Novel CDK19-Targeted Radiotracers: A Potential Design Strategy to Improve the Pharmacokinetics and Tumor Uptake.

Cyclin-dependent kinase 19 (CDK19) is overexpressed in prostate cancer, making it an attractive target for both imaging and therapy. Since little is known about the optimized approach for radioligands of nuclear proteins, linker optimization strategies were used to improve pharmacokinetics and tumor absorption, including the adjustment of the length, flexibility/rigidity, and hydrophilicity/lipophilicity of linkers. Molecular docking was conducted for virtual screening and followed by IC50 determination. Both BALB/c mice and P-16 xenografts were used for tissue distribution and PET/CT imaging. The ligand 68Ga-10c demonstrated high absorption in tumor 5 min after injection and sustains long-term imaging within 3 h. Furthermore, 68Ga-10c exhibited slow clearance within the tumor and was predominantly metabolized in both the liver and kidneys, showing the potential to alleviate metabolic pressure and enhance tissue safety. Therefore, the linker optimization strategy is well suited for CDK19 and provides a reference for the radioactive ligands of other nuclear targets.

Identification of a hub gene VCL for atherosclerotic plaques and discovery of potential therapeutic targets by molecular docking.

BACKGROUND: Atherosclerosis (AS) is a pathology factor for cardiovascular diseases and instability of atherosclerotic plaques contributes to acute coronary events. This study identified a hub gene VCL for atherosclerotic plaques and discovered its potential therapeutic targets for atherosclerotic plaques. METHODS: Differential expressed genes (DEGs) were screened between unstable and stable plaques from GSE120521 dataset and then used for construction of a protein-protein interactions (PPI) network. Through topological analysis, hub genes were identified within this PPI network, followed by construction of a diagnostic model. GSE41571 dataset was utilized to validate the diagnostic model. A key hub gene was identified and its association with immune characteristics and pathways were further investigated. Molecular docking and molecular dynamics (MD) simulation were employed to discover potential therapeutic targets. RESULTS: According to the PPI network, 3 tightly connected protein clusters were found. Topological analysis identified the top 5 hub genes, Vinculin (VCL), Dystrophin (DMD), Actin alpha 2 (ACTA2), Filamin A (FLNA), and transgelin (TAGLN). Among these hub genes, VCL had the highest diagnostic value. VCL was selected for further analysis and we found that VCL was negatively correlated with immune score and AS-related inflammatory pathways. Next, we identified 408 genes that were highly correlated with VCL and determined potential drug candidates. The results from molecular docking and MD simulation showed compound DB07117 combined with VCL protein stably, the binding energy is -7.7 kcal/mol, indicating that compound DB07117 was a potential inhibitor of VCL protein. CONCLUSION: This study identified VCL as a key gene for atherosclerotic plaques and provides a potential therapeutic target of VCL for the treatment of atherosclerotic plaques.

Organic management increases beneficial microorganisms and promotes the stability of microecological networks in tea plantation soil.

Introduction: Organic agriculture is highly regarded by people for its commitment to health, ecology, care, and fairness. The soil microbial community responds quickly to environmental changes and is a good indicator for evaluating soil microecology. Therefore, from the perspective of soil microbial communities, elucidating the impact of organic management on soil microecology in tea plantations has great significance for improving local tea plantation systems. Methods: The study collected bulk soil from organic management (OM) and conventional management (CM) tea plantations in Pu'er City, a major tea-producing area in China, and analyzed their species diversity, structural composition, and co-occurrence networks using metagenomics technology. Results: Compared with CM, the diversity index (Shannon) and evenness index (Heip) of soil fungi increased by 7.38% and 84.2% in OM tea plantations, respectively. The relative abundance of microorganisms related to the nitrogen cycle increased. Specifically, there was a significant increase in Rhodobiales, a 2-fold increase in Nitrospirae, and approximately 1.95 and 2.03 times increases in unclassified genera within Betaproteobacteria and Deltaproteobacteria, respectively. The relative abundance of plant residue degradation species, Gemmatimonadetes, Ascomycota, and Basidiomycota, increased by 2.8, 1, and 1.4 times, respectively. The OM was conducive to the establishment of collaborative relationships among bacterial species and increased the diversity and complexity of species relationships in fungal communities. The network stability of soil ecosystems was promoted. The organic tea plantations' keystone taxa contained mycorrhizal fungi (Pezoloma_ericae, Rhizophagus_irregularis, Rhizophagus_clarus), as well as species involved in soil nitrogen metabolism (Acidobacteria_bacterium, Acidobacteriia_bacterium_AA117, Sphingomonas_sp._URHD0007, Enhydrobacter_aerosaccus), pathogen (Erysiphe_pulchra), and parasites (Paramycosporidium saccamoeba). The partial least squares method (PLS-SEM) indicated that OM affected N-NH4+ negatively, increasing the abundance of fungi, and thereby positively affecting the Shannon index. Conclusion: In brief, reasonable organic management can improve the diversity of soil microorganisms, increase the relative abundance of beneficial bacteria in tea plantation soil, and promote the stability of the soil microbial ecological network.

Antiocclusion Visual Tracking Algorithm Combining Fully Convolutional Siamese Network and Correlation Filtering.

Machine learning only uses single-channel grayscale features to model the target, and the filter solution process is relatively simple. When the target has a large change relative to the initial frame, the tracking effect is poor. When there is the same kind of target interference in the target search area, the tracking results will be poor. The tracking algorithm based on the fully convolutional Siamese network can solve these problems. By learning the similarity measurement function, the similarity between the template and the target search area is evaluated, and the target area is found according to the similarity. It adopts offline pre-training and does not update online for tracking, which has a faster tracking speed. According to this study, (1) considering the accuracy and speed, the target tracking algorithm based on correlation filtering performs well. A sample adaptive update model is introduced to eliminate unreliable samples, which effectively enhances the reliability of training samples. With simultaneous changes in illumination and scale, fast motion and in-plane rotation IPR can still be maintained. (2) Determined by calculating the Hessian matrix, in the Struck function, Bike3 parameter adjustment can achieve fast tracking, and Boat5 ensures that the system stability is maintained in the presence of interference factors. The position of the highest scoring point in the fine similarity score map of the same size as the search image is obtained by bicubic interpolation as the target position. (3) The parallax discontinuity caused by the object boundary cannot be directly processed as a smooth continuous parallax. The MeanShift vector obtained by calculating the target template feature and the feature to be searched can increase the accuracy by 53.1%, reduce the robustness by 31.8%, and reduce the error by 28.6% in the SiamVGG algorithm.

Initial Assessment on Hydraulic Conductivity of Rock Mass and its Size Effect Using Drilling Data.

Predicting hydraulic conductivity and characterizing its size effect in jointed rock masses is fundamental to various geoscience and engineering disciplines. A new empirical method, using drilling data, is established to predict the hydraulic conductivity of a rock mass in the scanline direction. The effect of the scanline unit length on the distribution characteristics of hydraulic conductivity for boreholes in jointed rock masses is studied. In addition, the scanline length of boreholes was used to study the size effect of hydraulic conductivity of jointed rock masses, and a new model was proposed to determine the size effect of hydraulic conductivity. A mathematical method for representative volume element (RVE) determination was proposed based on the proposed size effect model of hydraulic conductivity. Some packer tests were conducted to validate the developed method for predicting hydraulic conductivity. The results show that (a) the predicted hydraulic conductivities are close to those determined from the packer tests; (b) the scanline unit lengths influence the distribution characteristics of hydraulic conductivity; (c) a large but fluctuating increase in hydraulic conductivity with increasing scanline length, and the fluctuation decreases with fewer fractures and joints; (d) the mathematical method for predicting RVE and KRVE is effective to make an initial evaluation on jointed rock masses with high fracture frequency.

Functional Screenings Identify Regulatory Variants Associated with Breast Cancer Susceptibility.

Genome-wide association studies (GWAS) have identified more than 2000 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, most of which are located in the non-coding region. However, the causal SNPs functioning as gene regulatory elements still remain largely undisclosed. Here, we applied a Dinucleotide Parallel Reporter sequencing (DiR-seq) assay to evaluate 288 breast cancer risk SNPs in nine different breast cancer cell lines. Further multi-omics analysis with the ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), DNase-seq (DNase I hypersensitive sites sequencing) and histone modification ChIP-seq (Chromatin Immunoprecipitation sequencing) nominated seven functional SNPs in breast cancer cells. Functional investigations show that rs4808611 affects breast cancer progression by altering the gene expression of NR2F6. For the other site, rs2236007, the alteration promotes the binding of the suppressive transcription factor EGR1 and results in the downregulation of PAX9 expression. The downregulated expression of PAX9 causes cancer malignancies and is associated with the poor prognosis of breast cancer patients. Our findings contribute to defining the functional risk SNPs and the related genes for breast cancer risk prediction.

Anti-depressant effect of curcumin-loaded guanidine-chitosan thermo-sensitive hydrogel by nasal delivery.

Curcumin, a polyphenol compound extracted from the roots of turmeric plants, possesses anti-depressant effect by regulating the levels of neuroendocrine immunological factors. The purpose of this study was to investigate the anti-depressant effect of curcumin through nasal delivery. The results of phase solubility, Fourier transform infrared spectra, Differential scanning calorimetry, X-ray powder diffractometry and 1H NMR spectra assays showed that curcumin/hydroxypropyl-ß-cyclodextrin complex had been obtained. The viscosity of hydrogel increased rapidly at the temperature range of 29-30 °C through the test of rheological property of Guanidine-Chitosan thermo-sensitive hydrogel. And the hydrogel had good mucoadhesion properties. The cumulative release rate of curcumin was 55% in 10 h in vitro drug release test. Curcumin-loaded (14.6, 29.2, or 58.4 µg/kg) thermo-sensitive hydrogel could reduce the immobility time of mice in force swimming test and tail suspension test, while could not increase the independent behavioral activity of mice. In addition, curcumin-loaded (14.6, 29.2, or 58.4 µg/kg) thermo-sensitive hydrogel could increase the concentration of Norepinephrine, Dopamine, 5-Hydroxytryptamine and their metabolites in hippocampus and striatum. In conclusion, thermo-sensitive hydrogel delivery system can be seen as a promising formulation of curcumin for the treatment of depression through nasal delivery.

Expression and Functional Analysis of a Novel Group of Legume-specific WRKY and Exo70 Protein Variants from Soybean.

Legumes fix atmospheric nitrogen through symbiosis with microorganisms and contain special traits in nitrogen assimilation and associated processes. Recently, we have reported a novel WRKY-related protein (GmWRP1) and a new clade of Exo70 proteins (GmExo70J) from soybean with homologs found only in legumes. GmWRP1 and some of the GmExo70J proteins are localized to Golgi apparatus through a novel N-terminal transmembrane domain. Here, we report further analysis of expression and functions of the novel GmWRP1 and GmExo70J genes. Promoter-GUS analysis in Arabidopsis revealed distinct tissue-specific expression patterns of the GmExo70J genes not only in vegetative but also in reproductive organs including mature tissues, where expression of previously characterized Exo70 genes is usually absent. Furthermore, expression of some GmExo70J genes including GmExo70J1, GmExo70J6 and GmExo70J7 increases greatly in floral organ-supporting receptacles during the development and maturation of siliques, indicating a possible role in seed development. More importantly, suppression of GmWRP1, GmExo70J7, GmExo70J8 and GmExo70J9 expression in soybean using virus- or artificial microRNA-mediated gene silencing resulted in accelerated leaf senescence and reduced nodule formation. These results strongly suggest that legume-specific GmWRP1 and GmExo70J proteins play important roles not only in legume symbiosis but also in other processes critical for legume growth and development.

Therapeutic effect of liposomal prostaglandin E1 in acute lower limb ischemia as an adjuvant to hybrid procedures.

Prostaglandin E1 (PGE1) is widely used in the treatment of limb ischemia for its potent vasodilatory and antiplatelet effects. In order to assess the curative effect of liposomal PGE1 (lipo-PGE1) as an adjuvant to surgery in patients with acute lower limb ischemia (ALLI), 204 patients who underwent hybrid procedures (operative thromboembolectomy or bypass and necessary endovascular interventions) for ALLI were randomly divided into a blank control group and a lipo-PGE1 group (intravenous infusion of 20 µg/day for 12-14 consecutive days following surgery). Patients were followed-up for 6 months after surgical revascularization for clinical events. The primary study endpoint, which was the combined incidence of perioperative (30 days) mortality (POM) and major adverse limb events (MALE; amputation or major intervention), was significantly reduced in patients treated with lipo-PGE1 (5.1% compared with 13.2% in the control group). The overall incidence of clinical events, including POM, MALE and major adverse cardiovascular events, was significantly reduced in patients receiving lipo-PGE1 (8.2%) compared with the controls (20.8%). Hybrid procedures are an improved method for treating ALLI and may remedy underlying lesions of vessels following thromboembolectomy.

[Effect of CO2 fertilization on residual concentration of cypermethrin in rhizosphere of C3 and C4 plant].

In order to achieve sustainable economic and environmental development in China, CO2-emission reduction and phytoremediation of polluted soil must be resolved. According to the effect of biological carbon sequestration on rhizosphere microenvironment, we propose that phytoremediation of polluted soil can be enhanced by CO2 fertilization, and hope to provide information for resolving dilemma of CO2-emission reduction and phytoremediation technology. In this study, effects of CO2 fertilization on cypermethrin reduction in rhizosphere of C3-plant (bush bean) and C4-plant (maize) were investigated. Results showed that dry weight of shoot and root of bush bean (C3 plant) was increased by CO2 fertilization. Relative to ambient CO2, dry weight of root was increased by 54.3%, 31.9% and 30.0% in soil added with 0, 20 and 40 mg x kg(-1) cypermethrin respectively. Microbial biomass was increased by CO2 fertilization in rhizosphere soil added with 0 mg x kg(-1) cypermethrin, but negative effect was found in rhizosphere soil added with 20 and 40 mg x kg(-1) cypermethrin. CO2 fertilization slightly affected residual concentration of cypermethrin in rhizosphere soil added with 0 mg x kg(-1) cypermethrin, but significantly decreased residual concentration of cypermethrin as 24.0% and 16.9% in soil added with 20 and 40 mg x kg(-1) relative to ambient CO2. In maize plant, however, plant growth, microbial biomass and residual cypermethrin concentration in rhizosphere was slightly affected by CO2 fertilization, and even negative effect was observed. This study indicated that CO2 fertilization decreases the residual concentration of cypermethrin in rhizosphere of C3-plant, and it is possible to enhance phytoremediation of organic-polluted soil by C3-plant through CO2 fertilization. However, further study is needed for C4-plant.