Unmodificated stepless regulation of CRISPR/Cas12a multi-performance.

As CRISPR technology is promoted to more fine-divided molecular biology applications, its inherent performance finds it increasingly difficult to cope with diverse needs in these different fields, and how to more accurately control the performance has become a key issue to develop CRISPR technology to a new stage. Herein, we propose a CRISPR/Cas12a regulation strategy based on the powerful programmability of nucleic acid nanotechnology. Unlike previous difficult and rigid regulation of core components Cas nuclease and crRNA, only a simple switch of different external RNA accessories is required to change the reaction kinetics or thermodynamics, thereby finely and almost steplessly regulating multi-performance of CRISPR/Cas12a including activity, speed, specificity, compatibility, programmability and sensitivity. In particular, the significantly improved specificity is expected to mark advance the accuracy of molecular detection and the safety of gene editing. In addition, this strategy was applied to regulate the delayed activation of Cas12a, overcoming the compatibility problem of the one-pot assay without any physical separation or external stimulation, and demonstrating great potential for fine-grained control of CRISPR. This simple but powerful CRISPR regulation strategy without any component modification has pioneering flexibility and versatility, and will unlock the potential for deeper applications of CRISPR technology in many finely divided fields.

DEAD-box helicase 1 inhibited CD8+ T cell antitumor activity by inducing PD-L1 expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) does not respond well to current treatments, even immune checkpoint inhibitors. PD-L1 (programmed cell death ligand 1 or CD274 molecule)-mediated immune escape of tumor cells may be a key factor affecting the efficacy of immune checkpoint inhibitor (ICI) therapy. However, the regulatory mechanisms of PD-L1 expression and immune escape require further exploration. Here, we observed that DDX1 (DEAD-box helicase 1) was overexpressed in HCC tissues and associated with poor prognosis in patients with HCC. Additionally, DDX1 expression correlated negatively with CD8+ T cell frequency. DDX1 overexpression significantly increased interferon gamma (IFN-γ)-mediated PD-L1 expression in HCC cell lines. DDX1 overexpression decreased IFN-γ and granzyme B production in CD8+ T cells and inhibited CD8+ T cell cytotoxic function in vitro and in vivo. In conclusion, DDX1 plays an essential role in developing the immune escape microenvironment, rendering it a potential predictor of ICI therapy efficacy in HCC.

Large Enhancement of Polarization in a Layered Hybrid Perovskite Ferroelectric Semiconductor via Molecular Engineering.

Switchable spontaneous polarization is the vital property of ferroelectrics, which leads to other key physical properties such as piezoelectricity, pyroelectricity, and nonlinear optical effects, etc. Recently, organic-inorganic hybrid perovskites with 2D layered structure have become an emerging branch of ferroelectric materials. However, most of the 2D hybrid ferroelectrics own relatively low polarizations (<15 µC cm-2 ). Here, a strategy to enhance the polarization of these hybrid perovskites by using ortho-, meta-, para-halogen substitution is developed. Based on (benzylammonium)2 PbCl4 (BZACL), the para-chlorine substituted (4-chlorobenzylammonium)2 PbCl4 (4-CBZACL) ferroelectric semiconductor shows a large spontaneous polarization (23.3 µC cm-2 ), which is 79% larger than the polarization of BZACL. This large enhancement of polarization is successfully explained via ab initio calculations. The study provides a convenient and efficient strategy to promote the ferroelectric property in the hybrid perovskite family.

Halogen-Regulated Tc and X-ray Radiation Detection in 2D Hybrid Perovskite Ferroelastic Semiconductor.

Organic-inorganic hybrid perovskites (OIHPs) have received particular attention due to their characteristic structural tunability and flexibility. These features make OIHPs behave with excellent modifications on macroscopic properties, such as ferroicity or semiconductor performances, etc. Herein, we report two 2D hybrid stibium-based halide perovskite (C3H7N)3Sb2X9 (X = Br, 1; Cl, 2) ferroelastic semiconductor possessing dual switching properties of dielectric and second harmonic generation (SHG). Notably, these two hybrids exhibit halogen-regulated ferroelasticity and semiconductor properties. There is a significant difference in Curie temperature (Tc) and X-ray radiation detection sensitivity (S), i.e., the ΔTc and ΔS are 38 K and 87 µC Gyair-1 cm-2, respectively. Meanwhile, crystals 1 and 2 do not show dark current drift in cyclic measurements of different radiation doses with stable switching ratios of 30 and 10, separately. Meanwhile, these results were proven by scientific experimental results and density functional theory (DFT) calculations. Our work presents a facile and practical method to regulate macroproperties on the molecular level, providing a new vision to develop hybrid perovskite ferroic-photoelectric materials.

DNA-based molecular classifiers for the profiling of gene expression signatures.

Although gene expression signatures offer tremendous potential in diseases diagnostic and prognostic, but massive gene expression signatures caused challenges for experimental detection and computational analysis in clinical setting. Here, we introduce a universal DNA-based molecular classifier for profiling gene expression signatures and generating immediate diagnostic outcomes. The molecular classifier begins with feature transformation, a modular and programmable strategy was used to capture relative relationships of low-concentration RNAs and convert them to general coding inputs. Then, competitive inhibition of the DNA catalytic reaction enables strict weight assignment for different inputs according to their importance, followed by summation, annihilation and reporting to accurately implement the mathematical model of the classifier. We validated the entire workflow by utilizing miRNA expression levels for the diagnosis of hepatocellular carcinoma (HCC) in clinical samples with an accuracy 85.7%. The results demonstrate the molecular classifier provides a universal solution to explore the correlation between gene expression patterns and disease diagnostics, monitoring, and prognosis, and supports personalized healthcare in primary care.

A PAM-free CRISPR/Cas12a ultra-specific activation mode based on toehold-mediated strand displacement and branch migration.

CRISPR (clustered regularly interspaced short palindromic repeats) technology has achieved great breakthroughs in terms of convenience and sensitivity; it is becoming the most promising molecular tool. However, only two CRISPR activation modes (single and double stranded) are available, and they have specificity and universality bottlenecks that limit the application of CRISPR technology in high-precision molecular recognition. Herein, we proposed a novel CRISPR/Cas12a unrestricted activation mode to greatly improve its performance. The new mode totally eliminates the need for a protospacer adjacent motif and accurately activates Cas12a through toehold-mediated strand displacement and branch migration, which is highly universal and ultra-specific. With this mode, we discriminated all mismatch types and detected the EGFR T790M and L858R mutations in very low abundance. Taken together, our activation mode is deeply incorporated with DNA nanotechnology and extensively broadens the application boundaries of CRISPR technology in biomedical and molecular reaction networks.

Molecular Engineering Regulation Achieving Out-of-Plane Polarization in Rare-Earth Hybrid Double Perovskites for Ferroelectrics and Circularly Polarized Luminescence.

Out-of-plane polarization is a highly desired property of two-dimensional (2D) ferroelectrics for application in vertical sandwich-type photoferroelectric devices, especially in ultrathin ferroelectronic devices. Nevertheless, despite great advances that have been made in recent years, out-of-plane polarization remains unrealized in the 2D hybrid double perovskite ferroelectric family. Here, from our previous work 2D hybrid double perovskite HQERN ((S3HQ)4EuRb(NO3)8, S3HQ=S-3-hydroxylquinuclidinium), we designed a molecular strategy of F-substitution on organic component to successfully obtain FQERN ((S3FQ)4EuRb(NO3)8, S3FQ=S-3-fluoroquinuclidinium) showing circularly polarized luminescence (CPL) response. Remarkably, compared to the monopolar axis ferroelectric HQERN, FQERN not only shows multiferroicity with the coexistence of multipolar axis ferroelectricity and ferroelasticity but also realizes out-of-plane ferroelectric polarization and a dramatic enhancement of Curie temperature of 94 K. This is mainly due to the introduction of F-substituted organic cations, which leads to a change in orientation and a reduction in crystal lattice void occupancy. Our study demonstrates that F-substitution is an efficient strategy to realize and optimize ferroelectric functional characteristics, giving more possibility of 2D ferroelectric materials for applications in micro-nano optoelectronic devices.

A Spatially Controlled Proximity Split Tweezer Switch for Enhanced DNA Circuit Construction and Multifunctional Transduction.

DNA strand displacement reactions are vital for constructing intricate nucleic acid circuits, owing to their programmability and predictability. However, the scarcity of effective methods for eliminating circuit leakages has hampered the construction of circuits with increased complexity. Herein, a versatile strategy is developed that relies on a spatially controlled proximity split tweezer (PST) switch to transduce the biomolecular signals into the independent oligonucleotides. Leveraging the double-stranded rigidity of the tweezer works synergistically with the hindering effect of the hairpin lock, effectively minimizing circuit leakage compared with sequence-level methods. In addition, the freely designed output strand is independent of the target binding sequence, allowing the PST switch conformation to be modulated by nucleic acids, small molecules, and proteins, exhibiting remarkable adaptability to a wide range of targets. Using this platform, established logical operations between different types of targets for multifunctional transduction are successfully established. Most importantly, the platform can be directly coupled with DNA catalytic circuits to further enhance transduction performance. The uniqueness of this platform lies in its design straightforwardness, flexibility, scalable intricacy, and system compatibility. These attributes pave a broad path toward nucleic acid-based development of sophisticated transduction networks, making them widely applied in basic science research and biomedical applications.

Crystal Sponge Behavior in a Two-Dimensional Rare-Earth Hybrid Coordinate Polymer.

Stimuli-responsive multifunctional materials (SRMMs) have attracted tremendous attention due to their dynamic responses to external stimuli. However, it remains challenging to simultaneously achieve solvent-induced single-crystal to single-crystal (SCSC) transformation and structural phase transition after desolvation. Here, we report a two-dimensional (2D) rare-earth organic-inorganic hybrid coordinate polymer [(CH3)3NCH2Cl]2[Eu·H2O]2[CH2(SO3)2]4·2H2O (1) that exhibits a reversible SCSC transformation by changing to 2 ([(CH3)3NCH2Cl][Eu·H2O][CH2(SO3)2]2). Impressively, the SCSC transformation process couples with large changes in quantum efficiency dropped from 33.68% of 1 to 20.07% that of 2. Furthermore, polymer 2 shows an isomorphic structural phase transition associated with switching dielectric. Notably, the distance of the 2D layers shows reversible change during the two successive transition processes displaying a crystal sponge behavior. This work reveals the potential of rare-earth 2D hybrid coordination polymers in the design of multifunctional responsive materials and opens a new prospect to explore the construction of novel SRMMs.

Orthogonal Trichromatic Upconversion with High Color Purity in Core-Shell Nanoparticles for a Full-Color Display.

Materials with tunable emission colors has attracted increasing interest in both fundamental research and applications. As a key member of light-emitting materials family, lanthanide doped upconversion nanoparticles (UCNPs) have been intensively demonstrated to emit light in any color upon near-infrared excitation. However, realizing the trichromatic emission in UCNPs with a fixed composition remains a great challenge. Here, without excitation pulsed modulation and three different near-infrared pumping, we report an experimental design to fine-control emission in the full color gamut from core-shell-structured UCNPs by manipulating the energy migration through dual-channel pump scheme. We also demonstrate their potential application in full-color display. These findings may benefit the future development of convenient and versatile optical methos for multicolor tuning and open up the possibility of constructing full-color volumetric display systems with high spatiotemporal resolution.