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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.
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Sistemas CRISPR-Cas , Edición Génica , Sistemas CRISPR-Cas/genética , Endonucleasas/genética , ARN/genética , ARN Guía de Sistemas CRISPR-CasRESUMEN
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.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/metabolismo , Linfocitos T CD8-positivos , ARN Helicasas DEAD-box/metabolismo , Interferón gamma/metabolismo , Neoplasias Hepáticas/metabolismo , Microambiente TumoralRESUMEN
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.
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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.
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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.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Transcriptoma , Perfilación de la Expresión Génica , Neoplasias Hepáticas/genética , ADN , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
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.
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Sistemas CRISPR-Cas , Neoplasias Pulmonares , Humanos , Receptores ErbB/genética , Neoplasias Pulmonares/genética , MutaciónRESUMEN
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 94â 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.
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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.
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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.
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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.
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BACKGROUND: Laparoscopic anatomic mesohepatectomy for patients with hepatocellular carcinoma (HCC) remains technically challenging, especially for those with a massive tumor larger than 10 cm. METHODS: In this study, a 65-year-old man with a 13 × 10-cm2 solitary liver tumor located at segments 4, 5, and 8 underwent laparoscopic mesohepatectomy. To reduce the possibility of releasing cancer cells from the primary tumor, the in situ resection strategy for tumor removal was implemented. The intrafascial approach was used to dissect the right Glissonean pedicle, to transect the right anterior hepatic artery, and to ligate the right anterior portal vein. The extrafascial and transfissural approach was performed along the umbilical fissure to transect the Glissonean pedicle of segment 4. Indocyanine green (ICG) then was applied using "reverse staining" to visualize the resection extent and the right posterior hepatic duct (RPHD). During parenchymal resection, the right anterior Glissonean pedicle was adequately exposed and transected via the extrafascial approach above the plane of the RPHD. Finally, the right coronary ligament was dissected, and the tumor was removed. RESULTS: The operation was completed in 360 min, with a blood loss of 200 mL. The histopathologic diagnosis indicated a moderately differentiated HCC. The patient was discharged on postoperative day 8 without any complications. CONCLUSION: Laparoscopic in situ anatomic mesohepatectomy using combined intra- and extrafascial approaches with ICG navigation may be feasible for patients with a centrally located solitary massive HCC.
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Carcinoma Hepatocelular , Laparoscopía , Neoplasias Hepáticas , Anciano , Carcinoma Hepatocelular/cirugía , Hepatectomía , Humanos , Verde de Indocianina , Neoplasias Hepáticas/cirugía , MasculinoRESUMEN
An integrated digital magnetic resonance imaging spectrometer was proposed in this study. By using the FPGA chip Artix7 200T, timing control, data processing, digital frequency conversion and phase control were implemented into a single-chip, thus effectively improved timing accuracy and phase accuracy, while avoided the structural design complexity caused by multi-board connection and improved system integration and imaging quality.
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Imagen por Resonancia Magnética , Diseño de EquipoRESUMEN
BACKGROUND: Brood pollination mutualism is a special type of plant-pollinator interaction in which adult insects pollinate plants, and the plants provide breeding sites for the insects as a reward. To manifest such a mutualism between Stellera chamaejasme and flower thrips of Frankliniella intonsa, the study tested the mutualistic association of the thrips life cycle with the plant flowering phenology and determined the pollination effectiveness of adult thrips and their relative contribution to the host's fitness by experimental pollinator manipulation. RESULTS: The adult thrips of F. intonsa, along with some long-tongue Lepidoptera, could serve as efficient pollinators of the host S. chamaejasme. The thrips preferentially foraged half-flowering inflorescences of the plants and oviposited in floral tubes. The floral longevity was 11.8 ± 0.55 (mean ± se) days, which might precisely accommodate the thrips life cycle from spawning to prepupation. The exclusion of adult thrips from foraging flowers led to a significant decrease in the fitness (i.e., seed set) of host plants, with a corresponding reduction in thrips fecundity (i.e., larva no.) in the flowers. CONCLUSIONS: The thrips of F. intonsa and the host S. chamaejasme mutualistically interact to contribute to each other's fitness such that the thrips pollinate host plants and, as a reward, the plants provide the insects with brooding sites and food, indicating the coevolution of the thrips life cycle and the reproductive traits (e.g., floral longevity and morphology) of S. chamaejasme.
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Flores/fisiología , Polinización/fisiología , Thymelaeaceae/fisiología , Thysanoptera/fisiología , Animales , Larva , SimbiosisRESUMEN
OBJECTIVES: To evaluate the clinical impact and technical feasibility of augmented reality laparoscopic navigation (ARLN) system in laparoscopic splenectomy for massive splenomegaly. METHODS: The clinical data of 17 consecutive patients who underwent laparoscopic splenectomy using ARLN (ARLN group) and 26 patients without ARLN guidance (Non-ARLN group) between January 2018 and April 2020 were enrolled. Propensity score matching (PSM) analysis was performed between the patients with and without ARLN guidance at a ratio of 1:1. RESULTS: Mean intraoperative blood loss was significantly lower in the ARLN-group than in the Non-ARLN group (306.6 ml vs. 462.6 ml, p = 0.047). All the patients in the ARLN-group achieved successful splenic artery dissection, while surgical success was achieved in 12 patients in the Non-ARLN group (p = 0.044). Postoperative hospital stay was significantly longer in the Non-ARLN group (3.8 days vs. 4.5 days, p = 0.040). CONCLUSIONS: ARLN can provide feasible and accurate intraoperative image guidance, and it could be helpful in the performance of laparoscopic splenectomy for massive splenomegaly.
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Realidad Aumentada , Laparoscopía , Humanos , Estudios Retrospectivos , Esplenectomía , Esplenomegalia/cirugía , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of this study was to present a novel bile-duct obstructed area imaging (BOAI) and to investigate the feasibility and accuracy of this method in guiding hepatectomy for intrahepatic cholangiocarcinoma (ICC) with intrahepatic biliary obstruction. METHODS: From May 2017 to October 2019, eligible patients who underwent hepatectomy guided by BOAI were enrolled. Perioperative outcomes and operative data were analyzed. To assess the feasibility of BOAI and Glissonean pedicle approach, demarcations based on them were compared. To verify the accuracy of BOAI staining of the target territory, simple linear regression analysis, and intraclass correlation coefficient were used to examine the relationship between predicted resected liver volume (PRLV) and actual resected liver volume (ARLV). RESULTS: BOAI staining achieved valid demarcation in 15 (93.8%) of 16 patients, whereas the ischemic line achieved valid demarcation in only nine patients (57.3%; p = .017). ARLV and PRLV had a strong positive correlation (PRLV = 60.06 + 0.925 × ARLV; R = .945; p = .000). Meanwhile, ARLV (intraclass correlation coefficient = .971) achieved an excellent agreement with PRLV (p < .001). CONCLUSIONS: The novel BOAI staining method can provide valid, feasible, and accurate demarcation line and may be an effective method in the surgical treatment of intrahepatic biliary obstruction.
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Neoplasias de los Conductos Biliares/cirugía , Colangiocarcinoma/cirugía , Colestasis/cirugía , Colorantes/química , Diagnóstico por Imagen/métodos , Hepatectomía/métodos , Cirugía Asistida por Computador/métodos , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/diagnóstico por imagen , Colangiocarcinoma/patología , Colestasis/diagnóstico por imagen , Colestasis/patología , Estudios de Factibilidad , Femenino , Fluorescencia , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Two new phenylpropanoids, ainsbons A and B (1 and 2), along with a known analogue coniferyl diisovalerate (3) were isolated from the whole plant of Ainsliaea bonatii. Their structures were elucidated by analysis of NMR spectroscopic data and HRESIMS, and the absolute configuration of 2 was established by the optical rotation calculations. Compounds 1-3 were evaluated for their effects on LPS-induced nitric oxide production, and 1 and 3 showed inhibitory activities with IC50 values of 43.43 and 7.57 µM, respectively.
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Drosophila melanogaster crystal cells are a specialized type of blood cells for innate immune process upon injury. Under normal conditions, crystal cells rarely proliferate and constitute a small proportion of fly blood cells. Notch signaling has been known to guide the cell fate determination of crystal cells and maintain their survival. Here, we reported that protein phosphatase V (PpV), the unique catalytic subunit of protein phosphatase 6 in Drosophila, is a novel regulator of crystal cell proliferation and integrity. We found that PpV proteins highly accumulated in crystal cells in the larval hematopoietic organ termed the lymph gland. Silencing PpV using RNA interference led to increased crystal cell proliferation in a Notch-independent manner and induced crystal cell rupture dependent on Notch signaling. Moreover, additive PpV prevented the rupture of crystal cells in lymph glands upon a needle injury, suggesting the involvement of PpV in wound healing. Altogether, our results indicated that PpV plays a dual role in lymph glands, preventing crystal cell proliferation to limit the cell number, as well as inhibiting crystal cell rupture to maintain their survival.
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Bioleaching has gained significant attention as a cost-effective and environmentally friendly approach for extracting metals from low-grade ores and industrial byproducts. The application of acidophiles in bioleaching has been extensively studied. Among the various mechanisms leaching microorganisms utilize, quorum sensing (QS) is pivotal in regulating their life activities in response to population density. QS has been confirmed to regulate bioleaching, including cell morphology, community structure, biofilm formation, and cell metabolism. Potential applications of QS have also been proposed, such as increasing mineral leaching rates by adding signaling molecules. This review is helpful for comprehensively understanding the role of QS in bioleaching and promoting the practical application of QS-based strategies in bioleaching process optimization.
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AIM: To identify latent profiles of narrative competence in nursing students and examine the association between the potential competence profiles and professional identity from a person-centred perspective. BACKGROUND: According to the Ring theory of personhood, nursing students can develop their professional identities from individual, relational and social aspects through interaction with patients, as well as listening to, understanding and responding to patients' disease narratives. However, few studies have examined the relationship between narrative competence and professional identity through the quantitative method. DESIGN: A cross-sectional analytic study. METHODS: A total of 472 nursing students responded to the survey between March and May 2023. The Professional Identity Questionnaire for Nurse Students and the Narrative Competence Scale were given to participants. Latent profile analysis was conducted to identify narrative competence profiles. The Bolck-Croon-Hagenaars method was used to analyse whether these latent profiles for narrative competence affected nursing students' general, individual, interpersonal and social professional identities. RESULTS: Latent profiles were identified as "low narrative competence" (12.1â¯%), "relatively low narrative competence" (39.9â¯%), "moderate narrative competence" (40.1â¯%) and "high narrative competence" (7.9â¯%). The profiles only show level differences rather than combinations of competence areas. These profiles had varying effects on the nursing students' general professional identities, as well as their individual, relational and social professional identities. CONCLUSION: This study highlights the significance of providing tailored guidance and support to nursing students, taking into account their unique narrative competency profile, to promote the formation of professional identity from individual, relational and social aspects. Nursing educators should effectively distinguish nursing students with inadequate narrative competence and value patients' disease narratives to promote narrative competence and professional identity.
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BACKGROUND: The emergence of DNA nanotechnology has enabled the systematic design of diverse bionic dissipative behaviors under the precise control of nucleic acid nanodevices. Nevertheless, when compared to the dissipation observed in robust living systems, it is highly desirable to enhance the anti-interference for artificial DNA dissipation to withstand perturbations and facilitate repairs within the complex biological environments. RESULTS: In this study, we introduce strategically designed "trash cans" to facilitate kinetic control over interferences, transforming the stochastic binding of individual components within a homogeneous solution into a competitive binding process. This approach effectively eliminates incorrect binding and the accumulation of systemic interferences while ensuring a consistent pattern of energy fluctuation from response to silence. Remarkably, even in the presence of numerous interferences differing by only one base, we successfully achieve complete system reset through multiple cycles, effectively restoring the energy level to a minimum. SIGNIFICANCE: The system was able to operate stably without any adverse effect under conditions of irregular interference, high-abundance interference, and even multiplex interferences including DNA and RNA crosstalk. This work not only provides an effective paradigm for constructing robust DNA dissipation systems but also greatly broadens the potential of DNA dissipation for applications in high-precision molecular recognition and complex biological reaction networks.