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.