Effect of sodium alginate-gelatin-polyvinyl pyrrolidone microspheres on cucumber plants, soil, and microbial communities under lead stress.

Lead is highly persistent and toxic in soil, hindering plant growth. Microspheres are a novel, functional, and slow-release preparation commonly used for controlled release of agricultural chemicals. However, their application in the remediation of Pb-contaminated soil has not been studied; furthermore, the remediation mechanism involved has not been systematically assessed. Herein, we evaluated the Pb stress mitigation ability of sodium alginate-gelatin-polyvinyl pyrrolidone composite microspheres. Microspheres effectively attenuated the Pb toxic effect on cucumber seedlings. Furthermore, they boosted cucumber growth, increased peroxidase activity, and chlorophyll content, while reducing malondialdehyde content in leaves. Microspheres promoted Pb enrichment in cucumber, especially in roots (about 4.5 times). They also improved soil physicochemical properties, promoted enzyme activity, and increased soil available Pb concentration in the short term. In addition, microspheres selectively enriched functional (heavy metal-tolerating and plant growth promoting) bacteria to adapt to and resist Pb stress by improving soil properties and nutrients. These results indicated that even a small amount (0.025-0.3 %) of microspheres can significantly reduce the adverse effects of Pb on plants, soil, and bacterial communities. Composite microspheres have shown great value in Pb remediation, and their application potential in phytoremediation is also worth evaluating to expand the application.

A Novel Myricetin Derivative with Anti-cancer Properties Induces Cell Cycle Arrest and Apoptosis in A549 Cells.

Lung cancer is the leading cause of cancer-related deaths worldwide, synthesizing and screening of novel anti-cancer drugs provides an alternative therapeutic strategy for renewal of the chemotherapy regimens against lung cancer. To this end, several compounds were synthesized based on the modification of the original myricetin, and their anti-tumor activity against the human non-small cell lung cancer (NSCLC) A549 cells were measured. Among the myricetin derivatives, S4-10 has displayed the highest antitumor efficacy in dose-dependent manner. The proliferation of A549 cells were significantly attenuated by given 6 µM of S4-10 both in vitro and in vivo. Further, the treatment of S4-10 also results in the inhibition of cell migration and invasiveness and the induction of cell apoptosis and G2 cycle arrest of A549 cells. Moreover, we found that S4-10 inhibits the progression of A549 cells through the sterol biosynthetic-cell apoptosis axis. These findings shed the light of developing S4-10 as a promising treatment agent for NSCLC.

Sodium alginate-based composite microspheres for controlled release of pesticides and reduction of adverse effects of copper in agricultural soils.

Excessive copper (Cu) concentrations pose significant health risks to both plants and humans. In this study, sodium alginate (SA)-gelatin (GEL)-polyvinyl pyrrolidone (PVP)- embedded dinotefuran (DIN) microspheres were prepared using spray-drying technology. The loading content and encapsulation efficiency of optimal microspheres determined by physical modifications were 19.77% and 99.32%, respectively. In addition, the microspheres showed variable stimuli-responsive controlled release capacities in different temperatures and types of soil, as well as showed better control efficiency of larvae of Protaetia brevitarsis at pesticide application in the early stage, with the potential ability to control pest outbreaks at high temperatures. In addition, blank microspheres improved the growth and physiological activity of cucumber seedlings, reduced copper content in leaves, increased soil nutrient content, and prevented soil acidification. Further, the use of blank microspheres increased the relative abundance of soil beneficial functional bacteria communities, which mediate heavy metal (HM) immobilization/tolerance and promote plant growth. Redundancy analysis (RDA) and Spearman correlation analysis showed that these beneficial functional bacteria were mainly positively correlated with soil EC, A-N, and N-N. In summary, this study showed that the technique of combining physically modified carrier materials with pesticides has the potential to reduce Cu contamination in the surrounding agricultural soil during pesticide application, thereby reducing Cu uptake by crops.

Different CT slice thickness and contrast-enhancement phase in radiomics models on the differential performance of lung adenocarcinoma.

BACKGROUND: To investigate the effects of computed tomography (CT) reconstruction slice thickness and contrast-enhancement phase on the differential diagnosis performance of radiomic signature in lung adenocarcinoma. METHODS: A total of 187 patients who had been pathologically confirmed with lung adenocarcinoma and nonadenocarcinoma were divided into a training cohort (n = 149) and validation cohort (n = 38). All the patients underwent contrast-enhanced CT and the images were reconstructed with different slice thickness. The radiomic features were extracted from different slice thickness and scan phase. The logistic regression (LR) algorithm was used to build a machine learning model for each group. The area under the curve (AUC) obtained from the receiver operating characteristic (ROC) curve and DeLong test was used to evaluate its discriminating performance. RESULTS: Finally, 34 image features and five semantic features were selected to establish a radiomics model. Based on the three contrast-enhanced CT phases and four reconstruction slice thickness, 12 groups of radiomics models showed good discrimination ability with the AUCs range from 0.9287 to 0.9631, sensitivity range from 0.8349 to 0.9083, specificity range from 0.825 to 0.925 in the training group. Similar results were observed in the validation group. However, there was no statistical significance between the different CT scan phase groups and different slice thickness (p > 0.05). CONCLUSIONS: The radiomic analysis of contrast-enhanced CT can be used for the differential diagnosis of lung adenocarcinoma. Moreover, different slice thickness and contrast-enhanced scan phase did not affect the discriminating ability in the radiomics models.

Lirilumab and Avelumab Enhance Anti-HPV+ Cervical Cancer Activity of Natural Killer Cells via Vav1-Dependent NF-κB Disinhibition.

BACKGROUND: We investigated the efficacy and mechanism of the anti-KIR immunotherapy lirilumab and anti-PD-L1 immunotherapy avelumab on natural killer (NK) cell activity against HPV+ cervical cancer. METHODS: NK cell-mediated lysis of autologous biopsy-derived malignant cervical squamous cells and normal cervical squamous cells were measured by europium-release cytotoxicity assays. Cytokine and granzyme B release were measured by ELISPOT effector-cell-based assays and ELISA. Murine cervical cancer tumor models were constructed to assess implanted tumor volumes over time and intratumoral immune cell infiltration. Receptor-crosslinking and plate-immobilized antibody stimulation studies, with or without p65 and Vav1 silencing, were used to investigate NF-κB pathway disinhibition in NK cells. RESULTS: Lirilumab and avelumab each enhanced NK cell disinhibition and NK cell-mediated lysis of autologous cervical cancer cells in vitro while reducing HPV+ tumor volumes and increasing intratumoral NK cell infiltration and cytolysis in vivo. Moreover, lirilumab and avelumab each promoted NK cell NF-κB disinhibition as well as stimulated cytokine and granzyme B expression in a NF-κB-dependent manner. Lirilumab+avelumab enhanced all aforementioned effects compared to either monotherapy. Vav1 silencing eliminated disinhibition of NF-κB signaling by lirilumab and avelumab, indicating their disinhibiting effects are Vav1-dependent. CONCLUSIONS: This study supports a novel approach to enhancing NK cell lysis against HPV+ cervical cancer cells through combining lirilumab and avelumab.

An AAV vaccine targeting the RBD of the SARS-CoV-2 S protein induces effective neutralizing antibody titers in mice and canines.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in catastrophic damage worldwide. Accordingly, the development of powerful, safe, easily accessible vaccines with long-term effectiveness is understood as an urgently needed countermeasure against this ongoing pandemic. Guided by this strong promise of using AAVs, we here designed, optimized, and developed an AAV-based vaccines (including AAV-RBD(max), AAV-RBD(wt), AAV-2xRBD, and AAV-3xRBD) that elicit strong immune responses against the RBD domain of the SARS-CoV-2 S protein. These immunogenic responses have proven long-lived, with near peak levels for at least six months in mice. Notably, the sera immunized with AAV-3xRBD vaccine contains powerful neutralizing antibodies against the SARS-CoV-2 pseudovirus. Further evidence proven that potent specific antibodies could also be elicited in canines after vaccination with AAV-3xRBD vaccine.

Chromatin Remodeling Induced by ARID1A Loss in Lung Cancer Promotes Glycolysis and Confers JQ1 Vulnerability.

ARID1A is a key mammalian SWI/SNF complex subunit that is mutated in 5% to 11% of lung cancers. Although recent studies have elucidated the mechanism underlying dysregulation of the switch/sucrose non-fermentable (SWI/SNF) complexes in cancers, the significance of ARID1A loss and its implications in lung cancers remain poorly defined. This study investigates how ARID1A loss affects initiation and progression of lung cancer. In genetically engineered mouse models bearing mutant Kras and a deficient Trp53 allele (KP), ARID1A loss (KPA) promoted lung tumorigenesis. Analysis of the transcriptome profiles of KP and KPA tumors suggested enhanced glycolysis following ARID1A loss, and expression of the glycolytic regulators Pgam1, pyruvate kinase M (Pkm), and Pgk1 was significantly increased in ARID1A-deficient lung tumors. Furthermore, ARID1A loss increased chromatin accessibility and enhanced hypoxia-inducible factor-1α (HIF1α) binding to the promoter regions of Pgam1, Pkm, and Pgk1. Loss of ARID1A in lung adenocarcinoma also resulted in loss of histone deacetylase 1 (HDAC1) recruitment, increasing acetylation of histone-4 lysine at the promoters of Pgam1, Pkm, and Pgk1, and subsequently enhancing BRD4-driven transcription of these genes. Metabolic analyses confirmed that glycolysis is enhanced in ARID1A-deficient tumors, and genetic or pharmacologic inhibition of glycolysis inhibited lung tumorigenesis in KPA mice. Treatment with the small molecule bromodomain and extraterminal protein (BET) inhibitor JQ1 compromised both initiation and progression of ARID1A-deficient lung adenocarcinoma. ARID1A negatively correlated with glycolysis-related genes in human lung adenocarcinoma. Overall, ARID1A loss leads to metabolic reprogramming that supports tumorigenesis but also confers a therapeutic vulnerability that could be harnessed to improve the treatment of ARID1A-deficient lung cancer. SIGNIFICANCE: This study links ARID1A loss with enhanced glycolysis in lung cancer and demonstrates the preclinical efficacy of BET inhibitor therapy as a strategy to combat tumor growth.

Controlled release of dinotefuran with temperature/pH-responsive chitosan-gelatin microspheres to reduce leaching risk during application.

Neonicotinoid-based pesticides are extensively used owing to their broad insecticidal spectrum and activity. We developed neonicotinoid dinotefuran (DIN)-loaded chitosan-gelatin microspheres using a spray-drying technology, resulting in a pH- and temperature-responsive controlled-release system. Upon introducing chitosan into the triple-helix structure of gelatin, the physically modified gelatin microspheres became smooth, round, and solid, improving their thermal storage stability. The spray-drying parameters were optimized using three-dimensional surface plots. When scaled up under optimal conditions, the corresponding loading content and encapsulation efficiency were 21.5% and 98.17%, respectively. Compared with commercial dinotefuran granules, our biodegradable composite carriers achieved the immobilization of dinotefuran to reduce pesticide leaching by 5.57-19.89% in soil, improved the soil half-life of DIN, and improved its cumulative absorption by plants. Therefore, the microspheres showed better efficacy against Trialeurodes vaporariorum. Our results confirm that this simple approach can improve the utilization efficiency of neonicotinoids, decrease leaching loss, and promote ecological safety.

Bio-based clothianidin-loaded solid dispersion using composite carriers to improve efficacy and reduce environmental toxicity.

BACKGROUND: Neonicotinoids comprise one of the most extensively used classes of pesticides worldwide owing to their broad insecticidal spectrum and excellent biological performance. However, their toxicity to honeybee (Apis mellifera Linnaeus) and silkworm (Bombyx Mori) limits their further application. To address this issue, clothianidin as a model neonicotinoid was developed into a novel controlled-release formulation employing advantaged solid dispersion (SD) technology using composite carriers. RESULTS: In this research, the clothianidin-loaded SD was characterized using integrated methods to elucidate its formation mechanism, showing that clothianidin was embedded into the carrier homogeneously in small crystalline entities. The composite carriers, which are both renewable and environmentally friendly, can significantly prolong the release of clothianidin from seven to 25 days, compared with that of PEG 8000 as a single carrier. Based on the excellent controlled release profiles, it reduced the acute toxicity to A. mellifera and B. mori by 57.68- and 85.32-fold (respectively) compared with that of the conventional formulation. Furthermore, the SD displayed favorable efficacy and persistency against Asian citrus psyllid (Hemiptera: Psyllidae). CONCLUSION: This novel strategy opens up a simple and powerful avenue for improving efficacy and promoting the environmental safety of neonicotinoid insecticides to be used in sustainable crop protection.

Neurog2 directly converts astrocytes into functional neurons in midbrain and spinal cord.

Conversion of astrocytes into neurons in vivo offers an alternative therapeutic approach for neuronal loss after injury or disease. However, not only the efficiency of the conversion of astrocytes into functional neurons by single Neurog2, but also the conundrum that whether Neurog2-induced neuronal cells (Neurog2-iNs) are further functionally integrated into existing matured neural circuits remains unknown. Here, we adopted the AAV(2/8) delivery system to overexpress single factor Neurog2 into astrocytes and found that the majority of astrocytes were successfully converted into neuronal cells in multiple brain regions, including the midbrain and spinal cord. In the midbrain, Neurog2-induced neuronal cells (Neurog2-iNs) exhibit neuronal morphology, mature electrophysiological properties, glutamatergic identity (about 60%), and synapse-like configuration local circuits. In the spinal cord, astrocytes from both the intact and lesioned sources could be converted into functional neurons with ectopic expression of Neurog2 alone. Notably, further evidence from our study also proves that Neurog2-iNs in the intact spinal cord are capable of responding to diverse afferent inputs from dorsal root ganglion (DRG). Together, this study does not merely demonstrate the feasibility of Neurog2 for efficient in vivo reprogramming, it gives an indication for the Neurog2-iNs as a functional and potential factor in cell-replacement therapy.

Ce-Based Nanoparticles Loaded with Cisplatin for Tumour Radiotherapy.

The combination of radiotherapy and chemotherapy is a common and useful treatment mode for tumours. But traditional methods inevitably lead to a variety of side effects. A drug delivery system (DDS), which has good biocompatibility and strong anti-tumour ability, is expected to solve this problem. Studies have shown that Ce-based nanoparticles (NPs) have good radiosensitization effect through the photoelectric effect. Hence, cisplatin-loaded LiLuF4 :Ce3+scintillation NPs (NP + Cis) were first constructed in this study, which was synthesized by the crystal precipitation method and characterized by transmission electron microscopy (TEM). Subsequently, its toxicity was verified, and the radiosensitization effect and basic radiosensitization mechanism on tumour cells and tumour-bearing mice were researched. Results showed that NP + Cis triggered massive DNA damage and effectively inhibited cell viability in vitro under the exposure of X-ray irradiation (IR). Moreover, the experiments in vivo showed that the NP + Cis had higher biosafety, which could absorb enough irradiation and produce a synergistic inhibitory effect on tumours through the releasing of Cis. NP + Cis can improve the performance of DDS in chemoradiotherapy.

[Synthesis of heptakis(2,3,6-tri-O-methoxymethyl)-beta-cyclodextrin and its application in gas chromatography].

A new chiral stationary phase for gas chromatography, heptakis (2, 3, 6-tri-O-methoxymethyl)-beta-cyclodextrin, was synthesized by substituting the 2,3,6-OH groups of beta-cyclodextrin with methoxymethyl groups, and a coated capillary column for gas chromatography was made by coating this new stationary phase with static method. The chromatographic properties and separation abilities of the prepared stationary phase were studied. The test results showed that it possessed good separation abilities to Grob test mixture, disubstituted benzene isomers (e. g. nitrotoluenes, bromotoluenes, dichlorobenzenes, dimethylbenzenes) and some chiral compounds such as methyl 2-hydroxypropionates, ethyl 2-hydroxypropionates, methyl 2-methylsulfonylpropionates. The comparison of chiral separation results between 2,3,6-tri-O-methoxymethyl-beta-cyclodextrin and 2,3,6-tri-O-methyl-beta-cyclodextrin showed that the separation abilities of the two stationary phases were different and complementary to each other for some chiral ester enantiomers.