Shape memory polymers (SMPs) and their composites (SMPCs) are smart materials that can be stably deformed and then return to their original shape under external stimulation, thus having a memory of their shape. Three-dimensional (3D) printing is an advanced technology for fabricating products using a digital software tool. Four-dimensional (4D) printing is a new generation of additive manufacturing technology that combines shape memory materials and 3D printing technology. Currently, 4D-printed SMPs and SMPCs are gaining considerable research attention and are finding use in various fields, including biomedical science. This review introduces SMPs, SMPCs, and 4D printing technologies, highlighting several special 4D-printed structures. It summarizes the recent research progress of 4D-printed SMPs and SMPCs in various fields, with particular emphasis on biomedical applications. Additionally, it presents an overview of the challenges and development prospects of 4D-printed SMPs and SMPCs and provides a preliminary discussion and useful reference for the research and application of 4D-printed SMPs and SMPCs.

This paper investigates a multiplayer reach–avoid differential game in 3-dimensional (3D) space, which involves multiple pursuers, multiple evaders, and a designated target region. The evaders aim to reach the target region, while the pursuers attempt to guard the target region by capturing the evaders. This class of research holds significant practical value. However, the complexity of the problem escalates substantially with the growing number of players, rendering its solution extremely challenging. In this paper, the multiplayer game is divided into many subgames considering the cooperation among pursuers, reducing the computational burden, and obtaining numerically tractable strategies for players. First, the Apollonius sphere, a fundamental geometric tool for analyzing the 3D differential game, is formulated, and its properties are proved. Based on this, the optimal interception point for the pursuer to capture the evader is derived and the winning conditions for the pursuer and evader are established. Then, based on the Apollonius sphere, the optimal state feedback strategies of players are designed, and simultaneously, the optimal one-to-one pairings are obtained. Meanwhile, the Value function of the multiplayer reach–avoid differential game is explicitly given and is proved to satisfy Hamilton–Jacobi–Isaacs (HJI) equation. Moreover, the matching algorithm for the case with pursuers outnumbered evaders is provided through constructing a weighted bipartite graph, and the cooperative tactics for multiple pursuers are proposed, inspired by the Harris’ Hawks intelligent cooperative hunting tactics. Finally, numerical simulations are conducted to illustrate the effectiveness of the theoretical results for both cases where the number of adversary players is equal and unequal between the 2 groups.

Connexin 43 (CX43) is one of the major components of gap junctions, the structures responsible for the intercellular communication and transmission of the electrical impulse in the left ventricle. There is limited information on the histological changes of CX43 with age and their effect on electrophysiology, especially in humans. Here, we analyzed left ventricular biopsies from living donors starting at midlife to characterize age-related CX43 remodeling. We assessed its quantity, degree of lateralization, and spatial heterogeneity together with fibrotic deposition. We observed no significant age-related remodeling of CX43. Only spatial heterogeneity increased slightly with age, and this increase was better explained by biological age than by chronological age. Importantly, we found that CX43 features varied considerably among individuals in our population with no relevant relationship to age or fibrosis content, in contrast to animal species. We used our experimental results to feed computational models of human ventricular electrophysiology and to assess the effects of interindividual differences in specific features of CX43 and fibrosis on conduction velocity, action potential duration, and arrhythmogenicity. We found that larger amounts of fibrosis were associated with the highest arrhythmic risk, with this risk being increased when fibrosis deposition was combined with a reduction in CX43 amount and/or with an increase in CX43 spatial heterogeneity. These mechanisms underlying high arrhythmic risk in some individuals were not associated with age in our study population. In conclusion, our data rule out CX43 remodeling as an age-related arrhythmic substrate in the population beyond midlife, but highlight its potential as a proarrhythmic factor at the individual level, especially when combined with increased fibrosis.

Magnetically actuated mobile robots demonstrate attractive advantages in various medical applications due to their wireless and programmable executions with tiny sizes. Confronted with complex application scenarios, however, it requires more flexible and adaptive deployment and utilization methods to fully exploit the functionalities brought by magnetic robots. Herein, we report a design and utilization strategy of magnetic soft robots using a mixture of magnetic particles and non-Newtonian fluidic soft materials to produce programmable, hardened, adhesive, reconfigurable soft robots. For deployment, their ultrasoft structure and adhesion enable them to be spread on various surfaces, achieving magnetic actuation empowerment. The reported technology can potentially improve the functionality of robotic end-effectors and functional surfaces. Experimental results demonstrate that the proposed robots could help to grasp and actuate objects 300 times heavier than their weight. Furthermore, it is the first time we have enhanced the stiffness of mechanical structures for these soft materials by on-demand programmable hardening, enabling the robots to maximize force outputs. These findings offer a promising path to understanding, designing, and leveraging magnetic robots for more powerful applications.

Jade is most valued in Chinese culture since ancient times. For unearthed jade artifacts, the alteration color resulting from weathering effects and human activities provides information for cultural heritage conservation, archaeology, and history. Currently, the noninvasive 3-dimensional characterization of jade artifacts with high chemical and spatial resolution remains challenging. In this work, we applied femtosecond pump–probe microscopy and second harmonic generation microscopy techniques to study the black alteration of an ancient jade artifact of the late Spring and Autumn period (546 to 476 BC). The direct cause of the “mercury alteration” phenomena was discovered to be the conversion of metacinnabar from buried cinnabar in the tomb. Furthermore, a 3-dimensional optical reconstruction of the black alteration was achieved, providing a high-resolution method for analyzing the blackening mechanism without the need of sample damage. Our approach opens up new opportunities to extract microscopic spatiochemical information for a broad range of alteration colors in jade artifacts.

Metallic lithium represents a promising anode candidate to be utilized in future high-energy lithium batteries. However, the undesirable dendrite growth and fragile solid-electrolyte interphase (SEI) pose critical challenge for pursuing further practical application. In contrast to traditional approaches of using inert/lithiophilicity coating, here, we demonstrate a reverse strategy of introducing a highly conductive and lithophobic carbon fabric (CF) scaffold on lithium foil to guide a favorable nucleation site of lithium far away from the anode/separator interface. The CF scaffold with high conductivity can couple with inner electric field for achieving a uniform distribution of the lithium-ion flux, while the lithophobic feature offers the condition to guide the preferred deposition of lithium onto the underlying lithium foil, which greatly reduces the risk of dendrite-induced short circuits. Moreover, the SEI immersed in the CF scaffold is well supported by CF fibers and therefore exhibits extremely high stability during charge–discharge cycles. As a result, the lithium/CF anodes show >2,000-h stable cycling at 0.5 mA cm⁻². Lithium metal batteries equipped with our lithium/CF anode deliver a high capacity retention of ~99.99% per cycle, i.e., retain ~97.3% capacity after 200 cycles. The unique interface-regulation strategy is versatile for various conductive scaffolds (e.g., ultrathin and ultralight conductive fabrics), exhibiting high superiority for highly safe lithium metal batteries.

Brown adipose tissue (BAT) is the major site of non-shivering thermogenesis and crucial for systemic metabolism. Under chronic cold exposures and high-fat diet challenges, BAT undergoes robust remodeling to adapt to physiological demands. However, whether and how BAT regenerates after acute injuries are poorly understood. Here, we established a novel BAT injury and regeneration model (BAT-IR) in mice and performed single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq to determine cellular and transcriptomic dynamics during BAT-IR. We further defined distinct fibro-adipogenic and myeloid progenitor populations contributing to BAT regeneration. Cell trajectory and gene expression analyses uncovered the involvement of MAPK, Wnt, and Hedgehog (Hh) signaling pathways in BAT regeneration. We confirmed the role of Hh signaling in BAT development through Myf5^Cre-mediated conditional knockout (cKO) of the Sufu gene to activate Hh signaling in BAT and muscle progenitors. Our BAT-IR model therefore provides a paradigm to identify conserved cellular and molecular mechanisms underlying BAT development and remodeling.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

Living tissues often have anisotropic and heterogeneous organizations, in which developmental processes are coordinated by cells and extracellular matrix modeling. Cells have the capability of modeling matrix in long distance; however, the biophysical mechanism is largely unknown. We investigated the dynamic remodeling of collagen I (COL) fibril matrix by cell contraction with designed patterns of cell clusters. By considering cell dynamic contractions, our molecular dynamics simulations predicted the anisotropic patterns of the observed COL bundling in experiments with various geometrical patterns without spatial limitation. The pattern of COL bundling was closely related to the dynamic remodeling of fibril under cell active contraction. We showed that cell cytoskeletal integrity (actin filaments and microtubules), actomyosin contractions, and endoplasmic reticulum calcium channels acting as force generations and transductions were essential for fiber bundling inductions, and membrane mechanosensory components integrin and Piezo played critical roles as well. This study revealed the underlying mechanisms of the cell mechanics-induced matrix remodeling in large scales and the associated cellular mechanism and should provide important guidelines for tissue engineering in potential biomedical applications.

T-cell-based immunotherapy is gaining momentum in cancer treatment; however, our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained. The objective of this study was to explore the function of interferon regulatory factor 4 (IRF4) in antitumor CD8⁺ T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma model. To achieve this, we generated an Irf4^GFP-DTR mouse strain and discovered that CD8⁺ tumor-infiltrating lymphocytes (TILs) expressing high levels of IRF4.GFP exhibited a more differentiated PD-1^high cell phenotype. By administering diphtheria toxin to tumor-bearing Irf4^GFP-DTR mice, we partially depleted IRF4.GFP⁺ TILs and observed an accelerated tumor growth. To specifically explore the function of IRF4 in antitumor CD8⁺ T cells, we conducted 3 adoptive cell therapy (ACT) models. Firstly, depleting IRF4.GFP⁺ CD8⁺ TILs derived from ACT significantly accelerated tumor growth, emphasizing their crucial role in controlling tumor progression. Secondly, deleting the Irf4 gene in antitumor CD8⁺ T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8⁺ TILs, completely abolishing the antitumor effects of ACT. Lastly, we performed a temporal deletion of the Irf4 gene in antitumor CD8⁺ T cells during ACT, starting from 20 days after tumor implantation, which significantly compromised tumor control. Therefore, sustained expression of IRF4 is essential for maintaining CD8⁺ T cell immunity in the melanoma model, and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.

Byzantine agreement, the underlying core of blockchain, aims to make every node in a decentralized network reach consensus. Classical Byzantine agreements unavoidably face two major problems. One is 1/3 fault-tolerance bound, which means that the system to tolerate f malicious players requires at least 3f + 1 players. The other is the security loopholes from its classical cryptography methods. Here, we propose a Byzantine agreement framework with unconditional security to break this bound with nearly 1/2 fault tolerance due to multiparty correlation provided by quantum digital signatures. It is intriguing that quantum entanglement is not necessary to break the 1/3 fault-tolerance bound, and we show that weaker correlation, such as asymmetric relationship of quantum digital signature, can also work. Our work strictly obeys two Byzantine conditions and can be extended to any number of players without requirements for multiparticle entanglement. We experimentally demonstrate three-party and five-party consensus for a digital ledger. Our work indicates the quantum advantage in terms of consensus problems and suggests an important avenue for quantum blockchain and quantum consensus networks.

Cortical organoids represent cutting-edge models for mimic human brain development during the early and even middle stage of pregnancy, while they often fail to recreate the complex microenvironmental factors, such as physiological hypoxia. Herein, to recapitulate fetal brain development, we propose a novel cortical organoid-on-a-chip with physiological hypoxia and further explore the effects of tanshinone IIA (Tan IIA) in neural differentiation. The microfluidic chip was designed with a micropillar array for the controlled and efficient generation of cortical organoids. With low oxygen, the generated cortical organoids could recapitulate key aspects of early-gestational human brain development. Compared to organoids in normoxic culturing condition, the promoted neurogenesis, synaptogenesis and neuronal maturation were observed in the present microsystem, suggesting the significance of physiological hypoxia in cortical development. Based on this model, we have found that Chinese herbal drug Tan IIA could promote neural differentiation and maturation, indicating its potential therapeutic effects on neurodevelopmental disorders as well as congenital neuropsychiatric diseases. These results indicate that the proposed biomimetic cortical organoid-on-a-chip model with physiological hypoxia can offer a promising platform to simulate prenatal environment, explore brain development, and screen natural neuroactive components.

Non-alcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), is a leading cause of cirrhosis and liver cancer worldwide; nevertheless, there are no Food and Drug Administration-approved drugs for treating NASH until now. Peroxisome proliferator-activated receptor alpha (PPARα) is an interesting therapeutic target for treating metabolic disorders in the clinic, including NASH. Herpetrione, a natural lignan compound isolated from Tibetan medicine Herpetospermum caudigerum, exerts various hepatoprotective effects, but its efficacy and molecular mechanism in treating NASH have not yet been elucidated. Here, we discovered that herpetrione lessened lipid accumulation and inflammation in hepatocytes stimulated with oleic acid and lipopolysaccharide, and effectively alleviated NASH caused by a high-fat diet or methionine-choline-deficient diet by regulating glucolipid metabolism, insulin resistance, and inflammation. Mechanistically, RNA-sequencing analyses further showed that herpetrione activated PPAR signaling, which was validated by protein expression. Furthermore, the analysis of molecular interactions illustrated that herpetrione bound directly to the PPARα protein, with binding sites extending to the Arm III domain. PPARα deficiency also abrogated the protective effects of herpetrione against NASH, suggesting that herpetrione protects against hepatic steatosis and inflammation by activation of PPARα signaling, thereby alleviating NASH. Our findings shed light on the efficacy of a natural product for treating NASH, as well as the broader prospects for NASH treatment by targeting PPARα.

Histone deacetylases (HDACs) are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis. However, whether and how HDACs regulate iron metabolism and ferroptosis (an iron-dependent form of cell death) remain unclear. Here, the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models. Mice lacking Hdac3 expression in the liver (Hdac3-LKO mice) have significantly reduced hepatic Hamp mRNA (encoding the peptide hormone hepcidin) and altered iron homeostasis. Transcription profiling of Hdac3-LKO mice suggests that the Hippo signaling pathway may be downstream of Hdac3. Moreover, using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap (Yes-associated protein) significantly reduced Hamp mRNA levels. Using a promoter reporter assay, we then identified 2 Yap-binding repressor sites within the human HAMP promoter region. We also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus, suggesting activation of Yap. Notably, knock-in mice expressing a constitutively active form of Yap (Yap K342M) phenocopied the altered hepcidin levels observed in Hdac3-LKO mice. Mechanistically, we show that iron-overload-induced ferroptosis underlies the liver injury that develops in Hdac3-LKO mice, and knocking down Yap expression in Hdac3-LKO mice reduces both iron-overload- and ferroptosis-induced liver injury. These results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.

Fibroblast activation protein (FAP) is among the most popular targets in nuclear medicine imaging and cancer theranostics. Several small-molecule moieties (FAPI-04, FAPI-46, etc.) are used for developing FAP-targeted theranostic agents. Nonetheless, the circulation time of FAP inhibitors is relatively short, resulting in rapid clearance via kidneys, low tumor uptake, and associated unsatisfactory treatment efficacy. To address the existing drawbacks, we engineered 3 peptides named FD1, FD2, and FD3 with different circulation times through solid-phase peptide synthesis. All the 3 reported peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance. The diagnostic and therapeutic potential of the agents labeled with ⁶⁸Ga and ¹⁷⁷Lu was assessed in several tumor models exhibiting different levels of FAP expression. While radiolabeled FD1 was rapidly excreted from kidneys, radiolabeled FD2/FD3 have significantly prolonged circulation, increased tumor uptake, and decreased kidney accumulation. Our findings indicated that [⁶⁸Ga]Ga-DOTA-FD1 positron emission tomography (PET) effectively detected FAP dynamics, whereas [¹⁷⁷Lu]Lu-DOTA-FD2 and [¹⁷⁷Lu]Lu-DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing tumor models, including pancreatic cancer cell models characterized by abundant stroma. Moreover, a pilot translational investigation demonstrated that [⁶⁸Ga]Ga-DOTA-FD1 had the capability to identify both primary and metastatic tumors with precision and distinction. In summary, we developed [⁶⁸Ga]Ga-DOTA-FD1 for same-day PET imaging of FAP dynamics and [¹⁷⁷Lu]Lu-DOTA-FD2 and [¹⁷⁷Lu]Lu-DOTA-FD3 for effective radioligand therapy of FAP-overexpressing tumors.