Vinylene-linked Donor-π-Acceptor Metal-Covalent Organic Framework for Enhanced Photocatalytic CO2 Reduction.

Intramolecular charge separation driving force and linkage chemistry between building blocks are critical factors for enhancing the photocatalytic performance of metal-covalent organic frameworks (MCOF) based photocatalyst. However, robust achieving both simultaneously has yet to be challenging despite ongoing efforts. Here we develop a fully  π-conjugated vinylene-linked multivariate donor-π-acceptor MCOF (D-π-A, termed UJN-1)by integrating integrating benzyl cyanides linker with multiple functional building blocks of electron-rich triphenylamine and electron-deficient copper-cyclic trinuclear units (Cu-CTUs) moieties, featuring with strong intramolecular charge separation driving force, extended conjugation degree of skeleton, and abundant active sites. The incorporation of Cu-CTUs acceptor with electron-withdrawing ability and concomitantly giant charge separation driving force can efficiently accelerate the photogenerated electrons transfer from triphenylamine to Cu-CTUs, revealing by experiments and theoretical calculations. Benefiting from the synergistically effect of D-π-A configuration and vinylene linkage, the highly-efficient charge spatial separation is achieved. Consequently, UJN-1 exhibits an excellent CO formation rate of 114.8 µmol g-1 in 4 h without any co-catalysts or sacrificial reagents under visible light, outperforming those analogous MCOFs with imine-linked (UJN-2, 28.9 µmol g-1) and vinylene-linked COF without Cu-CTU active sites (UJN-3, 50.0 µmol g-1), emphasizing the role of charge separation driving force and linkage chemistry in designing novel COFs-based photocatalyst.

Tree richness increased biomass carbon sequestration and ecosystem stability of temperate forests in China: Interacted factors and implications.

Biodiversity loss and forest degradation have received increasing attention worldwide, and their effects on forest biomass carbon storage and stability have not yet been well defined. This study examined 1275 tree plots using the field survey method to quantify the effects of tree diversity, tree sizes, and mycorrhizal symbiont abundance on biomass carbon storages (Cs) and NDVI (Normalized Difference Vegetation Index)-based ecosystem stability (standard deviation/mean NDVI = NDVI_S) during the field survey period from 2008 to 2018. Our data showed Cs and NDVI_S averaged at 31-108 t ha-1 and 32.04-49.28, respectively, and positive relations between Cs and NDVI_S were observed (p < 0.05). Large forest-type and regional variations were found in these two parameters. Broadleaf forests had 74% of Cs (p < 0.05) of the conifer forests, but no differences were in NDVI_S. Cold regions at high latitudes had 71% of NDVI_S in the warm regions at low latitudes, while no differences were in Cs. Moist regions at high longitudes had 2.04 and 1.28-fold higher Cs and NDVI_S (p < 0.05). The >700 m a.s.l. regions had 1.24-fold higher Cs (p < 0.01) than the <700 m a.s.l. regions, but similar NDVI_S (p > 0.05). Nature Reserves had 1.94-fold higher Cs but 30% lower NDVI_S than outside Reserves (p < 0.001). > 40-year-old forests had 1.3- and 2-fold higher Cs and NDVI_S than the young forests. Structural equation modeling and hierarchical partitioning revealed the driving paths responsible for these variations. Tree richness was positively associated with Cs and ecosystem stability, contributing 21.6%-30.6% to the total effects on them; tree sizes significantly promoted the Cs, but had negligible impacts on NDVI_S. MAT's total effects on NDVI_S of conifer forests were 40% higher than that of broadleaf forests, MAP's total effects on Cs varied with forest types; arbuscular mycorrhizal tree dominance exhibited a smaller positive impact on Cs and ecosystem stability in comparison to other factors. Our findings underscore that the significance of climatic-adapted forest management, diversity conservation, and big-sized tree protections can support the achievement of carbon neutrality in China from biomass carbon sequestration and ecosystem stability.

Multiwalled Carbon Nanotube-Templated Nickel Porphyrin Covalent Organic Framework for Pencil-Drawn Noninvasive Respiration Sensors.

Paper-integrated configuration with miniaturized functionality represents one of the future main green electronics. In this study, a paper-based respiration sensor was prepared using a multiwalled carbon nanotube-templated nickel porphyrin covalent organic framework (MWCNTs@COFNiP-Ph) as an electrical identification component and pencil-drawn graphite electric circuits as interdigitated electrodes (IDEs). The MWCNTs@COFNiP-Ph not only inherited the high gas sensing performance of porphyrin and the aperture induction effect of COFs but also overcame the shielding effect between phases through the MWCNT template. Furthermore, it possessed highly exposed M-N4 metallic active sites and unique periodic porosity, thereby effectively addressing the key technical issue of room-temperature sensing for the respiration sensor. Meanwhile, the introduction of a pencil-drawing approach on common printing papers facilitates the inexpensive and simple manufacturing of the as-fabricated graphite IDE. Based on the above advantages, the MWCNTs@COFNiP-Ph respiration sensor had the characteristics of wide detection range (1-500 ppm), low detection limit (30 ppb), acceptable flexibility for toluene, and rapid response/recovery time (32 s/116 s). These advancements facilitated the integration of the respiration sensor into surgical masks and clothes with maximum functionality at a minimized size and weight. Moreover, the primary internal mechanism of COFNiP-Ph for this efficient toluene detection was investigated through in situ FTIR spectra, thereby directly elucidating that the chemisorption interaction of oxygen modulated the depletion layers, resulting in alterations in sensor resistance upon exposure to the target gas. The encouraging results revealed the feasibility of employing a paper-sensing system as a wearable platform in green electronics.

Radioactive ADME Demonstrates ARV-110's High Druggability Despite Low Oral Bioavailability.

Proteolysis-targeting chimeras (PROTACs) have emerged as potentially effective therapeutic medicines, but their high molecular weight and poor solubility directly impact their oral bioavailability. This work synthesized 14C-labeled bavdegalutamide (ARV-110) as a model compound of PROTACs to evaluate its ADME features. Compared with targeted antitumor drugs, the use of food increased oral bioavailability of ARV-110 in rats from 10.75% to 20.97%, which is still undesirable. However, the therapeutic effect of ARV-110 at a low dose was much better than that of enzalutamide, demonstrating the specific catalytic medicinal properties of PROTACs. Moreover, the specific distribution of ARV-110 in subcutaneous prostate tumors was determined by quantitative whole-body autoradiography (QWBA). Notably, the specificity and activity of PROTACs take precedence over their oral absorption, and high oral bioavailability is not necessary to produce excellent therapeutic effects. This work presents a roadmap for developing future PROTAC medications from a radioactive drug metabolism and pharmacokinetics (DMPK) perspective.

Ultrasensitive Paper-Based Photoelectrochemical Biosensor for Acetamiprid Detection Enabled by Spin-State Manipulation and Polarity-Switching.

Efficient carrier separation is vitally crucial to improving the detection sensitivity of photoelectrochemical (PEC) biosensors. Here, we developed a facile strategy to efficiently regulate the carrier separation efficiency of the photoactive matrix BiOI and In2S3 signal label functionalized paper chip by manipulation of electrons spin-state and rational design of electron transport pathways. The spin-dependent electronic structures of BiOI and In2S3 were regulated via enhanced electron-spin parallel alignment induced by an external magnetic field, markedly retarding carrier recombination and extending their lifetime. Simultaneously, with the progress of the target-induced catalytic hairpin assembly process, the transfer path of photogenerated carriers was changed, leading to a switch in photocurrent polarity from cathode to anode. This reversed electron transport pathway not only boosted the separation ability of photogenerated electrons but also eliminated false-positive and false-negative signals, thereby further improving the detection sensitivity. As a proof of concept, the well-designed magnetic field-stimulated paper-based PEC biosensor showed highly selectivity and sensitivity for acetamiprid assay with a wide linear range of 1 fM to 20 nM and an ultralow detection limit of 0.73 fM. This work develops a universal strategy for improving the sensitivity of biosensors and exhibits enormous potential in the fields of bioanalysis and clinical diagnosis.

Host-Guest Interaction Mediated Perovskite@Metal-Organic Framework Z-Scheme Heterojunction Enabled Paper-Based Photoelectrochemical Sensing.

Exploring the high-performance photoelectronic properties of perovskite quantum dots (QDs) is desirable for paper-based photoelectrochemical (PEC) sensing;however, challenges remain in improving their stability and fundamental performance. Herein, a novel Z-scheme heterostructure with host-guest interaction by the confinement of CH3NH3PbBr3 QDs within Cu3(BTC)2 metal-organic framework (MOF) crystal (MAPbBr3@Cu3(BTC)2) is successfully constructed on the paper-based PEC device for ultrasensitive detection of Ochratoxin A (OTA), with the assistance of the exciton-plasmon interaction (EPI) effect. The host-guest interaction is estabilished by encapsulating MAPbBr3 QDs as guests within Cu3(BTC)2 MOF as a host, which prevents MAPbBr3 QDs from being damaged in the polar system, offering access to long-term stability with high-performance PEC properties. Benefiting from the precise alignment of energy levels, the photogenerated charge carriers can migrate according to the Z-scheme charge-transfer pathway under the driving force of the internal electric field, achieving a high photoelectric conversion efficiency. Upon OTA recognition, the EPI effect is activated to modulate the exciton response in MAPbBr3 QDs by accelerating radiative decay, finally achieving sensitive OTA sensing with a detection limit of 0.017 pg mL-1. We believe this work renders new insight into designing host-guest Z-scheme heterojunctions in constructing the paper-based PEC sensing platforms for environmental monitoring.

Pulsed Laser-Bleaching Semiconductor and Photodetector.

Pulsed lasers alter the optical properties of semiconductors and affect the photoelectric function of the photodetectors significantly, resulting in transient changes known as bleaching. Bleaching has a profound impact on the control and interference of photodetector applications. Experiments using pump-probe techniques have made significant contributions to understanding ultrafast carrier dynamics. However, there are few theoretical studies to the best of our knowledge. Here, carrier dynamic models for semiconductors and photodetectors are established, respectively, employing the rectified carrier drift-diffusion model. The pulsed laser bleaching effect on seven types of semiconductors and photodetectors from visible to long-wave infrared is demonstrated. Additionally, a continuous bleaching method is provided, and the finite-difference time-domain (FDTD) method is used to solve carrier dynamic theory models. Laser parameters for continuous bleaching of semiconductors and photodetectors are calculated. The proposed bleaching model and achieved laser parameters for continuous bleaching are essential for several applications using semiconductor devices, such as infrared detection, biological imaging, and sensing.

MiR-3571 modulates traumatic brain injury by regulating the PI3K/AKT signaling pathway via Fbxo31.

To investigate the effect of miR-3571 on traumatic brain injury (TBI) via the regulation of neuronal apoptosis through F-box-only protein 31/phosphoinositide 3-kinase/protein kinase B (Fbxo31/PI3K/AKT). We established TBI rat and cell models. Hematoxylin‒eosin (HE) and Nissl staining were used to observe brain injury and the number of Nissl bodies, respectively. Cell proliferation and apoptosis were assessed by 5-ethynyl-2'-deoxyuridine (EdU), terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and flow cytometry. Gene and protein expression was measured via reverse transcription quantitative polymerase chain reaction (RT‒qPCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). In this study, miR-3571 was highly expressed in TBI models. Inhibition of miR-3571 expression can suppress autophagy, reduce the expression of proinflammatory cytokines, and reduce neuronal apoptosis, thus alleviating the pathological conditions of tissue congestion, edema and structural damage after TBI. These experiments demonstrated that miR-3571 could target and regulate the level of Fbxo31. Knockdown of Fbxo31 weakened the remission effect of the miR-3571 inhibitor on TBI and promoted neurological damage; moreover, overexpression of Fbxo31 enhanced the protective effect on neural function, whereas the PI3K/AKT pathway inhibitor LY294002 increased the damage caused by miR-3571 on neural function and weakened the protective effect of Fbxo31. In conclusion, miR-3571 regulates the PI3K/AKT signaling pathway by reducing Fbxo31 expression, promotes neuronal apoptosis and exacerbates TBI.

Forest carbon stocks increase with higher dominance of ectomycorrhizal trees in high latitude forests.

Understanding the mechanisms controlling forest carbon accumulation is crucial for predicting and mitigating future climate change. Yet, it remains unclear whether the dominance of ectomycorrhizal (EcM) trees influences the carbon accumulation of entire forests. In this study, we analyzed forest inventory data from over 4000 forest plots across Northeast China. We find that EcM tree dominance consistently exerts a positive effect on tree, soil, and forest carbon stocks. Moreover, we observe that these positive effects are more pronounced during unfavorable climate conditions, at lower tree species richness, and during early successional stages. This underscores the potential of increasing the dominance of native EcM tree species not only to enhance carbon stocks but also to bolster resilience against climate change in high-latitude forests. Here we show that forest managers can make informed decisions to optimize carbon accumulation by considering various factors such as mycorrhizal types, climate, successional stages, and species richness.

Cu Single-Atom Nanozyme-Mediated Electrochemiluminescence Biosensor for Highly Sensitive Detection of MicroRNA-622.

MicroRNA (miRNA) detection is a critical aspect of disease diagnosis, and recent studies indicate that miRNA-622 could be a potential target for lung cancer. Herein, Cu single atoms were anchored on graphitic carbon nitride (Cu SAs@CN) as a coreaction accelerator applied in luminol-H2O2 system, thereby establishing an efficient and sensitive electrochemiluminescence (ECL) biosensor for miRNA-622 detection. Cu SAs@CN was explored to possess excellent enzyme-like activities that promote the generation of abundant reactive oxygen species, which amplified ECL emission. Meanwhile, in order to improve the accuracy and sensitivity for miRNA-622 detection, the highly specific trans-cleavage ability of CRISPR/Cas12a was combined with a catalytic hairpin assembly strategy. Therefore, an ECL biosensor for miRNA-622 detection was systematically constructed as a proof of concept, achieving an ultralow limit of detection of 1.09 fM, and the feasibility was demonstrated in human serum samples. The findings of this research provide a promising strategy to enhance the ECL response using versatile single-atom catalysts, thus advancing the development of ECL biosensing applications.

Aptamer responsive DNA Functionalized hydrogels electrochemiluminescence biosensor for the detection of adenosine triphosphate.

DNA hydrogel represents a noteworthy biomaterial. The preparation of biosensors by combining DNA hydrogel with electrochemiluminescence can simplify the modification process and raise the experimental efficiency. In this study, an electrochemiluminescence (ECL) biosensor based on DNA hydrogel was fabricated to detect adenosine triphosphate (ATP) simply and quickly. CdTe-Ru@SiO2 nanospheres capable of ECL resonance energy transfer (RET) were synthesized and encapsulated CdTe-Ru@SiO2 in the DNA hydrogel to provide strong and stable ECL signals. DNA hydrogel avoided the labeling of ECL signal molecules. The aptamer of ATP as the linker of the hydrogel for the specificity of ATP detection. The cross-linked structure of the aptamer and the polymer chains was opened by ATP, and then the decomposition of the DNA hydrogel initiated the escape of CdTe-Ru@SiO2 to generate an ECL signal. The designed biosensor detected ATP without too much modification and complex experimental steps on the electrode surface, with good specificity and stability, and a wide linear range. The detection range was 10-5000 nM, and the detection limit was 6.68 nM (S/N = 3). The combination of DNA hydrogel and ECL biosensor provided a new way for clinical detection of ATP and other biomolecule.

Near-infrared light-driven lab-on-paper cathodic photoelectrochemical aptasensing for di(2-ethylhexyl)phthalate based on AgInS2/Cu2O/FeOOH photocathode.

Di(2-ethylhexyl)phthalate (DEHP) is commonly released from plastics in aqueous environment, which can disrupt endocrine system and cause adverse effects on public health. There is a pressing need to highly sensitive detect DEHP. Herein, a near-infrared (NIR) light-driven lab-on-paper cathodic photoelectrochemical aptasensing platform integrated with AgInS2/Cu2O/FeOOH photocathode and "Y"-like ternary conjugated DNA nanostructure-mediated "ON-OFF" catalytic switching of hemin monomer-to-dimer was established for ultrasensitive DEHP detection. Profiting from the collaborative roles of the effective photosensitization of NIR-response AgInS2 and the fast hole extraction of FeOOH, the NIR light-activated AgInS2/Cu2O/FeOOH photocathode generated a markedly enhanced photocathodic signal. The dual hemin-labelled "Y"-like ternary conjugated DNA nanostructures made the hemin monomers separated in space and they maintained highly active to catalyze in situ generation of electron acceptors (O2). The hemin monomers were relocated in close proximity with the help of target-induced allosteric change of DNA nanostructures, which could spontaneously dimerize into catalytically inactive hemin dimers and fail to mediate electron acceptors generation, resulting in a decreased photocathodic signal. Therefore, the ultrasensitive DEHP detection was realized with a linear response range of 1 pM-500 nM and a detection limit of 0.39 pM. This work rendered a promising prototype to construct powerful paper-based photocathodic aptasensing system for sensitive and accurate screening of DEHP in aqueous environment.

Da-yuan-yin decoction alleviates ulcerative colitis by inhibiting complement activation, LPS-TLR4/NF-κB signaling pathway and NET formation.

ETHNOPHARMACOLOGICAL RELEVANCE: Da-yuan-yin decoction (DYY) is a classical traditional Chinese medicine prescription for ulcerative colitis (UC). AIM OF STUDY: This study explored the protective effects and mechanisms of DYY on UC. MATERIALS AND METHODS: The mice were fed 2.5% dextran sulfate sodium (DSS) for 7 days to establish UC. On the second day, DYY (0.4 g/kg, 0.8 g/kg, 1.6 g/kg) was orally administered daily for 7 consecutive days. The colon tissues and serum were measured by histopathological examination and biochemical analysis. RESULTS: DYY significantly reduced the disease activity index (DAI) and severity of colon shortening and alleviated pathological changes in the colon tissue. DYY restored the protein expression of intestinal tight junction (TJ) protein (ZO-1, occludin and claudin-3). DYY remarkably decreased the level of lipopolysaccharide (LPS), Lactic acid (LA), circulating free DNA (cfDNA), complement (C3, C3a, C3c, C3aR1, C5a and C5aR1) and regulated the levels of inflammatory cytokines in serum. DYY significantly inhibited the expressions of nuclear factor kappa-B p65 (NF-κB p65) and Toll-like receptor 4 (TLR4), citrullinated histone H3 (CitH3) and myeloperoxidase (MPO), reactive oxygen species (ROS) peptidylarginine deiminase 4 (PAD4) and CD 11b, the mRNA levels of PADI4, MPO and ELANE in colon tissues. CONCLUSIONS: DYY significantly attenuated DSS-induced UC, which was related with regulating the inflammatory response by the inhibition of complement activation, the LPS-TLR4/NF-κB signaling pathway and neutrophil extracellular traps (NETs) formation. DYY is a potential therapeutic agent for UC.

New insights into the destabilization of fat globules in ultra-instantaneous UHT milk induced by added plasmin: Molecular mechanisms and the effect of membrane structure on plasmin action.

Residual plasmin activity in whole ultra-instantaneous UHT (UI-UHT) milk causes rapid fat rise during storage, seriously affecting consumers' purchase intentions. In this work, the molecular mechanisms underlying fat destabilization in whole UI-UHT milk by added plasmin were investigated based on the hydrolysis behavior of interfacial proteins. By using SDS-PAGE and peptidomic analysis, we found that the hydrolysis of interfacial proteins by plasmin led to a decrease in the amount and coverage of interfacial proteins and an increase in zeta-potential value, causing the flocculation and coalescence of fat globules. Moreover, the hydrolysis pattern varied in different categories of interfacial proteins by plasmin. In total, 125 peptides in all samples were identified. Plasmin tended to hydrolyze most major milk fat globule membrane (MFGM) proteins into protein fragments (>10 kDa) rather than peptides (<10 kDa). In contrast, peptides derived from caseins were more preferentially identified within a relatively short incubation time. It was the co-hydrolysis of caseins and some major MFGM proteins as anchors that destroyed the stability of MFGM. Furthermore, studies on the effect of trilayer membrane structure remaining at the interface on the hydrolysis rate of major MFGM proteins by plasmin revealed that ADPH and BTN were very sensitive to plasmin action, while PAS 7 was very resistant to plasmin action. Overall, membrane structure reduced the susceptibility of some major MFGM proteins to plasmin and provided protective effects. Therefore, this study provided important insights into the hydrolysis behavior of interfacial proteins in whole UI-UHT milk induced by plasmin.

Women's experiences with Centering-Based Group Care in Zhejiang China: A pilot study.

BACKGROUND: The group prenatal care model, which caters to women with low medical needs but high support needs, has become a highly prevalent and innovative approach implemented globally. For Centering-Based Group Care (CBGC) to remain effective, women's evaluations of the quality of care and perspectives about the model are crucial. AIM: This study aimed to describe women's appraisal of CBGC quality and explore the experiences of women in the mixed-methods pilot study conducted in Zhejiang, China. METHODS: From August 2021 to December 2022, 20 women provided complete quantitative data using the Quality of Prenatal Care Questionnaire before hospital discharge. Semi-structured interviews were conducted at 6 months postpartum. Qualitative data were analysed using Colaizzi's method. FINDINGS: The mean (standard deviation) total score (of the 5) of the questionnaire was 4.43 (0.1) with a good quality of CBGC. Qualitative research identified five themes: motivations and concerns for participation, the appeal of interactive learning, the development of community ties and social support, healing from psychological trauma with CBGC, and suggestions for CBGC enhancement. DISCUSSION: Women rated CBGC quality as good and benefited significantly from it in the study. As a new alternative option, the women's accounts suggested that CBGC performed excellently in enhancing knowledge, strengthening social bonds, and providing psychological support. CONCLUSION: CBGC quality cannot be determined based on limited the sample size. This pilot study provides evidence regarding the beneficial effects of knowledge, socialization, and psychological healing on CBGC. Further research is suggested to measure CBGC effectiveness and quality.

A validated LC-MS/MS method for the quantitation of daratumumab in rat serum using rapid tryptic digestion without IgG purification and reduction.

Daratumumab, a humanized monoclonal antibody utilized in treating immunoglobulin light-chain amyloidosis and relapsed/refractory multiple myeloma, was quantified in rat serum through a simple, economical and effective liquid chromatography tandem-mass spectrometry (LC-MS/MS) method. A surrogate peptide, LLIYDASNR, derived from trypsin hydrolysis, was quantitatively analyzed with LLIYDASN [13C6, 15N4] RAT as an internal standard. This corrected variations from sample pretreatment and mass spectrometry response, involving denaturation and trypsin hydrolysis in a two-step process lasting approximately 1 hour. Methodological validation demonstrated a linear range of 1 µg/mL to 1000 µg/mL in rat serum. Precision, accuracy, matrix effect, sensitivity, stability, selectivity, carryover, and interference met acceptance criteria. The validated LC-MS/MS approach was successfully applied to a pharmacokinetic study of daratumumab in rats at an intravenous dose of 15 mg/kg.

Self-standing perylene diimide covalent organic framework membranes for trace TMA sensing at room temperature.

The unprecedented demand for highly selective, real-time monitoring and low-power gas sensors used in food quality control has been driven by the increasing popularity of the Internet of Things (IoT). Herein, the self-standing perylene diimide based covalent organic framework membranes (COFMPDI-THSTZ) were prepared via liquid-liquid interfacial synthesis method. By incorporating the perylene diimide monomer into the COFM through molecular engineering, COFMPDI-THSTZ based sensor demonstrated an outstanding trimethylamine (TMA)-sensing performance at room temperature. Benefited from the TMA-accessible self-standing membrane morphology, π-electron delocalization effect, and extensive surface area with continuous nanochannels, the specific and highly sensitive TMA measurement has been achieved within the range of 0.03-400 ppm, with an exceptional theoretical detection limit as low as 10 ppb. Moreover, the primary internal mechanism of COFMPDI-THSTZ for this efficient TMA detection was investigated through in-situ FT-IR spectra, thereby directly elucidating that the chemisorption interaction of oxygen modulated the depletion layers on sensing material surface, resulting in alterations in sensor resistance upon exposure to the target gas. For practical usage, COFMPDI-THSTZ based sensor exhibited exceptional real-time in-situ sensing capabilities, further confirmed their potential for application in dynamic prediction evaluation of marine fish products and quality monitoring in IoT.

Z-Scheme Heterojunction Excited by DNA-Programmed Upconversion Nanotransducers for a Near-Infrared Light-Actuated Lab-on-Paper Device.

Herein, a flexible near-infrared (NIR) light-actuated photoelectrochemical (PEC) lab-on-paper device was constructed toward miRNA-122 detection, utilizing the combination of DNA-programmed NaYF4/Yb,Tm upconversion nanoparticles (UCNPs) and the Z-scheme AgI/WO3 heterojunction grown in situ on gold nanoparticle-decorated 3D cellulose fibers. The UCNPs were employed as light transducers for converting NIR light into ultraviolet/visible (UV/vis) light to excite the nanojunction. The multiple diffraction of NaYF4/Yb,Tm matched the absorption band of the Z-scheme AgI/WO3 heterojunction, resulting in enhanced PEC photocurrent output. This prepared Z-scheme heterojunction effectively directed charge migration and highly facilitated the electron-hole pair separation. Target miRNA-122 activated the nonenzyme catalytic hairpin assembly signal amplification strategy, generating duplexes which caused the exfoliation of NaYF4/Yb,Tm UCNPs from the biosensor electrode and lowered the photocurrent under 980 nm irradiation. Under optimized circumstances, the proposed NIR-actuated PEC lab-on-paper device presented accurate miRNA-122 detection within a wide linear range of 10 fM-100 nM with a low limit of detection of 2.32 fM, providing a reliable strategy in the exploration of NIR-actuated PEC biosensors for low-cost, high-performance bioassay in clinical applications.

Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an extracellular enzyme responsible for hydrolyzing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), the endogenous agonist for the stimulator of interferon genes (STING) pathway. Inhibition of ENPP1 can trigger STING and promote antitumor immunity, offering an attractive therapeutic target for cancer immunotherapy. Despite progress in the discovery of ENPP1 inhibitors, the diversity in chemical structures and the efficacy of the agents are far from desirable, emphasizing the demand for novel inhibitors. Herein, we describe the design, synthesis, and biological evaluation of a series of ENPP1 inhibitors based on the pyrido[2,3-d]pyrimidin-7-one scaffold. Optimization efforts led to compound 31 with significant potency in both ENPP1 inhibition and STING pathway stimulation in vitro. Notably, 31 demonstrated in vivo efficacy in a syngeneic 4T1 mouse triple negative breast cancer model. These findings provide a promising lead compound with a novel scaffold for further drug development in cancer immunotherapy.

Rolling circle amplification assisted CRISPR/Cas12a dual-cleavage photoelectrochemical biosensor for highly sensitive detection of miRNA-21.

BACKGROUND: MicroRNA-21 has been determined to be the only microRNA overexpressed in 11 types of solid tumors, making it an excellent candidate as a biomarker for disease diagnosis and therapy. Photoelectrochemical (PEC) biosensors have been widely used for quantification of microRNA-21. However, most PEC biosensing processes still suffer from some problems, such as the difficulty of avoiding the influence of interferents in complex matrices and the false-positive signals. There is a pressing need for establishing a sensitive and stable PEC method to detect microRNA-21. RESULTS: Herein, a nicking endonuclease-mediated rolling circle amplification (RCA)-assisted CRISPR/Cas12a PEC biosensor was fabricated for ultrasensitive detection of microRNA-21. The p-p type heterojunction PbS QDs/Co3O4 polyhedra were prepared as the quencher, thus the initial PEC signal attained the "off" state. Furthermore, the target was specifically identified and amplified by the RCA process. Then, its product single-stranded DNA S1 activated the cis- and trans-cleavage abilities of CRISPR/Cas12a, leading to almost all of the PbS QDs/Co3O4 polyhedra to leave the electrode surface, the p-n semiconductor quenching effect to be disrupted, and the signal achieving the "super-on" state. This pattern of PEC signal changed from "off" to "on" eliminated the interference of false-positive signals. The proposed PEC biosensor presented a satisfactory linear relationship ranging from 1 fM to 10 nM with a detection limit of 0.76 fM (3 Sb/N). SIGNIFICANCE AND NOVELTY: With innovatively synthesized PbS QDs/Co3O4 polyhedra as the effective quencher for PEC signal, the CRISPR/Cas12a dual-cleavage PEC biosensor possessed excellent selectivity, stability and repeatability. Furthermore, the detection of various miRNAs can be realized by changing the relevant base sequences in the constructed PEC biosensor. It also provides a powerful strategy for early clinical diagnosis and biomedical research.