Transforming Albumin into a Trojan Horse of Immunotherapy-Resistant Colorectal Cancer with a High Microsatellite Instability.

The therapeutic response of microsatellite instability-high (MSI-H) colorectal cancer (CRC) to immune checkpoint inhibitors (ICI) is indeed surprising; however, the emergence of acquired resistance poses an even greater threat to the survival of these patients. Herein, bioinformatics analysis of MSI-H CRC samples revealed that Wnt signaling pathway represents a promising target for acquired immune reactivation, while subsequent analysis and biochemical testing substantiated the inclination of Wnt-hyperactive CRC cells to engage in macropinocytosis with human serum albumin (HSA). These findings have inspired us to develop an engineered HSA that not only possesses the ability to specifically target cancer cells but also effectively suppresses the Wnt/ß-catenin cascade within these malignant cells. In pursuit of this objective, a comprehensive screening of reported Wnt small-molecule inhibitors was conducted to evaluate their affinity with HSA, and it was discovered that Carnosic acid (CA) exhibited the highest affinity while simultaneously revealing multiple binding sites. Further investigation revealed that CA HSA the capability to engineer HSA into spherical and size-tunable nanostructures known as eHSA (Engineering HSA particle), which demonstrated optimized macropinocytosis-dependent cellular internalization. As anticipated, eHSA effectively suppressed the Wnt signaling pathway and reactivated the acquired immune response in vivo. Furthermore, eHSA successfully restored sensitivity to Anti-PD1's anticancer effects in both subcutaneous and orthotopic mouse homograft models of MSI-H CRC, as well as a humanized hu-PBMC patient-derived orthotopic xenograft (PDOX) mouse model of MSI-H CRC, all while maintaining a favorable safety profile. The collective implementation of this clinically viable immune reactivation strategy not only enables the delivery of Wnt inhibitors for CRC therapy, but also serves as an exemplary demonstration of precision-medicine-guided nanopharmaceutical development that effectively harnesses specific cellular indications in pathological states.

A Transdermal Prion-Bionics Supermolecule as a RAB3A Antagonist for Enhancing Facial Youthfulness.

The mechanism research of skin wrinkles, conducted on volunteers underwent high-intensity desk work and mice subjected to partial sleep deprivation, revealed a significant reduction in dermal thickness associated with the presence of wrinkles. This can be attributed to the activation of facial nerves in a state of hysteria due to an abnormally elevated interaction between SNAP25 and RAB3A proteins involved in the synaptic vesicle cycle (SVC). Facilitated by AI-assisted structural design, a refined peptide called RSIpep is developed to modulate this interaction and normalize SVC. Drawing inspiration from prions, which possess the ability to protect themselves against proteolysis and invade neighboring nerve cells through macropinocytosis, RSIpep is engineered to demonstrate a GSH-responsive reversible self-assembly into a prion-like supermolecule (RSIprion). RSIprion showcases protease resistance, micropinocytosis-dependent cellular internalization, and low adhesion with constituent molecules in the cuticle, thereby endowing it with the transdermic absorption and subsequent biofunction in redressing the frenzied SVC. As a facial mud mask, it effectively reduces periorbital and perinasal wrinkles in the human face. Collectively, RSIprion not only presents a clinical potential as an anti-wrinkle prion-like supermolecule, but also exemplifies a reproducible instance of bionic strategy-guided drug development that bestows transdermal ability upon the pharmaceutical molecule.

Novel Isolating Approaches to Circulating Tumor Cell Enrichment Based on Microfluidics: A Review.

Circulating tumor cells (CTCs), derived from the primary tumor and carrying genetic information, contribute significantly to the process of tumor metastasis. The analysis and detection of CTCs can be used to assess the prognosis and treatment response in patients with tumors, as well as to help study the metastatic mechanisms of tumors and the development of new drugs. Since CTCs are very rare in the blood, it is a challenging problem to enrich CTCs efficiently. In this paper, we provide a comprehensive overview of microfluidics-based enrichment devices for CTCs in recent years. We explore in detail the methods of enrichment based on the physical or biological properties of CTCs; among them, physical properties cover factors such as size, density, and dielectric properties, while biological properties are mainly related to tumor-specific markers on the surface of CTCs. In addition, we provide an in-depth description of the methods for enrichment of single CTCs and illustrate the importance of single CTCs for performing tumor analyses. Future research will focus on aspects such as improving the separation efficiency, reducing costs, and increasing the detection sensitivity and accuracy.

Radio frequency electric field-enhanced sensing based on the Rydberg atom-based superheterodyne receiver.

We present enhanced sensing of a radio frequency (RF) electric field (E-field) by the combined polarizability of Rydberg atoms and the optimized local oscillator (LO) field of a superheterodyne receiver. Our modified theoretical model reveals the dependencies of the sensitivity of E-field amplitude measurement on the polarizability of Rydberg states and the strength of the LO field. The enhanced sensitivities of the megahertz (MHz) E-field are demonstrated at the optimal LO field for three different Rydberg states ${\rm 43D}_{5/2}$, ${\rm 60S}_{1/2}$, and ${\rm 90S}_{1/2}$. The sensitivity of 63 MHz for the ${\rm 90S}_{1/2}$ state reaches 9.6 $\times 10^{-5}\rm \,V/m/\sqrt {Hz}$, which is approximately an order of magnitude higher than those already published. This result closely approaches the sensitivity limit of a 1 cm passive dipole antenna without using an impedance matching network. This atomic sensor based on the Rydberg Stark effect with heterodyne technique is expected to boost an alternative solution to electric dipole antennas.

A bionic mimosa soft robot based on a multi-responsive PNIPAM-PEGDA hydrogel composition.

Deformation plays a vital role in the survival of natural organisms. One example is that plants deform themselves to face the sun for sufficient sunlight exposure, which allows them to produce nutrients through photosynthesis. Drawing inspiration from nature, researchers have been exploring the development of 3D deformable materials. However, the traditional approach to manufacturing deformable hydrogels relies on complex technology, which limits their potential applications. In this study, we simulate the stress variations observed in the plant tissue to create a 3D structure from a 2D material. Using UV curing technology, we create a single-layer poly(N-isopropylacrylamide) hydrogel sheet with microchannels that exhibit distinct swelling rates when subjected to stimulation. After a two-step curing process, we produce a poly(N-isopropylacrylamide)-polyethylene glycol diacrylatedouble-layer structure that can be manipulated to change its shape by controlling the light and solvent content. Based on the double-layer structure, we fabricate a dual-response driven bionic mimosa robot that can perform a variety of functions. This soft robot can not only reversibly change its shape but also maintain a specific shape without continuous stimulation. Its capacity for reversible deformation, resulting from internal stress, presents promising application prospects in the biomedical and soft robotics domain. This study delivers an insightful framework for the development of programmable soft materials.

Classical and novel properties of Holliday junction resolvase SynRuvC from Synechocystis sp. PCC6803.

Cyanobacteria, which have a photoautotrophic lifestyle, are threatened by ultraviolet solar rays and the reactive oxygen species generated during photosynthesis. They can adapt to environmental conditions primarily because of their DNA damage response and repair mechanisms, notably an efficient homologous recombination repair system. However, research on double-strand break (DSB) repair pathways, including the Holliday junction (HJ) resolution process, in Synechocystis sp. PCC6803 is limited. Here, we report that SynRuvC from cyanobacteria Synechocystis sp. PCC6803 has classical HJ resolution activity. We investigated the structural specificity, sequence preference, and biochemical properties of SynRuvC. SynRuvC strongly preferred Mn2+ as a cofactor, and its cleavage site predominantly resides within the 5'-TG↓(G/A)-3' sequence. Interestingly, novel flap endonuclease and replication fork intermediate cleavage activities of SynRuvC were also determined, which distinguish it from other reported RuvCs. To explore the effect of SynRuvC on cell viability, we constructed a knockdown mutant and an overexpression strain of Synechocystis sp. PCC6803 (synruvCKD and synruvCOE) and assessed their survival under a variety of conditions. Knockdown of synruvC increased the sensitivity of cells to MMS, HU, and H2O2. The findings suggest that a novel RuvC family HJ resolvase SynRuvC is important in a variety of DNA repair processes and stress resistance in Synechocystis sp. PCC6803.

Dynamic Multiple Object Segmentation with Spatio-Temporal Filtering.

This article primarily focuses on the localization and extraction of multiple moving objects in images taken from a moving camera platform, such as image sequences captured by drones. The positions of moving objects in the images are influenced by both the camera's motion and the movement of the objects themselves, while the background position in the images is related to the camera's motion. The main objective of this article was to extract all moving objects from the background in an image. We first constructed a motion feature space containing motion distance and direction, to map the trajectories of feature points. Subsequently, we employed a clustering algorithm based on trajectory distinctiveness to differentiate between moving objects and the background, as well as feature points corresponding to different moving objects. The pixels between the feature points were then designated as source points. Within local regions, complete moving objects were segmented by identifying these pixels. We validated the algorithm on some sequences in the Video Verification of Identity (VIVID) program database and compared it with relevant algorithms. The experimental results demonstrated that, in the test sequences when the feature point trajectories exceed 10 frames, there was a significant difference in the feature space between the feature points on the moving objects and those on the background. Correctly classified frames with feature points accounted for 67% of the total frames.The positions of the moving objects in the images were accurately localized, with an average IOU value of 0.76 and an average contour accuracy of 0.57. This indicated that our algorithm effectively localized and segmented the moving objects in images captured by moving cameras.

Recent Advances in Microrobots Powered by Multi-Physics Field for Biomedical and Environmental Applications.

Microrobots powered by multi-physics fields are becoming a hotspot for micro-nano manufacturing. Due to the small size of microrobots, they can easily enter small spaces that are difficult for ordinary robots to reach and perform a variety of special tasks. This gives microrobots a broad application prospect in many fields. This paper describes the materials, structures, and driving principles of microrobots in detail and analyzes the advantages and limitations of their driving methods in depth. In addition, the paper discusses the detailed categorization of the action forms of microrobots and explores their diversified motion modes and their applicable scenarios. Finally, the article highlights the wide range of applications of microrobots in the fields of biomedicine and environmental protection, emphasizing their great potential for solving real-world problems and advancing scientific progress.

Rydberg atom electric field sensing for metrology, communication and hybrid quantum systems.

Rydberg atoms-based electric field sensing has developed rapidly over the past decade. A variety of theoretical proposals and experiment configurations are suggested and realized to improve the measurement metrics, such as intensity sensitivity, bandwidth, phase, and accuracy. The Stark effect and electromagnetically induced transparency (EIT) or electromagnetically induced absorption (EIA) are fundamental physics principles behind the stage. Furthermore, various techniques such as amplitude- or frequency-modulation, optical homodyne read-out, microwave superheterodyne and frequency conversion based on multi-wave mixing in atoms are utilized to push the metrics into higher levels. In this review, different technologies and the corresponding metrics they had achieved were presented, hoping to inspire more possibilities in the improvement of metrics of Rydberg atom-based electric field sensing and broadness of application scenarios.

Nanomechanical Analysis of Living Small Extracellular Vesicles to Identify Gastric Cancer Cell Malignancy Based on a Biomimetic Peritoneum.

Gastric cancer is one of the most prevalent digestive malignancies. The lack of effective in vitro peritoneal models has hindered the exploration of the potential mechanisms behind gastric cancer's peritoneal metastasis. An accumulating body of research indicates that small extracellular vesicles (sEVs) play an indispensable role in peritoneal metastasis of gastric cancer cells. In this study, a biomimetic peritoneum was constructed. The biomimetic model is similar to real peritoneum in internal microstructure, composition, and primary function, and it enables the recurrence of peritoneal metastasis process in vitro. Based on this model, the association between the mechanical properties of sEVs and the invasiveness of gastric cancer was identified. By performing nanomechanical analysis on sEVs, we found that the Young's modulus of sEVs can be utilized to differentiate between malignant clinical samples (ascites) and nonmalignant clinical samples (peritoneal lavage). Furthermore, patients' ascites-derived sEVs were verified to stimulate the mesothelial-to-mesenchymal transition, thereby promoting peritoneal metastasis. In summary, nanomechanical analysis of living sEVs could be utilized for the noninvasive diagnosis of malignant degree and peritoneal metastasis of gastric cancer. This finding is expected to contribute future treatments.

Rewiring chaperone-mediated autophagy in cancer by a prion-like chemical inducer of proximity to counteract adaptive immune resistance.

Chaperone-mediated autophagy (CMA), a proteolytic system contributing to the degradation of intracellular proteins in lysosomes, is upregulated in tumors for pro-tumorigenic and pro-survival purposes. In this study, bioinformatics analysis revealed the co-occurrence of upregulated CMA and PD-L1 accumulation in metastatic melanoma with adaptive immune resistance (AIR) to anti-PD1 treatment, suggesting the potential therapeutic effects of rewiring CMA for PD-L1 degradation. Furthermore, this co-occurrence is attributed to IFN-γ-mediated compensatory up-regulation of PD-L1 and CMA, accompanied by enhanced macropinocytosis. Drawing inspiration from the cellular uptake of prions via macropinocytosis, a prion-like chemical inducer of proximity called SAP was engineered using self-assembly of the designed chiral peptide PHA. By exploiting sensitized macropinocytosis, SAP clandestinely infiltrates tumor cells and subsequently disintegrates into PHA, which reprograms CMA by inducing PD-L1 close to HSPA8. SAP degrades PD-L1 in a CMA-dependent manner and effectively restores the anti-tumor immune response in both allografting and Hu-PDX melanoma mouse models with AIR while upholding a high safety profile. Collectively, the reported SAP not only presents an immune reactivation strategy with clinical translational potential for overcoming AIR in cutaneous melanomas but serves as a reproducible example of precision-medicine-guided drug development that fully leverages specific cellular indications in pathological states.

Micromixing within microfluidic devices: Fundamentals, design, and fabrication.

As one of the hot spots in the field of microfluidic chip research, micromixers have been widely used in chemistry, biology, and medicine due to their small size, fast response time, and low reagent consumption. However, at low Reynolds numbers, the fluid motion relies mainly on the diffusive motion of molecules under laminar flow conditions. The detrimental effect of laminar flow leads to difficulties in achieving rapid and efficient mixing of fluids in microchannels. Therefore, it is necessary to enhance fluid mixing by employing some external means. In this paper, the classification and mixing principles of passive (T-type, Y-type, obstructed, serpentine, three-dimensional) and active (acoustic, electric, pressure, thermal, magnetic field) micromixers are reviewed based on the presence or absence of external forces in the micromixers, and some experiments and applications of each type of micromixer are briefly discussed. Finally, the future development trends of micromixers are summarized.

Exercise sensitizes PD-1/PD-L1 immunotherapy as a hypoxia modulator in the tumor microenvironment of melanoma.

Introduction: Hypoxia is associated with unfavorable prognoses in melanoma patients, and the limited response rates of patients to PD-1/PD-L1 blockade could be attributed to the immunosuppressive tumor microenvironment induced by hypoxia. Exercise offers numerous benefits in the anti-tumor process and has the potential to alleviate hypoxia; however, the precise mechanisms through which it exerts its anti-tumor effects remain unclear, and the presence of synergistic effects with PD-1/PD-L1 immunotherapy is yet to be definitively established. Methods: We established a B16F10 homograft malignant melanoma model and implemented two distinct exercise treatments (low/moderate-intensity swim) based on the mice's exercise status. The specific function manner of exercise-induced anti-tumor effects was determined through RNA sequencing and analysis of changes in the tumor microenvironment. Furthermore, moderate-intensity swim that exhibited superior tumor suppression effects was combined with Anti-PD-1 treatment to evaluate its in vivo efficacy in mouse models. Results: Exercise intervention yielded a considerable effect in impeding tumor growth and promoting apoptosis. Immunohistochemistry and RNA sequencing revealed improvements in tumor hypoxia and down-regulation of hypoxia-related pathways. Cellular immunofluorescence and ELISA analyses demonstrated a notable increase of cytotoxic T cell amount and a decrease of regulatory T cells, indicating an improvement of tumor immune microenvironment. In comparison to Anti-PD-1 monotherapy, tumor suppressive efficacy of exercise combination therapy was found to be enhanced with improvements in both the hypoxic tumor microenvironment and T cell infiltration. Conclusion: Exercise has the potential to function as a hypoxia modulator improving the tumor immune microenvironment, resulting in the promotion of anti-tumor efficacy and the facilitation of biologically safe sensitization of PD-1/PD-L1 immunotherapy.

An aquatic biomimetic butterfly soft robot driven by deformable photo-responsive hydrogel.

Taking inspiration from the locomotor behaviors of a butterfly, we have developed an underwater soft robot that imitates its movements. This biomimetic robot is constructed using a deformable photo-responsive material that exhibits high biological compatibility and impressive deformation capabilities in response to external stimuli. First, we investigate composite materials consisting of poly-N-isopropylacrylamide (PNIPAM) and multi-walled carbon nanotubes (MWCNTs). Then, using photocuring printing technology, we successfully fabricate a biomimetic butterfly soft robot utilizing these composite materials. The robot is driven by visible light, enabling it to achieve periodic wing movement and fly upward at an average speed of 3.63 mm s-1. In addition, the robot achieves additional functionalities such as flying over obstacles and carrying small objects during the ascending flight. These outcomes have a significant impact on the advancement of flexible biomimetic robots and offer valuable insights for the research of biomimetic robots driven by visible light.

A Bionic Venus Flytrap Soft Microrobot Driven by Multiphysics for Intelligent Transportation.

With the continuous integration of material science and bionic technology, as well as increasing requirements for the operation of robots in complex environments, researchers continue to develop bionic intelligent microrobots, the development of which will cause a great revolution in daily life and productivity. In this study, we propose a bionic flower based on the PNIPAM-PEGDA bilayer structure. PNIPAM is temperature-responsive and solvent-responsive, thus acting as an active layer, while PEGDA does not change significantly in response to a change in temperature and solvent, thus acting as a rigid layer. The bilayer flower is closed in cold water and gradually opens under laser illumination. In addition, the flower gradually opens after injecting ethanol into the water. When the volume of ethanol exceeds the volume of water, the flower opens completely. In addition, we propose a bionic Venus flytrap soft microrobot with a bilayer structure. The robot is temperature-responsive and can reversibly transform from a 2D sheet to a 3D tubular structure. It is normally in a closed state in both cold (T < 32 °C) and hot water (T > 32 °C), and can be used to load and transport objects to the target position (magnetic field strength < 1 T).

Biohybrid Soft Robots Powered by Myocyte: Current Progress and Future Perspectives.

Myocyte-driven robots, a type of biological actuator that combines myocytes with abiotic systems, have gained significant attention due to their high energy efficiency, sensitivity, biocompatibility, and self-healing capabilities. These robots have a unique advantage in simulating the structure and function of human tissues and organs. This review covers the research progress in this field, detailing the benefits of myocyte-driven robots over traditional methods, the materials used in their fabrication (including myocytes and extracellular materials), and their properties and manufacturing techniques. Additionally, the review explores various control methods, robot structures, and motion types. Lastly, the potential applications and key challenges faced by myocyte-driven robots are discussed and summarized.

Host DNA Demethylation Induced by DNMT1 Inhibition Up-Regulates Antiviral OASL Protein during Influenza a Virus Infection.

Influenza A virus (IAV) is a leading cause of human respiratory infections and poses a major public health concern. IAV replication can affect the expression of DNA methyltransferases (DNMTs), and the subsequent changes in DNA methylation regulate gene expression and may lead to abnormal gene transcription and translation, yet the underlying mechanisms of virus-induced epigenetic changes from DNA methylation and its role in virus-host interactions remain elusive. Here in this paper, we showed that DNMT1 expression could be suppressed following the inhibition of miR-142-5p or the PI3K/AKT signaling pathway during IAV infection, resulting in demethylation of the promotor region of the 2'-5'-oligoadenylate synthetase-like (OASL) protein and promotion of its expression in A549 cells. OASL expression enhanced RIG-I-mediated interferon induction and then suppressed replication of IAV. Our study elucidated an innate immunity mechanism by which up-regulation of OASL contributes to host antiviral responses via epigenetic modifications in IAV infection, which could provide important insights into the understanding of viral pathogenesis and host antiviral defense.

Quantum sensing of microwave electric fields based on Rydberg atoms.

Microwave electric field (MW E-field) sensing is important for a wide range of applications in the areas of remote sensing, radar astronomy and communications. Over the past decade, Rydberg atoms have been used in ultrasensitive, wide broadband, traceable, stealthy MW E-field sensing because of their exaggerated response to MW E-fields, plentiful optional energy levels and integratable preparation methods. This review first introduces the basic concepts of quantum sensing, the properties of Rydberg atoms and the principles of quantum sensing of MW E-fields with Rydberg atoms. An overview of this very active research direction is gradually expanding, covering the progress of sensitivity and bandwidth in Rydberg atom-based microwave sensing, superheterodyne quantum sensing with microwave-dressed Rydberg atoms, quantum-enhanced sensing of MW E-field and recent advanced quantum measurement systems and approaches to further improve the performance of MW E-field sensing. Finally, a brief outlook on future development directions is provided.

Generation and Characterization of a Replication-Competent Human Adenovirus Type 55 Encoding EGFP.

Human adenovirus 55 (HAdV-55) has recently caused outbreaks of acute respiratory disease (ARD), posing a significant public threat to civilians and military trainees. Efforts to develop antiviral inhibitors and quantify neutralizing antibodies require an experimental system to rapidly monitor viral infections, which can be achieved through the use of a plasmid that can produce an infectious virus. Here, we used a bacteria-mediated recombination approach to construct a full-length infectious cDNA clone, pAd55-FL, containing the whole genome of HadV-55. Then, the green fluorescent protein expression cassette was assembled into pAd55-FL to replace the E3 region to obtain a recombinant plasmid of pAd55-dE3-EGFP. The rescued recombinant virus rAdv55-dE3-EGFP is genetically stable and replicates similarly to the wild-type virus in cell culture. The virus rAdv55-dE3-EGFP can be used to quantify neutralizing antibody activity in sera samples, producing results in concordance with the cytopathic effect (CPE)-based microneutralization assay. Using an rAdv55-dE3-EGFP infection of A549 cells, we showed that the assay could be used for antiviral screening. Our findings suggest that the rAdv55-dE3-EGFP-based high-throughput assay provides a reliable tool for rapid neutralization testing and antiviral screening for HAdV-55.

A multi-stimulus-responsive bionic fish microrobot for remote intelligent control applications.

In nature, all creatures have their unique characteristics that allow them to adapt to the complex and changeable living environments. In recent years, bionic fish has received increased attention from the research community, and many fish-like microrobots driven by the Marangoni effect have been developed. They are generally characterized by easy operation and rapid driving. However, traditional fish-like microrobots can only be driven by a single stimulus and move on two-dimensional (2D) gas-liquid interfaces, which greatly limits their ability in obstacle avoidance and transportation. In this article, we propose a multi-stimulus-responsive bionic fish microrobot, which is made of temperature-responsive hydrogel poly(N-isopropylacrylamide) (pNIPAM). This microrobot is impregnated with carbon nanotubes (CNTs) and Fe3O4 and therefore has magnetic and photothermal conversion properties. Under the action of optical, magnetic or ethanol molecules, the microrobot can perform complex programmable translational motion on 2D surfaces and controllable rising and sinking, while realizing motion simulation and obstacle avoidance. The microrobot is expected to be used for a wide range of applications in intelligent control systems.