Computer-assisted discovery and evaluation of potential ribosomal protein S6 kinase beta 2 inhibitors.

S6K2 is an important protein in mTOR signaling pathway and cancer. To identify potential S6K2 inhibitors for mTOR pathway treatment, a virtual screening of 1,575,957 active molecules was performed using PLANET, AutoDock GPU, and AutoDock Vina, with their classification abilities compared. The MM/PB(GB)SA method was used to identify four compounds with the strongest binding energies. These compounds were further investigated using molecular dynamics (MD) simulations to understand the properties of the S6K2/ligand complex. Due to a lack of available 3D structures of S6K2, OmegaFold served as a reliable 3D predictive model with higher evaluation scores in SAVES v6.0 than AlphaFold, AlphaFold2, and RoseTTAFold2. The 150 ns MD simulation revealed that the S6K2 structure in aqueous solvation experienced compression during conformational relaxation and encountered potential energy traps of about 19.6 kJ mol-1. The virtual screening results indicated that Lys75 and Lys99 in S6K2 are key binding sites in the binding cavity. Additionally, MD simulations revealed that the ligands remained attached to the activation cavity of S6K2. Among the compounds, compound 1 induced restrictive dissociation of S6K2 in the presence of a flexible region, compound 8 achieved strong stability through hydrogen bonding with Lys99, compound 9 caused S6K2 tightening, and the binding of compound 16 was heavily influenced by hydrophobic interactions. This study suggests that these four potential inhibitors with different mechanisms of action could provide potential therapeutic options.

Sustained-release nitrate combined with microbial fuel cell: A novel strategy for PAHs and odor removal from sediment.

Nitrate addition is a biostimulation technique that can improve both the oxidation of acid volatile sulfide (AVS) through autotrophic denitrification and the biodegradation of polycyclic aromatic hydrocarbons (PAHs) via heterotrophic denitrification. However, during the remediation, parts of the dissolved nitrate in the sediment migrates from the sediment to the overlying water, leading to the loss of effective electron acceptor. To overcome this limitation, a combined approached was proposed, which involved nitrocellulose addition and a microbial fuel cell (MFC). Results indicated the nitrate could be slowly released and maintained at a higher concentration over long term. In the combined system, the removal efficiencies of PAHs and AVS were 71.56% and 89.76%, respectively. Furthermore, the voltage attained for the MFC-nitrocellulose treatment was maintained at 146.1 mV on Day 70, which was 5.37 times higher than that of the MFC-calcium nitrate treatment. Sediments with nitrocellulose resulted in lower levels of nitrate and ammonium in the overlying water. Metagenomic results revealed that the combined technology improved the expression of nitrogen-cycling genes. The introduction of MFC inhibited sulfide regeneration during incubation by suppressing the enzyme activity like EC4.4.1.2. The enhanced biostimulation provided potential for in-situ bioremediation utilizing MFC coupled with slow-released nitrate (i.e., nitrocellulose) treatment.

Occurrence and spatiotemporal distribution of PAHs and OPAHs in urban agricultural soils from Guangzhou City, China.

The occurrence of polycyclic aromatic hydrocarbon (PAH) derivatives in the environment is of growing concern because they exhibit higher toxicity than their parent PAHs. This study evaluated the large-scale occurrence and spatiotemporal distribution of 16 PAHs and 14 oxygenated PAHs (OPAHs) in urban agricultural soils from seven districts of Guangzhou City, China. Linear correlation analysis was conducted to explore the relationship between PAH and OPAH occurrence and a series of parameters. The compositional analysis, principal component analysis, diagnostic ratios, and principal component analysis coupled with a multiple linear regression model were used to identify the sources of PAHs and OPAHs in the soils. The average concentrations of ΣPAHs and ΣOPAHs (59.6 ± 31.1-213 ± 115.5 µg/kg) during the flood season were significantly higher than those during the dry season (42.1 ± 13.3-157.2 ± 98.2 µg/kg), which were due to relatively strong wet deposition during the flood season and weak secondary reactions during the dry season. Linear correlation analysis showed that soil properties, industrial activities, and agricultural activities (r = 0.27-0.96, p < 0.05) were responsible for the spatial distribution of PAHs during the dry season. The PAH distribution was mainly affected by precipitation during the flood season. The concentrations of ΣOPAHs were only related to the soil properties during the dry season because their occurrence was sensitive to secondary reactions, climate and meteorological conditions, and their water solubility. Our results further showed that coal combustion and traffic emissions were the dominant origins of PAHs and OPAHs during both the seasons. Wet deposition and runoff-induced transport also contributed to PAH and OPAH occurrence during the flood season. The results of this study can improve our understanding of the environmental risks posed by PAHs and OPAHs.

Biotransformation kinetics and pathways of typical synthetic progestins in soil microcosms.

Gestodene (GES), altrenogest (ALT), and medroxyprogesterone acetate (MPA) are three potent synthetic progestins detected in agricultural soils; however, their biotransformation outcomes in soils remain unclear. This study explored the biotransformation of these progestins in five agricultural soils with different physicochemical properties. The biotransformation data were well-described by a first-order decay model (R2 = 0.83-0.99), with estimated half-lives ranging between 12.1 and 188 h. Amplicon sequencing indicated that the presence of progestins changed the bacterial richness and community structure in the soils. Linear correlation, canonical correlation, and two-way correlation network analysis revealed that soil properties can affect biotransformation rates by interfering with progestin-soil interactions or with keystone taxa in soils. The clustermap demonstrated the formation of abundant transformation products (TPs). Isomerization and C4(5) hydrogenation were the major transformation pathways for GES (yields of ∼ 13.7 % and ∼ 10.6 %, respectively). Aromatic dehydrogenation was the major transformation pathway for ALT (yield of ∼ 17.4 %). The C17 hydrolysis with subsequent dehydration and hydrogenation was the major transformation pathway for MPA (yield of ∼ 196 %). In particular, some TPs exhibited progestagenic, androgenic, or estrogenic activity. This study highlights the importance of evaluating the ecotoxicity of progestin and TP mixtures for better understanding their risks in the environment.

The clinical application value of compound Stachys sieboldii Miq granules to stable COPD patients.

BACKGROUND: The aim of this paper was to explore the application value of Stachys sieboldii Miq granules which is a kind of traditional Chinese medicine (TCM) in stable chronic obstructive pulmonary disease (COPD) patients. METHODS: Randomized double-blind method was used to select 160 patients with stable COPD. The patients were randomly divided into placebo group and Stachys sieboldii Miq group. Both groups underwent test items for 2 months, detected plasma cytokines, Saint George Respiratory Questionnaire (SGRQ) scores, pulmonary function, and the frequency of acute exacerbation (AE) at week 12. Follow-up was done every 12 weeks till 48 weeks to record the frequency of AE. RESULTS: A total of 120 patients with 60 in each group were included. At week 12, there were significant differences in the plasma concentrations of TH17, IL-17A, IFN-γ and IL-10 between the two groups (all P=0.000). The proinflammatory factors TH17 and IL-17A were significantly lower in control group, while the anti-inflammatory factors IFN-γ and IL-10 were higher in the control group. And the SGRQ Score of Stachys sieboldii Miq group was significantly lower. There was no significant difference in lung function (FEV1, FVC, and FEV1/FVC) between the two groups (P=0.510, 0.529, and 0.843). Within 48 weeks, the AE frequency and change with time showed significant differences between the two groups (P=0.029), and the incidence of AE was reduced by 47.9% in Stachys sieboldii Miq group. CONCLUSIONS: Stachys sieboldii Miq granules reduced proinflammatory factors and increased anti-inflammatory factors in stable COPD patients, reducing the probability of inducing AE treatment.

Predictive model for the diagnosis of benign/malignant small pulmonary nodules.

There is some doubt that all nodules <8 mm are really mainly benign and that simple follow-up is adequate in all cases. The purpose of this study is to create a predictive model for the diagnosis of benign and malignant small pulmonary nodules.This was a retrospective case-control study of patients who had undergone pulmonary nodule resection at the Zhejiang University Jinhua Hospital. Patients with pulmonary nodules of ≤10 mm in size on chest high-resolution computed tomography were included. Patients' demographic characteristics, clinical features, and high-resolution computed tomography findings were collected. Logistic regression and receiver-operating characteristic analysis were used to create a predictive model for malignancy.A total of 216 patients were included: 160 with malignant and 56 with benign nodules. Nodule density (odds ratio [OR] = 0.996, 95% confidence interval [CI]: 0.993-0.998, P = .001), vascular penetration sign (OR = 3.49, 95% CI: 1.39-8.76, P = .008), nodule type (OR = 4.27, 95% CI: 1.48-12.29, P = .007), and incisure surrounding nodules (OR = 0.18, 95% CI: 0.04-0.84, P = .03) were independently associated with malignant nodules. These factors were used to create a mathematical model that had an area under the receiver-operating characteristic curve of 0.744. Using a cut-off of 0.762 resulted in 63.1% sensitivity and 75.0% specificity.This study proposes a pulmonary nodule prediction model that can estimate benign/malignant lung nodules with good sensitivity and specificity. Mixed ground-glass nodules, vascular penetration sign, density of lung nodules, and the absence of incisure signs are independently associated with malignant lung nodules.

Decision-making in primary onset middle-age type 2 diabetes mellitus: a BOLD-fMRI study.

Although type 2 diabetes mellitus (T2DM) is a well-recognized risk factor for dementia, the neural mechanisms that underlying cognitive impairment in T2DM remain unclear. We used functional magnetic resonance imaging (fMRI) during a computerized version of the Iowa Gambling Task to investigate the neural basis of decision making at the initial onset stage of T2DM. Eighteen newly diagnosed middle-aged T2DM patients, with no previous diabetic treatment history, and 18 matched controls were recruited. Results indicated that T2DM patients made more disadvantageous decisions than controls. Compared to healthy subjects, T2DM patients showed decreased activation in the ventral medial prefrontal cortex (VMPFC), orbitofrontal cortex (OFC) and anterior cingulate cortex, and increased activity in the dorsolateral prefrontal cortex, posterior cingulate cortex, insula and occipital lobes. IGT performance positively correlated with changes in brain activation in the VMPFC and OFC in both groups. Moreover, poor glycemic control was associated with decision-making function both in behavioral and brain activity in the VMPFC and OFC in patients. Conclusively, T2DM patients may suffer from weaknesses in their prefrontal cortex functions that lead to poorer decision-making under ambiguity, at least as assessed by the IGT.

miR-32 functions as a tumor suppressor and directly targets SOX9 in human non-small cell lung cancer.

PURPOSE: MicroRNA-32 (miR-32) is dysregulated in certain human malignancies and correlates with tumor progression. However, its expression and function in non-small cell lung cancer (NSCLC) remain unclear. Thus, the aim of this study was to explore the effects of miR-32 expression on NSCLC tumorigenesis and development. METHODS: Using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), we detected miR-32 expression in NSCLC cell lines and primary tumor tissues. The association of miR-32 expression with clinicopathological factors and prognosis was also analyzed. Then, the effects of miR-32 expression on the biological behavior of NSCLC cells were investigated. Finally, the potential regulatory effect of miR-32 on SOX9 expression was confirmed. RESULTS: miR-32 expression levels were significantly downregulated in NSCLC compared with the corresponding noncancerous lung tissues (P<0.001). In addition, decreased miR-32 expression was significantly associated with lymph node metastasis (P=0.002), advanced tumor/nodes/metastasis (TNM) classification stages (P<0.001), and shorter overall survival (P<0.001). Multivariate regression analysis corroborated that downregulated miR-32 expression was an independent unfavorable prognostic factor for NSCLC patients. In vitro studies demonstrated that miR-32 overexpression reduced A549 cell proliferation, migration, and invasion, and promoted apoptosis. Furthermore, SOX9 was confirmed as a direct target of miR-32, using a luciferase reporter assay. CONCLUSION: These findings indicate that miR-32 may act as a tumor suppressor in NSCLC and could serve as a novel therapeutic agent for miR-based therapy.

Decreased microRNA-224 and its clinical significance in non-small cell lung cancer patients.

BACKGROUND: MicroRNA-224 has been proven dysregulated in some human malignancies and correlated with tumor progression. However, its expression and clinical significance in non-small cell lung cancer (NSCLC) is still unclear. Thus, the aim of this study was to explore the effects of miR-224 in NSCLC tumorigenesis and development. METHODS: Using real-time quantitative RT-PCR, we detected miR-224 expression in NSCLC cell lines and primary tumor tissues. The association of miR-224 expression with clinicopathological factors and prognosis was also statistically analyzed. MTT, flow cytometric, Transwell invasion and migration assays, and scratch migration assay were used to test the proliferation, apoptosis, invasion, and migration of NSCLC cells after miR-224 mimics transfection. RESULTS: MiR-224 expression levels were significantly down-regulated in NSCLC compared to the corresponding noncancerous lung tissues (P <0.001). In addition, decreased miR-224 expression was significantly associated with lymph node metastasis (P = 0.002), advanced TNM stage (P <0.001), and shorter overall survival (P <0.001). Multivariate regression analysis corroborated that down-regulation of miR-224 was an independent unfavourable prognostic factor for patients with NSCLC. Furthermore, transfection of miR-224 mimics in NSCLC A549 cells was able to reduce cell proliferation, invasion, and migration, and promote cell apoptosis. CONCLUSIONS: These findings indicate that miR-224 may act not only as a novel diagnostic and prognostic marker, but also as a potential target for miR-based therapy of NSCLC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_198.

Single frequency sound propagation in flat waveguides with locally reactive impedance boundaries.

A coherent image source method is presented for evaluating single frequency sound propagation from a point source in a flat waveguide with two infinite and parallel locally reactive boundaries. The method starts from formulating reflections of the spherical sound radiation into integrals of plane wave expansion, and the analytical evaluation of the integrals is simplified by introducing a physically plausible assumption that wave front shapes remain the same before and after each reflection on a reflective boundary. The proposed model can determine coherently the sound fields at arbitrary receiver locations in a flat waveguide, even when one boundary is highly sound absorptive. Being compared with the classical wave theory and the existing coherent ray-based methods, it is shown that the proposed method provides considerable accuracy and advantages to predict sound propagation in flat waveguides with a sound absorptive ceiling and a reflective floor over a broad frequency range, particularly at large distances from the source where the existing methods are problematic.