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Abstract CRISPR diagnostics are effective but suffer from low signal transduction efficiency, limited sensitivity, and poor stability due to their reliance on the trans-cleavage of single-stranded nucleic acid fluorescent reporters. Here, we present CrisprAIE, which integrates CRISPR/Cas reactions with “one to more” aggregation-induced emission luminogen (AIEgen) lighting-up fluorescence generated by the trans-cleavage of Cas proteins to AIEgen-incorporated double-stranded DNA labeled with single-stranded nucleic acid linkers and Black Hole Quencher groups at both ends (Q-dsDNA/AIEgens-Q). CrisprAIE demonstrates superior performance in the clinical nucleic acid detection of norovirus and SARS-CoV-2 regardless of amplification. Moreover, the diagnostic potential of CrisprAIE is further enhanced by integrating it with spherical nucleic acid-modified AIEgens (SNA/AIEgens) and a portable cellphone-based readout device. The improved CrisprAIE system, utilizing Q-dsDNA/AIEgen-Q and SNA/AIEgen reporters, exhibits approximately 80- and 270-fold improvements in sensitivity, respectively, compared to conventional CRISPR-based diagnostics. We believe CrisprAIE can be readily extended as a universal signal generation strategy to significantly enhance the detection efficiency of almost all existing CRISPR-based diagnostics.

Retinal ischemia is an ophthalmic emergency often caused by cardiovascular diseases, leading to irreversible vision loss and even blindness. Innovative retinal ischemia treatments are needed due to limited options. The pathological mechanisms involve retinal cell apoptosis and microglial activation. The pituitary adenylate cyclase-activating polypeptide (PACAP) is a well distributed neuropeptide found in both central nervous system and peripheral organs. Though it shows great anti-apoptosis and anti-microglia activation properties, it is rapidly cleared by intravitreal injection. Herein, we established a novel poly(ethylene glycol) (PEG) hydrogel system by cross-linking 4arm-PEG-NHS and 4arm-PEG-NH2 to load PACAP (PACAP@Gel-PEG), which exhibited great fluidity, injectability, structural recovery ability, moderate swelling ratio and drug release ability that were appropriate for drug delivery. Then the safety and effectiveness of the PACAP@Gel-PEG were evaluated in vitro in three retinal cell lines (ARPE-19, 661 W and rRMC) and in vivo using the unilateral common carotid artery occlusion (UCCAO) mice model. The CCK-8 test and live/dead staining demonstrated that PACAP@Gel-PEG exhibited excellent biocompatibility in three retinal cell lines. Furthermore, after PACAP@Gel-PEG treatment, a great anti-apoptotic effect was observed in cells treated by CoCl2. Application of PACAP@Gel-PEG greatly improved the therapeutic efficacy of PACAP in restoring retinal function, maintaining retinal integrity, and suppressing apoptosis and microglia activation in retinal tissues. Moreover, in mice, the biosafety of PACAP@Gel-PEG was confirmed by H&E staining of systemic organs. Taken together, our results demonstrated PACAP@Gel-PEG as a promising therapeutic option for retinal ischemia, providing new strategies for vision restoration.

After the “6 • 1” Lushan earthquake, unstable rock mass was discovered in Zhangjiagou, posing a severe threat to the safety of the residents and their property below. The dangerous rock mass was evaluated using stability calculation and the discrete element numerical analysis method, and the seismic condition with the highest threat level was selected for kinematic analysis. Based on this research, a combination of analytical solution and numerical solution was used to design corresponding protective measures. The main conclusions are as follows : (1) The structure of the unstable rock mass in Zhangjiagou is broken, and a controlling structural plane is developed along the slope. (2) The stability calculations and numerical simulations show that the Zhangjiagou unstable rock mass will become unstable under natural, rainstorm and seismic conditions, with the longest movement distance occurring during an earthquake. (3) The failure mode of the dangerous rock mass under seismic conditions is a shatter-slip type, where the rock mainly slips during movement, and the jump height is small. Additionally, the slope shape significantly affects the characteristics of rockfall movement. (4) The collision and extrusion between rockfalls can change their motion characteristics and impact kinetic energy, potentially increasing the scope of the disaster. The research results can provide a reference for similar disaster prevention and control efforts.

Choroidal neovascularization (CNV), characterized as a prominent feature of wet age-related macular degeneration (AMD), is a primary contributor to visual impairment and severe vision loss globally, while the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells is dictated by angiogenic growth factors alone. Even though treatments targeting vascular endothelial growth factor (VEGF), like Ranibizumab, are widely administered, more than half of the patients still exhibit inadequate or null responses, emphasizing the imperative need for solutions to this problem. Here, aiming to explore therapeutic strategies from a novel perspective of endothelial cell metabolism, a biocompatible nanomedicine delivery system is constructed by loading RGD peptide-modified liposomes with 2-deoxy-D-glucose (RGD@LP-2-DG). RGD@LP-2-DG displayed good targeting performance towards endothelial cells and excellent in vitro and in vivo inhibitory effects on neovascularization were demonstrated. Moreover, our mechanistic studies revealed that 2-DG interfered with N-glycosylation, leading to the inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream signaling. Notably, the remarkable inhibitory effect on neovascularization and biocompatibility of RGD@LP-2-DG render it a highly promising and clinically translatable therapeutic candidate for the treatment of wet AMD and other angiogenic diseases, particularly in patients who are unresponsive to currently available treatments.

Abstract Fluorescent‐magneto nanoemitters have gained considerable attention for their applications in mechanical controlling‐assisted optical signaling. However, the incompatibility between magnetic and fluorescent components often leads to functional limitations in traditional magneto@fluorescence nanostructure. Herein, we introduce a new compact‐discrete spatial arrangement on a “fluorescence@magneto” core–shell nanostructure consisting of a close‐packed aggregation‐induced emission luminogen (AIEgen) core and a discrete magnetic shell. This structural design effectively eliminates the optical and magnetic interferences between the dual components by facilitating AIEgens loading in core region and reducing the magnetic feeding amount through effective exposure of the magnetic units. Thereby, the resulting magneto‐AIEgen nanoparticle (MANP) demonstrates “win‐win” performances: (i) high fluorescent intensity contributed by AIEgens stacking‐enhanced photoluminescence and reduced photons loss from the meager magnetic shell; (ii) marked magnetic activity due to magneto extraposition‐minimized magnetic shielding. Accordingly, the dual functions‐retained MANP provides a proof of concept for construction of an immunochromatographic sensing platform, where it enables bright fluorescent labeling after magnetically enriching and separating procalcitonin and lipoarabinomannan in clinical human serum and urine, respectively, for the clinical diagnosis of bacterial infections‐caused inflammation and tuberculosis. This study not only inspires the rational design of magnetic‐fluorescent nanoemitter but also highlights promising potential in magneto‐assisted point‐of‐care test and biomedicine applications.

Wet age-related macular degeneration (wet AMD) is a primary contributor to visual impairment and severe vision loss globally, but the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells (ECs) is mainly dictated by angiogenic growth factors. Even though treatments targeting vascular endothelial growth factor (VEGF), like ranibizumab, are widely administered, more than half of patients still exhibit inadequate or null responses, suggesting the involvement of other pathogenic mechanisms. With advances in research in recent years, it has become well recognized that EC metabolic regulation plays an active rather than merely passive responsive role in angiogenesis. Disturbances of these metabolic pathways may lead to excessive neovascularization in angiogenic diseases such as wet AMD, therefore targeted modulation of EC metabolism represents a promising therapeutic strategy for wet AMD. In this review, we comprehensively discuss the potential applications of EC metabolic regulation in wet AMD treatment from multiple perspectives, including the involvement of ECs in wet AMD pathogenesis, the major endothelial metabolic pathways, and novel therapeutic approaches targeting metabolism for wet AMD.

ABSTRACT: Staphylococcal enterotoxin A (SEA) is an important biotoxin, produced by Staphylococcus aureus under appropriate conditions, and often contaminates milk and dairy products. Herein, an anti-SEA monoclonal antibody (anti-SEA mAb) was prepared by injecting the SEA protein in BALB/c mice, and a novel immunochromatographic assay (ICA) was developed for the rapid and sensitive determination of SEA in pasteurized milk by using highly luminescent quantum dot beads (QB) as signal amplification probe. Given the 1020-fold enhancement in the photoluminescence intensity of QB to the original quantum dot, the proposed QB-ICA exhibits high sensitivity for SEA determination in real milk samples with a limit of detection of 1.89 ng/mL, and shows good dynamic linearity for SEA quantitative detection from 2 to 150 ng/mL within 15 min of test time. The proposed QB-ICA also shows good selectivity to SEA detection with a negligible cross-reaction to common analogs, including staphylococcal enterotoxins B, C, D, and E. In addition, the accuracy and precision of QB-ICA were assessed by analyzing SEA-fortified milk samples. The average recoveries of intra- and interassays range from 85.5 to 128.1%, and the coefficients of variation range from 4.6 to 14.2%, indicating an acceptable accuracy for the quantitative detection of SEA in real milk samples. In summary, this work provides a powerful and rapid analysis tool for the sensitive monitoring of SEA contamination in pasteurized milk samples.

To study the dynamic amplification effect of slope surfaces under the action of strong earthquakes, a three-dimensional model was established using a rocky slope in Mian County, Shaanxi Province, as an example. The discrete element software 3DEC is used to simulate the deformation and instability process of the slope under dynamic conditions, analyse the dynamic response characteristics of the slope surface, and study the difference in the dynamic response of the slope surface under different seismic wave input conditions. The main conclusions are that when considering the influence of seismic longitudinal waves, the vertical acceleration is significantly enhanced, and the PGA amplification factor of the slope is increased by approximately 1.62 times. The slope shape strongly affects the dynamic response characteristics of the slope surface. Under the action of strong earthquakes, the amplification of the slope shoulder and the slope turning point is very strong, followed by the protruding parts, and the amplification on both sides of the slope surface is the weakest. Under different input conditions, the horizontal PGA amplification factor at the slope turning point maintains a high value, especially when only the horizontal acceleration is input, and this part should be given special attention in the prevention of earthquake landslide disasters. The movement process of a landslide caused by strong earthquakes can be summarized as the initiation stage of the landslide-the high-speed movement stage of the squeeze collision-the accumulation stage. The research results can provide certain theoretical support for disaster prevention and mitigation in this region.

Hg2+ contamination in sewage can accumulate in the human body through the food chains and cause health problems. Herein, a novel aggregation-induced emission luminogen (AIEgen)-encapsulated hydrogel probe for ultrasensitive detection of Hg2+ was developed by integrating hydrophobic AIEgens into hydrophilic hydrogels. The working mechanism of the multi-fluorophore AIEgens (TPE-RB) is based on the dark through-bond energy transfer strategy, by which the energy of the dark tetraphenylethene (TPE) derivative is completely transferred to the rhodamine-B derivative (RB), thus resulting in intense photoluminescent intensity. The spatial networks of the supporting hydrogels further provide fixing sites for the hydrophobic AIEgens to enlarge accessible reaction surface for hydrosoluble Hg2+, as well create a confined reaction space to facilitate the interaction between the AIEgens and the Hg2+. In addition, the abundant hydrogen bonds of hydrogels further promote the Hg2+ adsorption, which significantly improves the sensitivity. The integrated TPE-RB-encapsulated hydrogels (TR hydrogels) present excellent specificity, accuracy and precision in Hg2+ detection in real-world water samples, with a 4-fold higher sensitivity compared to that of pure AIEgen probes. The as-developed TR hydrogel-based chemosensor holds promising potential as a robust, fast and effective bifunctional platform for the sensitive detection of Hg2+.

BackgroundThe elderly is a vulnerable group susceptible to toxic environmental factors; however, the association between unsafe water and osteoarthritis (OA) incident among this population is poorly investigated. This study aimed to examine the effects of drinking water sources on OA risk in the Chinese elderly population.MethodsData were obtained from the China Longitudinal Healthy Longevity Survey to perform a 16-year longitudinal study. All participants aged ≥65 years at baseline were potentially eligible. Information on drinking water sources was recorded via a structured questionnaire. The water source was classified as well, surface, spring, or tap. OA was selected as the health outcome. Cox proportional hazard models, adjusted socio-demographics, lifestyle, and chronic disease were used to estimate the hazard ratio (HR) for OA. Subgroup analyses were performed to assess the potential interactive effect.ResultsA total of 12,543 participants were included. With restriction to the longest follow-up time, the mean survival time of follow-up was 14.56 years. Among the cohort members, 1,585 members suffered from OA. In the full model, drinking from well water and spring water was associated with a higher risk of OA compared with drinking from tap water (HR: 1.37, 95% CI: 1.22–1.54; HR: 1.34, 95% CI: 1.03–1.74). Except for age, the effects of modifications from socioeconomic status, lifestyles, and health conditions were non-significant (p for interaction

Staphylococcal enterotoxin A (SEA) has presented enormous difficulties in dairy food safety and the sensitive detection of SEA provides opportunities for effective food safety controls and staphylococcal food poisoning tracebacks. Herein, a novel aggregation-induced emission (AIE)-based sandwich lateral flow immunoassay (LFIA) was introduced to detect SEA by using red-emissive AIE nanoparticles (AIENPs) as the fluorescent nanoprobe. The nanoprobe was constructed by directly immobilising antibodies on boronate-tagged AIENPs (PBA-AIENPs) via a boronate affinity reaction, which exhibited a high SEA-specific affinity and remarkable fluorescent performance. Under optimal conditions, the ultrasensitive detection of SEA in pasteurised milk was achieved within 20 min with a limit of detection of 0.04 ng mL−1. The average recoveries of the PBA-AIENP-LFIA ranged from 91.3% to 117.6% and the coefficient of variation was below 15%. It was also demonstrated that the PBA-AIENP-LFIA had an excellent selectivity against other SE serotypes. Taking advantage of the excellent sensitivity of this approach, real chicken and salad samples were further analysed, with a high versatility and accuracy. The proposed PBA-AIENP-LFIA platform shows promise as a potent tool for the identification of additional compounds in food samples as well as an ideal test method for on-site detections.

Lateral flow immunoassay (LFIA) based on fluorescent microbeads has attracted much attention for its use in rapid and accurate food safety monitoring. However, conventional fluorescent microbeads are limited by the aggregation-caused quenching effect of the loaded fluorophores, thus resulting in low signal intensity and insufficient sensitivity of fluorescent LFIA. In this study, a green-emitting fluorophore with an aggregation-induced emission (AIE) characteristic was encapsulated in polymer nanoparticles via an emulsification technique to form ultrabright fluorescent microbeads (denoted as AIEMBs). The prepared AIEMBs were then applied in a competitive LFIA (AIE-LFIA) as signal reporters for the rapid and highly sensitive screening of fumonisin B1 (FB1) in real corn samples. High sensitivity with a detection limit of 0.024 ng/mL for FB1 was achieved by the developed AIE-LFIA. Excellent selectivity, good accuracy, and high reliability of the AIE-LFIA were demonstrated, indicating a promising platform for FB1 screening.

Road traffic safety is a social issue of widespread concern. It is important for traffic managers to understand the distribution patterns of road traffic accidents. To this end, this study examines the spatial and temporal patterns of road traffic accidents from both accident frequency and accident severity perspectives. Road traffic accident data from 2016 to 2018 in Harbin, China, were used for the analysis. First, the spatial localization of accidents was completed using geocoding, and the localized accident data were classified by season. Then, density analysis was performed both with and without considering road network density. The results of the density analysis showed that when road network density was considered, accidents were mainly distributed in urban centers, while accidents were more dispersed when road network density was not considered. Third, a cluster analysis considering accident severity found that low-severity accident clusters occurred mostly in urban centers. High-severity accident clusters were mostly present in suburban areas. Finally, the results of these two methods are shown by using the comap technique. Areas of the city with a high frequency and severity of crashes in each season were identified. This study will help traffic management to have a more visual and intuitive understanding of the urban traffic safety situation and to take targeted measures to improve it accordingly.

Herein, we developed a paper-based smart sensing chip for the real-time, visual, and non-destructive monitoring of food freshness using a ratiometric aggregation-induced emission (AIE) luminogen (i.e., H+MQ, protonated 4-(triphenylamine)styryl)quinoxalin-2(1H)-one) as pH sensitive indicators. Upon exposure to amine vapors, the deprotonation of H+MQ occurs and triggers its color change from blue to yellow, with the fluorescence redshift from blue to amaranth. Consequently, we successfully achieved the sensitive detection of ammonia vapors by recording the bimodal color and fluorescence changes. Given the high sensitivity of H+MQ to ammonia vapor, a paper-based smart sensor chip was prepared by depositing H+MQ on the commercial qualitative filter paper through a physical deposition strategy. After being placed inside the sealed containers, the developed H+MQ-loaded paper chip was applied to the real-time monitoring of biogenic amine contents according to its color difference and ratio fluorescence change. The detection results were further compared with those obtained by the high-performance liquid chromatography method, which verified the feasibility of the designed paper chip for the food spoilage degree evaluation. Briefly, this work indicates that the designed H+MQ-loaded paper chip could be a promising approach for improving food freshness monitoring.

Abstract Herein, a facile self‐assembly strategy for coassembling oleic acid‐coated iron oxide nanoparticles (OC‐IONPs) with oleylamine‐coated gold nanoparticles (OA‐AuNPs) to form colloidal magnetic–plasmonic nanoassemblies (MPNAs) is reported. The resultant MPNAs exhibit a typical core–shell heterostructure comprising aggregated OA‐AuNPs as a plasmonic core surrounded by an assembled magnetic shell of OC‐IONPs. Owing to the high loading of OA‐AuNPs and reasonable spatial distribution of OC‐IONPs, the resultant MPNAs exhibit highly retained magnetic–plasmonic activities simultaneously. Using the intrinsic dual functionality of MPNAs as a magnetic separator and a plasmonic signal transducer, it is demonstrated that the assembled MPNAs can achieve the simultaneous magnetic manipulation and optical detection on the lateral flow immunoassay platform after surface functionalization with recognition molecules. In conclusion, the core–shell‐heterostructured MPNAs can serve as a nanoanalytical platform for the separation and concentration of target compounds from complex biological samples using magnetic properties and simultaneous optical sensing using plasmonic properties.

Background: Colloidal gold based lateral flow immunoassay (LFIA) commonly suffers from relatively low detection sensitivity due to the insufficient brightness of conventional gold nanoparticles (AuNPs) with the size of 20–40 nm. Methods: Herein, three kinds of gold nanobeads (GNBs) with the size of 94 nm, 129 nm, and 237 nm, were synthesized by encapsulating numerous hydrophobic AuNPs (10 nm) into polymer matrix. The synthesized GNBs exhibited the enhanced colorimetric signal intensity compared with 20–40 nm AuNPs. The effects of the size of GNBs on the sensitivity of LFIA with competitive format were assessed. Results: The results showed that the LFIA using 129 nm GNBs as amplified signal probes exhibits the best sensitivity for fumonisin B1 (FB1) detection with a cut-off limit (for visual qualitative detection) at 125 ng/mL, a half maximal inhibitory concentration at 11.27 ng/mL, and a detection limit at 1.76 ng/mL for detection of real corn samples, which are 8-, 3.82-, and 2.89-fold better than those of conventional AuNP40-based LFIA, respectively. The developed GNB-LFIA exhibited negligible cross-reactions with other common mycotoxins. In addition, the accuracy, precision, reliability, and practicability were demonstrated by determining real corn samples. Conclusions: All in all, the proposed study provides a promising strategy to enhance the sensitivity of competitive LFIA via using the GNBs as amplified signal probes.

In this study, we developed a completely contactless air conveyor system for transporting and positioning planar objects. The air conveyor forms a thin film underneath the object for support and simultaneously generates a controlled airflow that results in viscous traction. It is potentially applicable in the manufacturing process for semiconductor wafer or flat foodstuffs, where mechanical contact is expected to be avoided during transportation of the products to minimize contamination. The air conveyor employs duplicated arrays of actuating cells that are square pockets with a surrounding dam. A simple model is proposed to characterize the viscous force. The theoretical analysis reveals that the total force is the composition of an actuating force generated in the pocket areas and the side areas and a drag force generated in the dam areas. Experimental investigations are conducted on the basic characteristics of the film pressure distribution and the viscous force. The results show that the air film pressure is symmetrically distributed in the width direction but nonsymmetrically distributed in the length direction. The viscous force increases if the suction flow rate is enlarged or the gap thickness is narrowed. Comparison of the experimental results and the calculated results indicates that the model can provide an accurate prediction. A proportional–integral–derivative (PID) controller is applied for 1D-position control and position tracking. The actuating direction is selected using fast switching valves and the amplitude of the actuating force is adjusted using a control valve to vary the suction flow rate. The simulated and the experimental results verify the feasibility of the air conveyor system and the control method.

Abstract Class IIa histone deacetylases (Class IIa HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific roles of each class IIa HDAC isoform is hindered by the pan‐inhibitory effect of current inhibitors and a lack of tools to probe their functions beyond epigenetic regulation. In this study, a novel PROTAC‐based compound B4 is developed, which selectively targets and degrades HDAC7, resulting in the effective attenuation of a specific set of proinflammatory cytokines in both lipopolysaccharide (LPS)‐stimulated macrophages and a mouse model. By employing B4 as a molecular probe, evidence is found for a previously explored role of HDAC7 that surpasses its deacetylase function, suggesting broader implications in inflammatory processes. Mechanistic investigations reveal the critical involvement of HDAC7 in the Toll‐like receptor 4 (TLR4) signaling pathway by directly interacting with the TNF receptor‐associated factor 6 and TGFβ‐activated kinase 1 (TRAF6‐TAK1) complex, thereby initiating the activation of the downstream mitogen‐activated protein kinase/nuclear factor‐κB (MAPK/NF‐κB) signaling cascade and subsequent gene transcription. This study expands the insight into HDAC7's role within intricate inflammatory networks and highlights its therapeutic potential as a novel target for anti‐inflammatory treatments.

Aberrant changes in the gut microbiota are implicated in many diseases, including inflammatory bowel disease (IBD). Gut microbes produce diverse metabolites that can shape the immune system and impact the intestinal barrier integrity, indicating that microbe-mediated modulation may be a promising strategy for preventing and treating IBD. Although fecal microbiota transplantation and probiotic supplementation are well-established IBD therapies, novel chemical agents that are safe and exert strong effects on the gut microbiota are urgently needed. Herein, we report the total synthesis of heudelotinone and the discovery of 5S-heudelotinone (an enantiomer) as a potent agent against experimental colitis that acts by modulating the gut microbiota. 5S-Heudelotinone alters the diversity and composition of the gut microbiota and increases the concentration of short-chain fatty acids (SCFAs); thus, it regulates the intestinal immune system by reducing proinflammatory immune cell numbers, and maintains intestinal mucosal integrity by modulating tight junctions (TJs). Moreover, 5S-heudelotinone (2) ameliorates colitis-associated colorectal cancer (CAC) in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced in situ carcinoma model. Together, these findings reveal the potential of a novel natural product, namely, 5S-heudelotinone, to control intestinal inflammation and highlight that this product is a safe and effective candidate for the treatment of IBD and CAC.