve secure key distribution among multiple nodes and distributed sensing under the standard quantum limit. The continuous variables quantum key distribution protocol and the round-trip multiband structure are adopted to achieve the multinode secure key distribution. Meanwhile, the spectrum phase monitoring protocol is proposed to realize distributed sensing. It determines which node is vibrating by monitoring the frequency spectrum and restores the vibration waveform by monitoring the phase change. The scheme is experimentally demonstrated by simulating the vibration in a star structure network. Experimental results indicate that this multiuser quantum network can achieve a secret key rate of approximately 0.7 Mbits/s for each user under 10-km standard fiber transmission, and its network capacity is 8. In terms of distributed sensing, it can achieve a vibration response bandwidth ranging from 1 Hz to 2 kHz, a strain resolution of 0.50 \mathrm{n}\epsilon /\sqrt{\mathrm{Hz}}, and a spatial resolution of 0.20 m under shot-noise-limited detection. The proposed ISAQN scheme enables simultaneous quantum communication and distributed sensing in a multipoint network, laying a foundation for future large-scale quantum networks and high-precision sensing networks.

Nature, with its numerous surprising rules, serves as a rich source of creativity for the development of artificial intelligence, inspiring researchers to create several nature-inspired intelligent computing paradigms based on natural mechanisms. Over the past decades, these paradigms have revealed effective and flexible solutions to practical and complex problems. This paper summarizes the natural mechanisms of diverse advanced nature-inspired intelligent computing paradigms, which provide valuable lessons for building general-purpose machines capable of adapting to the environment autonomously. According to the natural mechanisms, we classify nature-inspired intelligent computing paradigms into 4 types: evolutionary-based, biological-based, social-cultural-based, and science-based. Moreover, this paper also illustrates the interrelationship between these paradigms and natural mechanisms, as well as their real-world applications, offering a comprehensive algorithmic foundation for mitigating unreasonable metaphors. Finally, based on the detailed analysis of natural mechanisms, the challenges of current nature-inspired paradigms and promising future research directions are presented.

Although cytochrome P450 enzymes are the most versatile biocatalysts in nature, there is insufficient comprehension of the molecular mechanism underlying their functional innovation process. Here, by combining ancestral sequence reconstruction, reverse mutation assay, and progressive forward accumulation, we identified 5 founder residues in the catalytic pocket of flavone 6-hydroxylase (F6H) and proposed a “3-point fixation” model to elucidate the functional innovation mechanisms of P450s in nature. According to this design principle of catalytic pocket, we further developed a de novo diffusion model (P450Diffusion) to generate artificial P450s. Ultimately, among the 17 non-natural P450s we generated, 10 designs exhibited significant F6H activity and 6 exhibited a 1.3- to 3.5-fold increase in catalytic capacity compared to the natural CYP706X1. This work not only explores the design principle of catalytic pockets of P450s, but also provides an insight into the artificial design of P450 enzymes with desired functions.

Addressing the urgent need for innovative depression treatments, this study heralds a breakthrough in major depressive disorder (MDD) therapy by intertwining clinical observations with neurobiological advancements. We analyzed brain-derived neurotrophic factor (BDNF) levels in serum exosomes from a diverse group of 60 individuals, including first-episode, drug-free MDD patients, medicated MDD patients, and healthy controls. Our results revealed a significant decrease in BDNF levels within MDD patients' exosomes, which notably increased post-medication, highlighting BDNF's potential as a biomarker for both MDD diagnosis and treatment efficacy. Advancing these clinical findings, we developed RVG-modified exosomes engineered to overexpress BDNF (RVG-BDNF-Exos), designed to directly target neuronal cells. Our findings demonstrate that these engineered exosomes can successfully traverse the blood–brain barrier, targeting neurons in the hippocampus and prefrontal cortex. In our mouse model of depression induced by lipopolysaccharide, RVG-BDNF-Exos treatment led to a significant increase of BDNF in these key brain regions, crucial for mood regulation and neurogenesis. This intervention modulated the BDNF/TrkB/AKT signaling pathway, central to neural plasticity and implicated in depression's pathogenesis. Behavioral assessments exhibited substantial improvements in depressive-like behaviors in mice treated with RVG-BDNF-Exos, including reduced immobility in Tail Suspension and Forced Swim Tests. Additionally, our treatment effectively decreased neuroinflammation, as evidenced by the reduction in microglia and astrocyte numbers. Moreover, RVG-BDNF-Exos treatment enhanced neurogenesis and regulated synaptic plasticity, as indicated by the increased expression of neuronal markers MAP2 and DCX, and synaptic proteins PSD95 and Syn-1. In conclusion, this study not only underscores the clinical potential of serum exosomal BDNF as a diagnostic and therapeutic marker for MDD but also demonstrates the efficacy of RVG-BDNF-Exos in alleviating depressive symptoms. Our findings pave the way for future targeted, personalized psychiatric treatments, offering a promising direction in MDD therapy.