Evolution of a bispecific G-quadruplex-forming circular aptamer to block IL-6/sIL-6R interaction for inflammation inhibition.

IL-6 (interleukin-6) is an essential cytokine that participates in many inflammatory and immune responses, and disrupting the interaction between IL-6 and its receptor sIL-6R (soluble form of IL-6 receptor) represents a promising treatment strategy for inflammation and related diseases. Herein we report the first-ever effort of evolving a bispecific circular aptamer, named CIL-6A6-1, that is capable of binding both IL-6 and sIL-6R with nanomolar affinities and is stable in serum for more than 48 hours. CIL-6A6-1 can effectively block the IL-6/sIL-6R interaction and significantly inhibit cell inflammation. Most importantly, this bispecific aptamer is much more effective than aptamers that bind IL-6 and sIL-6R alone as well as tocilizumab, a commercially available humanized monoclonal antibody against sIL-6R, highlighting the advantage of selecting bispecific circular aptamers as molecular tools for anti-inflammation therapy. Interestingly, CIL-6A6-1 is predicted to adopt a unique structural fold with two G-quadruplex motifs capped by a long single-stranded region, which differs from all known DNA aptamers. This unique structural fold may also contribute to its excellent functionality and high stability in biological complex media. We anticipate that our study will represent a significant step forward towards demonstrating the practical utility of bispecific DNA aptamers for therapeutic applications.

Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers.

KRAS is the most frequently dysregulated oncogene with high prevalence in NSCLC, colorectal cancer, and pancreatic cancer. FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation. However, there is still high unmet medical need for new agents targeting broader KRAS-driven tumors. An emerging and promising opportunity is to develop a pan KRAS inhibitor by suppressing the upstream protein SOS1. SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS state to GTP-bound KRAS state. Binding to its catalytic domain, small molecule SOS1 inhibitor has demonstrated the ability to suppress KRAS activation and cancer cell proliferation. RGT-018, a potent and selective SOS1 inhibitor, was identified with optimal drug-like properties. In vitro, RGT-018 blocked the interaction of KRAS:SOS1 with single digit nM potency and is highly selective against SOS2. RGT-018 inhibited KRAS signaling and the proliferation of a broad spectrum of KRAS-driven cancer cells as a single agent in vitro. Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling in tumor xenografts in vivo. Combination with MEK or KRASG12C inhibitors led to significant tumor regression. Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population.

A method for cabbage root posture recognition based on YOLOv5s.

Efficient, non-destructive cabbage harvesting is crucial for preserving its flavor and quality. Current cabbage harvesting mainly relies on mechanized automatic picking methods. However, a notable deficiency in most existing cabbage harvesting devices is the absence of a root posture recognition system to promptly adjust the root posture, consequently impacting the accuracy of root cutting during harvesting. To address this issue, this study introduces a cabbage root posture recognition method that combines deep learning with traditional image processing algorithms. Preliminary detection of the main root Region of Interest (ROI) areas of the cabbage is carried out through the YOLOv5s deep learning model. Subsequently, traditional image processing methods, the Graham algorithm, and the method of calculating the minimum circumscribed rectangle are employed to specifically detect the inclination angle of cabbage roots. This approach effectively addresses the difficulty in calculating the inclination angle of roots caused by occlusion from outer leaves. The results demonstrate that the precision and recall of this method are 98.7 % and 98.6 %, respectively, with an average absolute error of 0.80° and an average relative error of 1.34 % in posture. Using this method as a reference for mechanical harvesting can effectively mitigate cabbage damage rates.

Supercritical Fluid-extracted Citrus aurantium L. var. amara Engl. Essential Oil Nanoemulsion: Preparation, Characterization, and Its Sleep-promoting Effect.

To overcome the defects of Citrus aurantium L. var. amara Engl. essential oil (CAEO), such as high volatility and poor stability, supercritical fluid-extracted CAEO nanoemulsion (SFE-CAEO-NE) was prepared by the microemulsification method. Emulsifiers comprising Tween 80, polyoxyethylenated castor oil (EL-40), and 1,2-hexanediol, and an oil phase containing SFE-CAEO were used for microemulsification. We examined the physicochemical properties of SFE-CAEO-NE and steam distillation-extracted CAEO nanoemulsion (SDE-CAEO-NE), which were prepared using different concentrations of the emulsifiers. The mean particle size and zeta potential were 21.52 nm and -9.82 mV, respectively, for SFE-CAEO-NE, and 30.58 nm and -6.28 mV, respectively, for SDE-CAEO-NE, at an emulsifier concentration of 15% (w/w). SFE-CAEO-NE displayed better physicochemical properties compared with SDE-CAEO-NE. Moreover, its physicochemical properties were generally stable at different temperatures (-20-60℃), pH (3-8), and ionic strengths (0-400 mM). No obvious variations in particle size, zeta potential, and Ke were observed after storing this nanoemulsion for 30 days at 4℃, 25℃, and 40℃, suggesting that it had good stability. The sleep-promoting effect of SFE-CAEO-NE was evaluated using a mouse model of insomnia. The results of behavioral tests indicated that SFE-CAEO-NE ameliorated insomnia-like behavior. Moreover, SFE-CAEO- NE administration increased the serum concentrations of neurotransmitters such as 5-hydroxytryptamine and γ-aminobutyric acid, and decreased that of noradrenaline in mice. It also exerted a reparative effect on the function of damaged neurons. Overall, SFE-CAEO-NE displayed a good sleep-promoting effect.

Single-Round Circular Aptamer Discovery Using Bioinspired Magnetosome-Like Magnetic Chain Cross-Linked Graphene Oxide.

Circular aptamers are promising candidates for analytical and therapeutic applications due to their enhanced biological and structural stability. However, the process of circular aptamer selection remains a great challenge, as it requires multiple rounds of binding-separation-amplification that involves issues with nonspecific binding and amplification bias. Here, we develop a highly practical solution for reliable selection of circular aptamers in a single round based on magnetosome-like magnetic chain cross-linked graphene oxide (separation efficiency ≈ 105). High-affinity aptamer candidates can be rapidly selected from a preenriched circular DNA library, while low-affinity candidates are effectively adsorbed and separated by magnetosome-like magnetic chain cross-linked graphene oxide. With lipopolysaccharide as a representative model, the single-round selected lipopolysaccharide circular aptamer has been identified to have a high binding affinity with a Kd value of low to nanomolar range. Using this method, circular aptamers for protein and small-molecule targets were also successfully generated. We envision that this approach will accelerate the discovery of various new circular aptamers and open up a new avenue for analytical and therapeutic studies.

A Bioinspired Single-Atom Fe Nanozyme with Excellent Laccase-Like Activity for Efficient Aflatoxin B1 Removal.

The applications of natural laccases are greatly restricted because of their drawbacks like poor biostability, high costs, and low recovery efficiency. M/NC single atom nanozymes (M/NC SAzymes) are presenting as great substitutes due to their superior enzyme-like activity, excellent selectivity and high stability. In this work, inspired by the catalytic active center of natural enzyme, a biomimetic Fe/NC SAzyme (Fe-SAzyme) with O2-Fe-N4 coordination is successfully developed, exhibiting excellent laccase-like activity. Compared with their natural counterpart, Fe-SAzyme has shown superior catalytic efficiency and excellent stability under a wide range of pH (3.0-9.0), temperature (4-80 °C) and NaCl strength (0-300 mm). Interestingly, density functional theory (DFT) calculations reveal that the high catalytic performance is attributed to the activation of O2 by O2-Fe-N4 sites, which weakened the O─O bonds in the oxygen-to-water oxidation pathway. Furthermore, Fe-SAzyme is successfully applied for efficient aflatoxin B1 removal based on its robust laccase-like catalytic activity. This work provides a strategy for the rational design of laccase-like SAzymes, and the proposed catalytic mechanism will help to understand the coordination environment effect of SAzymes on laccase-like catalytic processes.

Cisplatin-loaded mesoporous polydopamine nanoparticles capped with MnO2 and coated with platelet membrane provide synergistic anti-tumor therapy.

A multifunctional nanoplatform was constructed in this work, with the goal of ameliorating the challenges faced with traditional cancer chemotherapy. Cisplatin (CP) was loaded into mesoporous polydopamine (mPDA) nanoparticles (NPs) with a drug loading of 15.8 ± 0.1 %, and MnO2 used as pore sealing agent. Finally, the NPs were wrapped with platelet membrane (PLTM). P-selectin on the PLTM can bind to CD44, which is highly expressed on the tumor cell membrane, so as to improve the targeting performance of the NPs. In addition, the CD47 on the PLTM can prevent the NPs from being phagocytosed by macrophages, which is conducive to immune escape. The final PLTM-CP@mPDA/MnO2 NPs were found to have a particle size of approximately 198 nm. MnO2 is degraded into Mn2+ in the tumor microenvironment, leading to CP release from the pores in the mPDA. CP both acts as a chemotherapy agent and can also increase the concentration of H2O2 in cells. Mn2+ can catalyze the conversion of H2O2 to OH, resulting in oxidative damage and chemodynamic therapy. In addition, Mn2+ can be used as a contrast agent in magnetic resonance imaging (MRI). In vitro and in vivo experiments were performed to explore the therapeutic effect of the NPs. When the concentration of CP is 30 µg/mL, the NPs cause approximately 50 % cell death. It was found that the PLTM-CP@mPDA/MnO2 NPs are targeted to cancerous cells, and in the tumor site cause extensive apoptosis. Tumor growth is thereby repressed. No negative off-target side effects were noted. MRI could be used to confirm the presence of the NPs in the tumor site. Overall, the nano-platform developed here provides cooperative chemotherapy and chemodynamic therapy, and can potentially be used for effective cancer treatment which could be monitored by MRI.

Nanozyme-integrated alcogel colorimetric sensor for rapid and on-site detection of tert-butyl hydroquinone.

Tert-butyl hydroquinone (TBHQ) stand as one of the most widely used antioxidants in food and daily chemical products. Rapid and sensitive monitoring of TBHQ holds considerable importance in safeguarding human health due to its potential risks. In this study, we devised an alcogel-based colorimetric sensor enabling the portable and visual detection of TBHQ. The Ce-UiO-66 nanozyme exhibiting remarkable oxidase-like activity, was synthesized and characterized, facilitating the catalysis of TBHQ oxidation to 2-tert-butyl-1,4-benzoquinone (TBBQ). The ensuing chromogenic reaction between TBBQ and ethylenediamine produced a stable and colored product, serving as a reliable indicator for the rapid and specific detection of TBHQ. Building upon this discovery, a portable and low-cost colorimetric sensor was fashioned by integrating the nanozyme into κ-carrageenan alcogel, thereby enabling on-site TBHQ detection via a smartphone-based sensing platform. The colorimetric sensor exhibited a detection limit of 0.8 µg mL-1, demonstrating robust performance across various matrices such as edible oils, cosmetics, and surface water. Recoveries ranged from 84.9 to 95.5%, with the sensor's accuracy further validated through gas chromatography-mass spectrometry. Our study presents an effective approach to rapid and convenient monitoring of TBHQ, exhibiting good extensibility and practicability.

Optimization of the Zhou Tian Formula extraction technology based on AHP-CRITIC method and analysis of transfer efficiency of key components based on HPLC fingerprinting.

INTRODUCTION: Zhou Tian Formula (ZTF) is an antidepressant traditional Chinese medicine utilized widely in clinical settings for the treatment of patients with depression. However, shortcomings persist in its extraction technology and quality control. OBJECTIVE: This study aimed to propose a methodology for ZTF extraction technology based on the analytic hierarchy process (AHP)-criteria importance through intercriteria correlation (CRITIC) method and to establish a quality control framework for the efficient transfer of index components. METHOD: Firstly, we analyzed the chemical components of ZTF and determined the optimal extraction technology. Secondly, we calculated the transfer efficiency of the index components during the conversion of water decoction to extract powder and subsequently to granules. Thirdly, we established HPLC fingerprints for 15 batches of ZTF water decoction, extract powder, and granules. We employed SIMCA software to analyze the chemicals responsible for variations in quality among different batches of ZTF granules. RESULTS: We determined the optimal extraction process. The average transfer efficiency of ferulic acid, puerarin, mirificin, isoferulic acid, and calycosin during the conversion of water decoction to extract powder and subsequently to granules exceeded 41%. The HPLC fingerprints of ZTF exhibited a similarity exceeding 0.890. Variable importance in projection values indicated that calycosin, ferulic acid, and puerarin were the primary contributors to quality variations. CONCLUSIONS: The AHP-CRITIC method, coupled with an orthogonal array design, could be used for exploring extraction technology. In addition, the rules governing the transfer of index components from water decoction to extract powder, and subsequently to granules, could be applied for the evaluation and quality assessment of ZTF.

Fabrication and evaluation of silver modified micro/nano structured titanium implant.

In order to enhance the antibacterial property of titanium implant without inducing obvious cytotoxicity, the combination of Ag nanolayer and micro/nano surface structure was conducted by magnetron sputtering and hot-alkali treatment in this study. A series of specimens (AH-Ti, AH-Ti/Ag0.25, AH-Ti/Ag1, AH-Ti/Ag2, and AH-Ti/Ag5) were prepared with different sputtering durations (0 min, 0.25 min, 1 min, 2 min, 5 min), respectively, all realizing long-term release of Ag+. In vitro experiments indicated that AH-Ti/Ag1 group possessed good cytocompatibility, nice osteogenic ability, and excellent antibacterial efficiency as well. In addition, AH-Ti/Ag0.25 showed good biocompatibility, while the reduction of S.aureus (78.5%) was not enough compared with AH-Ti/Ag1. Although the AH-Ti/Ag2 and AH-Ti/Ag5 group showed superior antibacterial activity, their obvious cytotoxicity caused low ALP and mineralization level. Therefore, the design of suitable Ag nanolayer coating combined with micro/nano surface structure (AH-Ti/Ag1) might be a promising strategy to enhance osteogenic property and maintain excellent antibacterial ability at the same time.

Evaluation of sustained drug release performance and osteoinduction of magnetron-sputtered tantalum-coated titanium dioxide nanotubes.

Modifying the drug-release capacity of titanium implants is essential for maintaining their long-term functioning. Titanium dioxide nanotube (TNT) arrays, owing to their drug release capacity, are commonly used in the biomaterial sphere. Their unique half open structure and arrangement in rows increase the drug release capacity. However, their rapid drug release ability not only reduces drug efficiency but also produces excessive local and systemic deposition of antibiotics. In this study, we designed a tantalum-coated TNT system for drug-release optimization. A decreased nanotube size caused by the tantalum nanocoating was observed through SEM and analyzed (TNT: 110 nm, TNT-Ta1: 80 nm, TNT-Ta3: 40 nm, TNT-Ta5: 20 nm, TNT-Ta7: <5 nm). XPS analysis revealed the distribution of the chemical components, especially that of the tantalum element. In vitro experiments showed that the tantalum nanocoating enhanced cell proliferation; in particular, TNT-Ta5 possessed the best cell viability (about 1.18 of TNT groups at 7d). It also showed that the tantalum nanocoating had a positive effect on osteogenesis (especially TNT-Ta5 and TNT-Ta7). Additionally, hydrophilic/hydrophobic drug (vancomycin/raloxifene) release results indicated that the TNT-Ta5 group possessed the most desirable sustained release capacity. Moreover, in this drug release system, the hydrophobic drug showed more sustained release capacity than the hydrophilic drug (vancomycin: sustained release for more than 48 h, raloxifene: sustained release for more than 168 h). More importantly, TNT-Ta5 is proved to be an appropriate drug release system, which possesses cytocompatibility, osteogenic capacity, and sustained drug release capacity.

Fish species mislabelling in China: evidence from a survey of frozen, dried, and surimi-based fish products marketed as cod-related species.

'Cod'-related species are among the most appreciated marine fish resources around the world, but are also prone to species mislabelling. In the present study, a total of 76 frozen, dried, and surimi-based fish products, sold as 'Cod' (59 products), 'Atlantic authentic Cod' (11 products), and 'Authentic Cod' (6 products), were collected in China. A species-specific LAMP (loop-mediated isothermal amplification) method was used to screen for the presence of Atlantic cod (Gadus morhua), Pacific cod (G. macrocephalus), Alaska pollock (G. chalcogrammus), Southern hake (Merluccius australis), which was cross-confirmed using real-time PCR and DNA sequencing methods. The results highlighted the greatest species diversity for 'Cod' products, and the identified species were from nine different families. It appears that the practice of assigning a specific type or category of species to the common name 'Cod' has not been widely advocated, and the misuse of this ambiguous common name has been a common practice for species adulteration, negatively impacting consumers' rights and marine conservation. To rebuild consumers' confidence, retail fish suppliers have differentiated their products by adding specific qualifiers in front of the common name 'Cod' on the label, such as 'Authentic cod' and 'Atlantic authentic cod'. The endeavour is highly meaningful, since Gadus morhua was identified as the species for a significant majority of 'Atlantic authentic cod' and 'Authentic cod' products (64.7%, 11/17), with the remaining six products identified as Alaskan pollock (G. chalcogrammus), Pacific cod (G. macrocephalus) and North Pacific hake (Merluccius productus). Despite the positive effort to reverse species mislabelling from retail on-line fish suppliers, a standardized fish nomenclature stipulated by the responsible authorities remains crucial for enhancing transparency and continuing to reduce species mislabelling.

Level and influencing factors of transition shock among new nurses in China: A multicenter cross-sectional study.

Background and Aims: New nurses are an important part of nursing teams. The failure of new nurses to successfully transition seriously affects personal career development and nursing work quality, and important influencing factors deserve the attention of nursing managers. At present, multicenter, large-sample investigations of transition shock among new nurses are lacking in China. This study aims to investigate the current level and influencing factors of transition shock among new nurses in China. Methods: We conducted a multicenter, cross-sectional study with 3414 new nurses from 16 provinces in 7 regions in China from October 22, 2021, to November 8, 2021. We used the snowball sampling method and an online questionnaire produced by the researchers to collect data; the questionnaire included questions on demographic information, a transition shock scale for new nurses and open-ended questions. Data were analyzed using SPSS version 24. Results: The effective response rate of this study was 97.89%, with 3342 effective participants from 189 hospitals in China, most of whom were female (94.88%). The study showed that the transition shock of new nurses in China was at a moderate level, with pre-job anxiety, unsatisfactory welfare treatment, resignation intention, adverse events, poor sleep quality, 1 or fewer exercise sessions per week, inability to balance work and life, and gluttony negatively affecting the transition shock of new nurses in China. Psychological shock was the strongest among the four dimensions of transition shock. Conclusions: The transition shock of new nurses, especially their psychological shock, deserves more attention from international society. Nursing managers should continue to take supportive measures to intervene in the factors influencing transition shock, with the aim of reducing the level of transition for new nurses, promoting their personal thriving, improving the quality of nursing work and increasing the retention rate of nurses.

A lightweight network for improving wheat ears detection and counting based on YOLOv5s.

Introduction: Recognizing wheat ears plays a crucial role in predicting wheat yield. Employing deep learning methods for wheat ears identification is the mainstream method in current research and applications. However, such methods still face challenges, such as high computational parameter volume, large model weights, and slow processing speeds, making it difficult to apply them for real-time identification tasks on limited hardware resources in the wheat field. Therefore, exploring lightweight wheat ears detection methods for real-time recognition holds significant importance. Methods: This study proposes a lightweight method for detecting and counting wheat ears based on YOLOv5s. It utilizes the ShuffleNetV2 lightweight convolutional neural network to optimize the YOLOv5s model by reducing the number of parameters and simplifying the complexity of the calculation processes. In addition, a lightweight upsampling operator content-aware reassembly of features is introduced in the feature pyramid structure to eliminate the impact of the lightweight process on the model detection performance. This approach aims to improve the spatial resolution of the feature images, enhance the effectiveness of the perceptual field, and reduce information loss. Finally, by introducing the dynamic target detection head, the shape of the detection head and the feature extraction strategy can be dynamically adjusted, and the detection accuracy can be improved when encountering wheat ears with large-scale changes, diverse shapes, or significant orientation variations. Results and discussion: This study uses the global wheat head detection dataset and incorporates the local experimental dataset to improve the robustness and generalization of the proposed model. The weight, FLOPs and mAP of this model are 2.9 MB, 2.5 * 109 and 94.8%, respectively. The linear fitting determination coefficients R2 for the model test result and actual value of global wheat head detection dataset and local experimental Site are 0.94 and 0.97, respectively. The improved lightweight model can better meet the requirements of precision wheat ears counting and play an important role in embedded systems, mobile devices, or other hardware systems with limited computing resources.

Pickering Emulsions Stabilized by Conjugated Zein-Soybean Polysaccharides Nanoparticles: Fabrication, Characterization and Functional Performance.

This study aims to fabricate zein-based colloidal nanoparticles, which were used to stabilize Pickering emulsions, by conjugation with soybean polysaccharide (SSPS) through the Maillard reaction. The physicochemical properties of the conjugated particles as well as the physical and oxidative stability of the fabricated Pickering emulsion that utilized conjugated colloidal particles with the volumetric ratio of water and oil at 50:50 were investigated. The grafting degree of zein and SSPS was verified through examination of FT-IR and fluorescence. Moreover, the conjugated Zein/SSPS nanoparticles (ZSP) that were prepared after dry heating for 48-72 h exhibit excellent colloidal stability across a range of pH values (4.0-10.0). Further, the wettability of ZSP decreased based on a contact angle analysis of θ~87°. Confocal laser scanning microscopy (CLSM) images indicated that ZSP particles were located around the oil droplets. Additionally, the ZSP effectively improved the oxidative stability of the Pickering emulsions, as demonstrated by a significant decrease in both peroxide value (PV) and thiobarbituric acid reactive substances (TBARS). The results of this study demonstrate that ZSP represents a promising food-grade Pickering emulsifier, capable of not only stabilizing emulsions but also inhibiting their oil oxidation.