Epitope prime editing shields hematopoietic cells from CD123 immunotherapy for acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant cancer characterized by abnormal differentiation of hematopoietic stem and progenitor cells (HSPCs). While chimeric antigen receptor T (CAR-T) cell immunotherapies target AML cells, they often induce severe on-target/off-tumor toxicity by attacking normal cells expressing the same antigen. Here, we used base editors (BEs) and a prime editor (PE) to modify the epitope of CD123 on HSPCs, protecting healthy cells from CAR-T-induced cytotoxicity while maintaining their normal function. Although BE effectively edits epitopes, complex bystander products are a concern. To enhance precision, we optimized prime editing, increasing the editing efficiency from 5.9% to 78.9% in HSPCs. Epitope-modified cells were resistant to CAR-T lysis while retaining normal differentiation and function. Furthermore, BE- or PE-edited HSPCs infused into humanized mice endowed myeloid lineages with selective resistance to CAR-T immunotherapy, demonstrating a proof-of-concept strategy for treating relapsed AML.

Rapid generation of long, chemically modified pegRNAs for prime editing.

The editing efficiencies of prime editing (PE) using ribonucleoprotein (RNP) and RNA delivery are not optimal due to the challenges in solid-phase synthesis of long PE guide RNA (pegRNA) (>125 nt). Here, we develop an efficient, rapid and cost-effective method for generating chemically modified pegRNA (125-145 nt) and engineered pegRNA (epegRNA) (170-190 nt). We use an optimized splint ligation approach and achieve approximately 90% production efficiency for these RNAs, referred to as L-pegRNA and L-epegRNA. L-epegRNA demonstrates enhanced editing efficiencies across various cell lines and human primary cells with improvements of up to more than tenfold when using RNP delivery and several hundredfold with RNA delivery of PE, compared to epegRNA produced by in vitro transcription. L-epegRNA-mediated RNP delivery also outperforms plasmid-encoded PE in most comparisons. Our study provides a solution to obtaining high-quality pegRNA and epegRNA with desired chemical modifications, paving the way for the use of PE in therapeutics and various other fields.

Spiral-concave Prussian Blue Crystals with Rich Steps: Growth Mechanism and Coordination Regulation.

Investigating the formation and transformation mechanisms of spiral-concave crystals holds significant potential for advancing innovative material design and comprehension. We examined the kinetics-controlled nucleation and growth mechanisms of Prussian Blue crystals with spiral concave structures, and constructed a detailed crystal growth phase diagram. The spiral-concave hexacyanoferrate (SC-HCF) crystals, characterized by high-density surface steps and a low stress-strain architecture, exhibit enhanced activity due to their facile interaction with reactants. Notably, the coordination environment of SC-HCF can be precisely modulated by the introduction of diverse metals. Utilizing X-ray absorption fine structure spectroscopy and in-situ ultraviolet-visible spectroscopy, we elucidated the formation mechanism of SC-HCF to Co-HCF facilitated by oriented adsorption-ion exchange (OA-IE) process. Both experimental data, and density functional theory confirm that Co-HCF possesses an optimized energy band structure, capable of adjusting the local electronic environment and enhancing the performance of the oxygen evolution reaction. This work not only elucidates the formation mechanism and coordination regulation for rich steps HCF, but also offers a novel perspective for constructing nanocrystals with intricate spiral-concave structures.

Convergent evolution toward a slow pace of life predisposes insular endotherms to anthropogenic extinctions.

Island vertebrates have evolved a number of morphological, physiological, and life history characteristics that set them apart from their mainland relatives. However, to date, the evolution of metabolism and its impact on the vulnerability to extinction of insular vertebrates remains poorly understood. This study used metabolic data from 2813 species of tetrapod vertebrates, including 695 ectothermic and 2118 endothermic species, to reveal that island mammals and birds evolved convergent metabolic strategies toward a slow pace of life. Insularity was associated with shifts toward slower metabolic rates and greater generation lengths in endotherms, while insularity just drove the evolution of longer generation lengths in ectotherms. Notably, a slow pace of life has exacerbated the extinction of insular endemic species in the face of anthropogenic threats. These findings have important implications for understanding physiological adaptations associated with the island syndrome and formulating conservation strategies across taxonomic groups with different metabolic modes.

High-Performance Organic-Inorganic Hybrid Conductive Hydrogels for Stretchable Elastic All-Hydrogel Supercapacitors and Flexible Self-Powered Integrated Systems.

Conductive polymer hydrogels exhibit unique electrical, electrochemical, and mechanical properties, making them highly competitive electrode materials for stretchable high-capacity energy storage devices for cutting-edge wearable electronics. However, it remains extremely challenging to simultaneously achieve large mechanical stretchability, high electrical conductivity, and excellent electrochemical properties in conductive polymer hydrogels because introducing soft insulating networks for improving stretchability inevitably deteriorates the connectivity of rigid conductive domain and decreases the conductivity and electrochemical activity. This work proposes a distinct confinement self-assembly and multiple crosslinking strategy to develop a new type of organic-inorganic hybrid conductive hydrogels with biphase interpenetrating cross-linked networks. The hydrogels simultaneously exhibit high conductivity (2000 S m-1), large stretchability (200%), and high electrochemical activity, outperforming existing conductive hydrogels. The inherent mechanisms for the unparalleled comprehensive performances are thoroughly investigated. Elastic all-hydrogel supercapacitors are prepared based on the hydrogels, showing high specific capacitance (212.5 mF cm-2), excellent energy density (18.89 µWh cm-2), and large deformability. Moreover, flexible self-powered luminescent integrated systems are constructed based on the supercapacitors, which can spontaneously shine anytime and anywhere without extra power. This work provides new insights and feasible avenues for developing high-performance stretchable electrode materials and energy storage devices for wearable electronics.

Advanced Strategies for Strengthening the Immune Activation Effect of Traditional Antitumor Therapies.

The utilization of traditional therapies (TTS), such as chemotherapy, reactive oxygen species-based therapy, and thermotherapy, to induce immunogenic cell death (ICD) in tumor cells has emerged as a promising strategy for the activation of the antitumor immune response. However, the limited effectiveness of most TTS in inducing the ICD effect of tumors hinders their applications in combination with immunotherapy. To address this challenge, various intelligent strategies have been proposed to strengthen the immune activation effect of these TTS, and then achieve synergistic antitumor efficacy with immunotherapy. These strategies primarily focus on augmenting the tumor ICD effect or facilitating the antigen (released by the ICD tumor cells) presentation process during TTS, and they are systematically summarized in this review. Finally, the existing bottlenecks and prospects of TTS in the application of tumor immune regulation are also discussed.

Amplification editing enables efficient and precise duplication of DNA from short sequence to megabase and chromosomal scale.

Duplication is a foundation of molecular evolution and a driver of genomic and complex diseases. Here, we develop a genome editing tool named Amplification Editing (AE) that enables programmable DNA duplication with precision at chromosomal scale. AE can duplicate human genomes ranging from 20 bp to 100 Mb, a size comparable to human chromosomes. AE exhibits activity across various cell types, encompassing diploid, haploid, and primary cells. AE exhibited up to 73.0% efficiency for 1 Mb and 3.4% for 100 Mb duplications, respectively. Whole-genome sequencing and deep sequencing of the junctions of edited sequences confirm the precision of duplication. AE can create chromosomal microduplications within disease-relevant regions in embryonic stem cells, indicating its potential for generating cellular and animal models. AE is a precise and efficient tool for chromosomal engineering and DNA duplication, broadening the landscape of precision genome editing from an individual genetic locus to the chromosomal scale.

Influence of Chloride Concentration on Fretting Wear Behavior of Inconel 600 Alloy.

The nickel-based alloy Inconel 600, strengthened by solution treatment, finds extensive application as a heat exchange pipe material in steam generators within nuclear power plants, owing to its exceptional resistance to high-temperature corrosion. However, fretting corrosion occurs at the contact points between the pipe and support frame due to gas-liquid flow, leading to wear damage. This study investigates the fretting wear behavior and damage mechanism of the nickel-based alloy Inconel 600 and 304 stainless steel friction pairs under point contact conditions in a water environment. Characterization was performed using laser confocal scanning microscopy and scanning electron microscopy equipped with energy-dispersive spectroscopy. Results indicate that the friction coefficient remains consistent across different chloride ion concentrations, while the wear volume increases with increasing chloride concentrations. Notably, friction coefficient oscillations are observed in the gross slip regime (GSR). Moreover, the stability of the oxide layer formed in water is compromised, diminishing its protective effect against wear. In the partial slip regime (PSR), friction coefficient oscillations are absent. An oxide layer forms within the wear scar, with significantly fewer cracks compared to those within the oxide layer in the GSR. It is worth noting that in GSR, the friction coefficient oscillates.

Direct ink writing 3D printing of low-dimensional nanomaterials for micro-supercapacitors.

Micro-supercapacitors (MSCs) have attracted significant attention for potential applications in miniaturized electronics due to their high power density, rapid charge/discharge rates, and extended lifespan. Despite the unique properties of low-dimensional nanomaterials, which hold tremendous potential for revolutionary applications, effectively integrating these attributes into MSCs presents several challenges. 3D printing is rapidly emerging as a key player in the fabrication of advanced energy storage devices. Its ability to design, prototype, and produce functional devices incorporating low-dimensional nanomaterials positions it as an influential technology. In this review, we delve into recent advancements and innovations in micro-supercapacitor manufacturing, with a specific focus on the incorporation of low-dimensional nanomaterials using direct ink writing (DIW) 3D printing techniques. We highlight the distinct advantages offered by low-dimensional nanomaterials, from quantum effects in 0D nanoparticles that result in high capacitance values to rapid electron and ion transport in 1D nanowires, as well as the extensive surface area and mechanical flexibility of 2D nanosheets. Additionally, we address the challenges encountered during the fabrication process, such as material viscosity, printing resolution, and seamless integration of active materials with current collectors. This review highlights the remarkable progress in the energy storage sector, demonstrating how the synergistic use of low-dimensional nanomaterials and 3D printing technologies not only overcomes existing limitations but also opens new avenues for the development and production of advanced micro-supercapacitors. The convergence of low-dimensional nanomaterials and DIW 3D printing heralds the advent of the next generation of energy storage devices, making a significant contribution to the field and laying the groundwork for future innovations.

Bacmethy: A novel and convenient tool for investigating bacterial DNA methylation pattern and their transcriptional regulation effects.

DNA methylation serves as the primary mode of epigenetic regulation in prokaryotes, particularly through transcriptional regulation. With the rapid implementation of third-generation sequencing technology, we are currently experiencing a golden age of bacterial epigenomics. However, there has been a lack of comprehensive research exploring the versatility and consequential impact of bacterial DNA methylome on cellular and physiological functions. There is a critical need for a user-friendly bioinformatics tool that can effectively characterize DNA methylation modification features and predict the regulation patterns. To address this gap, the current study introduces Bacmethy, an innovative tool that utilizes SMRT-seq data and offers a range of analytical modules. First, the tool classifies methylation sites in the genome, highlighting the distinct regulations present under varying modification fractions and location enrichment. Furthermore, this tool enables us to identify regulatory region methylation and potential cis and trans interactions between methylation sites and regulatory effectors. Using benchmark data sets and our data, we show that our tool facilitates the understanding of the distinctive traits of DNA methylation modifications and predicts transcriptional regulation effects on important physiological and pathological functions. Bacmethy code is freely available, and the Docker image is downloadable. Bacmethy has been made available as a user-friendly web server interface at https://bacmethy.med.sustech.edu.cn.

Minimizing the ratio of ionizable lipid in lipid nanoparticles for in vivo base editing.

Lipid nanoparticles (LNPs) have gained clinical approval as carriers for both siRNA and mRNA. Among the crucial components of LNPs, ionizable lipids play a pivotal role in determining the efficiency of RNA delivery. In this study, we synthesized a series of ionizable lipids, denoted as HTO, with a higher count of hydroxyl groups compared to SM-102. Remarkably, LNPs based on HTO12 lipid demonstrated comparable mRNA delivery efficiency and biosafety to those based on SM-102. However, the former reduced the ratio of ionizable lipid/total lipids to mRNA in LNPs by 2.5 times compared to SM-102. The HTO12 LNP efficiently encapsulated adenine base editor mRNA and sgRNA targeting Pcsk9, leading to substantial gene editing within the liver of mice and effective reduction of the target protein. Our study underscores that ionizable lipids with multiple hydroxyl groups may facilitate an improved lipid-to-mRNA ratio to minimize the dosage of ionizable lipids for in vivo delivery.

Surface Reconstruction for Selective Oxidation of Tetrahydroisoquinoline.

Integration of hydrogen evolution with the oxidation of organic substances in one electrochemical system is highly desirable. However, achieving selective oxidation of organic substances in the integrated system is still highly challenging. In this study, a phosphorylated NiMoO4 nanoneedle-like array was designed as the catalytic active electrode for the integration of highly selective electrochemical dehydrogenation of tetrahydroisoquinolines (THIQs) with hydrogen production. The leaching of anions, including MoO42- and PO43-, facilitates the reconstruction of the catalyst. As a result, nickel oxyhydroxides with the doping of PO43- and richness of defects are in situ formed. In situ Raman and density functional theory calculations have shown that the high catalytic activity is attributed to the in situ formed PO43- involved NiOOH substance. In the dehydrogenation process, the involved C-H bond but not the N-H bond is first destroyed. A two-electrode system was then fabricated with the optimized electrode that shows a benchmark current density of 10 mA cm-2 at 1.783 V, providing a yield of 70% for dihydroisoquinolines. A robust stability was also shown for this integrated electrochemical system. The understanding of the reconstruction behavior and the achievement of selective dehydrogenation will provide some hints for electrochemical synthesis.

3D Printed MXene-Based Wire Strain Sensors with Enhanced Sensitivity and Anisotropy.

Stretchable strain sensors play a crucial role in intelligent wearable systems, serving as the interface between humans and environment by translating mechanical strains into electrical signals. Traditional fiber strain sensors with intrinsic uniform axial strain distribution face challenges in achieving high sensitivity and anisotropy. Moreover, existing micro/nano-structure designs often compromise stretchability and durability. To address these challenges, a novel approach of using 3D printing to fabricate MXene-based flexible sensors with tunable micro and macrostructures.  Poly(tetrafluoroethylene) (PTFE) as a pore-inducing agent is added into 3D printable inks to achieve controllable microstructural modifications. In addition to microstructure tuning, 3D printing is employed for macrostructural design modifications, guided by finite element modeling (FEM) simulations. As a result, the 3D printed sensors exhibit heightened sensitivity and anisotropy, making them suitable for tracking static and dynamic displacement changes. The proposed approach presents an efficient and economically viable solution for standardized large-scale production of advanced wire strain sensors.

Recent progress in the study of integrated solar cell-energy storage systems.

As fossil fuels continue to deplete, the development of sustainable and green energy sources has become crucial for human societal advancement. Among the various renewable energies, solar energy stands out as a promising substitute for conventional fossil fuels, offering widespread availability and a pollution-free solution. Solar cells, as devices that convert solar energy, are garnering significant focus. However, the intermittent nature of solar energy results in a high dependence on weather conditions of solar cells. Integrated solar cell-energy storage systems that integrate solar cells and energy storage devices may solve this problem by storing the generated electricity and managing the energy output. This review delves into the latest developments in integrated solar cell-energy storage systems, marrying various solar cells with either supercapacitors or batteries. It highlights their construction, material composition, and performance. Additionally, it discusses prevailing challenges and future possibilities, aiming to spark continued advancement and innovation in the sector.

Highly Ordered Gyroid Nanostructured Polymers: Facile Fabrication by Polymerizable Pluronic Surfactants.

Highly ordered, network-nanostructured polymers offer compelling geometric features and application potential. However, their practical utilization is hampered by the restricted accessibility. Here, we address this challenge using commercial Pluronic surfactants with a straightforward modification of tethering polymerizable groups. By leveraging lyotropic self-assembly, we achieve facile production of double-gyroid mesophases, which are subsequently solidified via photoinduced cross-linking. The exceptionally ordered periodicities of Ia3d symmetry in the photocured polymers are unambiguously confirmed by synchrotron small-angle X-ray scattering (SAXS), which can capture single-crystal-like diffraction patterns. Electron density maps reconstructed from SAXS data complemented by transmission electron microscopy analysis further elucidate the real-space gyroid assemblies. Intriguingly, by tuning the cross-linking through thiol-acrylate chemistry, the mechanical properties of the polymer are modulated without compromising the integrity of Ia3d assemblies. The 3-D percolating gyroid nanochannels demonstrate an ionic conductivity that surpasses that of disordered structures, offering promising prospects for scalable fabrication.

A High Efficiency, Low Resistance Antibacterial Filter Formed by Dopamine-Mediated In Situ Deposition of Silver onto Glass Fibers.

The coating of filter media with silver is typically achieved by chemical deposition and aerosol processes. Whilst useful, such approaches struggle to provide uniform coating and are prone to blockage. To address these issues, an in situ method for coating glass fibers is presented via the dopamine-mediated electroless metallization method, yielding filters with low air resistance and excellent antibacterial performance. It is found that the filtration efficiency of the filters is between 94 and 97% and much higher than that of silver-coated filters produced using conventional dipping methods (85%). Additionally, measured pressure drops ranged between 100 and 150 Pa, which are lower than those associated with dipped filters (171.1 Pa). Survival rates of Escherichia coli and Bacillus subtilis bacteria exposed to the filters decreased to 0 and 15.7%±1.49, respectively after 2 h, with no bacteria surviving after 6 h. In contrast, survival rates of E. coli and B. subtilis bacteria on the uncoated filters are 92.5% and 89.5% after 6 h. Taken together, these results confirm that the in situ deposition of silver onto fiber surfaces effectively reduces pore clogging, yielding low air resistance filters that can be applied for microbial filtration and inhibition in a range of environments.

STMP and PVPA as Templating Analogs of Noncollagenous Proteins Induce Intrafibrillar Mineralization of Type I Collagen via PCCP Process.

The phosphorylated noncollagenous proteins (NCPs) play a vital role in manipulating biomineralization, while the mechanism of phosphorylation of NCPs in intrafibrillar mineralization of collagen fibril has not been completely deciphered. Poly(vinylphosphonic acid) (PVPA) and sodium trimetaphosphate (STMP) as templating analogs of NCPs induce hierarchical mineralization in cooperation with indispensable sequestration analogs such as polyacrylic acid (PAA) via polymer-induced liquid-like precursor (PILP) process. Herein, STMP-Ca and PVPA-Ca complexes are proposed to achieve rapid intrafibrillar mineralization through polyelectrolyte-Ca complexes pre-precursor (PCCP) process. This strategy is further verified effectively for remineralization of demineralized dentin matrix both in vitro and in vivo. Although STMP micromolecule fails to stabilize amorphous calcium phosphate (ACP) precursor, STMP-Ca complexes facilely permeate into intrafibrillar interstices and trigger phase transition of ACP to hydroxyapatite within collagen. In contrast, PVPA-stabilized ACP precursors lack liquid-like characteristic and crystallize outside collagen due to rigid conformation of PVPA macromolecule, while PVPA-Ca complexes infiltrate into partial intrafibrillar intervals under electrostatic attraction and osmotic pressure as evidenced by intuitionistic 3D stochastic optical reconstruction microscopy (3D-STORM). The study not only extends the variety and size range of polyelectrolyte for PCCP process but also sheds light on the role of phosphorylation for NCPs in biomineralization.

Three-Dimensional Printing of Hydrogels for Flexible Sensors: A Review.

The remarkable flexibility and heightened sensitivity of flexible sensors have drawn significant attention, setting them apart from traditional sensor technology. Within this domain, hydrogels-3D crosslinked networks of hydrophilic polymers-emerge as a leading material for the new generation of flexible sensors, thanks to their unique material properties. These include structural versatility, which imparts traits like adhesiveness and self-healing capabilities. Traditional templating-based methods fall short of tailor-made applications in crafting flexible sensors. In contrast, 3D printing technology stands out with its superior fabrication precision, cost-effectiveness, and satisfactory production efficiency, making it a more suitable approach than templating-based strategies. This review spotlights the latest hydrogel-based flexible sensors developed through 3D printing. It begins by categorizing hydrogels and outlining various 3D-printing techniques. It then focuses on a range of flexible sensors-including those for strain, pressure, pH, temperature, and biosensors-detailing their fabrication methods and applications. Furthermore, it explores the sensing mechanisms and concludes with an analysis of existing challenges and prospects for future research breakthroughs in this field.

Nanoplatform-based strategies for enhancing the lethality of current antitumor PDT.

Photodynamic therapy (PDT) exhibits great application prospects in future clinical oncology due to its spatiotemporal controllability and good biosafety. However, the antitumor efficacy of PDT is seriously hindered by many factors, including tumor hypoxia, limited light penetration ability, and strong defense mechanisms of tumors. Considering that it is difficult to completely solve the first two problems, enhancing the lethality of antitumor PDT has become a good idea to extend its clinical application. Herein, we summarize the nanoplatform-involved strategies to effectively amplify the tumoricidal capability of current PDT and then discuss the present bottlenecks and prospects of the nanoplatform-based PDT sensitization strategies in tumor therapy. We hope this review will provide some references for others to design high-performance PDT nanoplatforms for tumor therapy.

Ningxin-Tongyu-Zishen formula alleviates the senescence of granulosa cells on D-galactose-induced premature ovarian insufficiency mice.

Ningxin-Tongyu-Zishen formula (NTZF) is a clinical experience formula for the treatment of premature ovarian insufficiency (POI) in traditional Chinese medicine (TCM), and the potential mechanism is unknown. For in vivo experiments, POI mouse models (C57BL/6 mice), were constructed by subcutaneous injection of D-galactose (D-gal, 200 mg/kg). After treatment of NTZF (10.14, 20.27, 40.54 g/kg;) or estradiol valerate (0.15 mg/kg), ovarian function, oxidative stress (OS) and protein expression of Sirt1/p53 were evaluated. For in vitro experiments, H2O2 (200 µM) was used to treat KGN to construct ovarian granulosa cells (OGCs) cell senescence model. Pretreatment with NTZF (1.06 mg/mL) or p53 inhibitor (Pifithrin-α, 1 µM) was performed before induction of senescence, and further evaluated the cell senescence, OS, mRNA and protein expression of Sirt1/p53. In vivo, NTZF improved ovarian function, alleviated OS and Sirt1/p53 signaling abnormalities in POI mice. In vitro experiments showed that NTZF reduced the level of OS and alleviated the senescence of H2O2-induced KGN. In addition, NTZF activated the protein expression of Sirt1, inhibited the mRNA transcription and protein expression of p53 and p21. Alleviating OGCs senescence and protecting ovarian function through Sirt1/p53 is one of the potential mechanisms of NTZF in the treatment of POI.