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.

Auxetic materials have been extensively studied for their design, fabrication and mechanical properties. These material systems exhibit unique mechanical characteristics such as high impact resistance, shear strength, and energy absorption capacity. Most existing auxetic materials are two-dimensional (2D) and demonstrate half-auxetic behavior, characterized by a negative Poisson's ratio when subjected to either tensile or compressive forces. Here, we present novel three-dimensional (3D) auxetic mechanical metamaterials, termed coupling chiral cuboids, capable of achieving negative Poisson's ratio under both tension and compression. We perform experiments, theoretical analysis, and numerical simulations to validate the wholly auxetic response of the proposed coupling chiral cuboids. Parametric studies are carried out to investigate the effects of structural parameters on the elastic modulus and Poisson's ratio of the coupling chiral cuboids. The results imply that the Poisson's ratio sign-switching from negative to positive can be implemented by manipulating the thickness of Z-shaped ligaments. Finally, the potential application of the coupling chiral cuboids as inner cores for impact-resistant sandwich panels is envisioned and validated. Test results demonstrate a remarkable 49.3% enhancement in energy absorption compared to conventional solid materials.

In recent years, the unique mechanism of sliding ferroelectricity with ultralow switching barriers has been experimentally verified in a series of 2-dimensional (2D) materials. However, its practical applications are hindered by the low polarizations, the challenges in synthesis of ferroelectric phases limited in specific stacking configurations, and the low density for data storage since the switching process involves large-area simultaneous sliding of a whole layer. Herein, through first-principles calculations, we propose a type of semi-sliding ferroelectricity in the single metal porphyrin molecule intercalated in 2D bilayers. An enhanced vertical polarization can be formed independent on stacking configurations and switched via sliding of the molecule accompanied by the vertical displacements of its metal ion anchored from the upper layer to the lower layer. Such semi-sliding ferroelectricity enables each molecule to store 1 bit data independently, and the density for data storage can be greatly enhanced. When the bilayer exhibits intralayer ferromagnetism and interlayer antiferromagnetic coupling, a considerable difference in Curie temperature between 2 layers and a switchable net magnetization can be formed due to the vertical polarization. At a certain range of temperature, the exchange of paramagnetic–ferromagnetic phases between 2 layers is accompanied by ferroelectric switching, leading to a hitherto unreported type of multiferroic coupling that is long-sought for efficient “magnetic reading + electric writing”.

Topological insulating states in 2-dimensional (2D) materials are ideal systems to study different types of quantized response signals due to their in gap metallic states. Very recently, the quantum spin Hall effect was discovered in monolayer TaIrTe₄ via the observation of quantized longitudinal conductance that rarely exists in other 2D topological insulators. The nontrivial Z₂ topological charges can exist at both charge neutrality point and the van Hove singularity point with correlation-effect-induced bandgap. On the basis of this model 2D material, we studied the switch of quantized signals between longitudinal conductance and transversal Hall conductance via tuning external magnetic field. In Z₂ topological phase of monolayer TaIrTe₄, the zero Chern number can be understood as 1 – 1 = 0 from the double band inversion from spin-up and spin-down channels. After applying a magnetic field perpendicular to the plane, the Zeeman split changes the band order for one branch of the band inversion from spin-up and spin-down channels, along with a sign charge of the Berry phase. Then, the net Chern number of 1 – 1 = 0 is tuned to 1 + 1 = 2 or −1 – 1 = −2 depending on the orientation of the magnetic field. The quantized signal not only provides another effective method for the verification of topological state in monolayer TaIrTe₄ but also offers a strategy for the utilization of the new quantum topological states based on switchable quantized responses.

Natural biomaterials have been showing extensive potential in wound healing; attempts therefore focus on productions achieving both antimicrobial and tissue regenerative abilities. Here, we construct a decellularized human colon tumor (DHCT)-derived scaffold for wound remolding via microfluidic bioprinting. The DHCT retains a series of growth factors, fibrin, and the collagen configuration, that favor tissue repair and reconstruction. Specifically, the scaffold shows superior abilities in cell migration and angiogenesis. The biocompatible scaffold is also imparted with tissue adhesion ability and photothermal effect due to the coating of biologically derived polydopamine on the surface. The strong photothermal effect under near-infrared irradiation also present the scaffold with an antibacterial rate exceeding 90%. Furthermore, in vivo experiments convinced that the polydopamine-integrated DHCT scaffold can markedly expedite the healing process of acute extensive wounds. These findings indicate that composite materials derived from natural tumors have substantial potential in pertinent clinical applications.

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.

Bone is a dynamic tissue reshaped by constant bone formation and bone resorption to maintain its function. The skeletal system accounts for approximately 70% of the total volume of the body, and continuous bone remodeling requires quantities of energy and material consumption. Adipose tissue is the main energy storehouse of the body and has a strong adaptive capacity to participate in the regulation of various physiological processes. Considering that obesity and metabolic syndrome have become major public health challenges, while osteoporosis and osteoporotic fractures have become other major health problems in the aging population, it would be interesting to explore these 2 diseases together. Currently, an increasing number of researchers are focusing on the interactions between multiple tissue systems, i.e., multiple organs and tissues that are functionally coordinated together and pathologically pathologically interact with each other in the body. However, there is lack of detailed reviews summarizing the effects of lipid metabolism on bone homeostasis and the interactions between adipose tissue and bone tissue. This review provides a detailed summary of recent advances in understanding how lipid molecules and adipose-derived hormones affect bone homeostasis, how bone tissue, as a metabolic organ, affects lipid metabolism, and how lipid metabolism is regulated by bone-derived cytokines.

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.