On inverse problems for several coupled PDE systems arising in mathematical biology.

In this paper, we propose and study several inverse problems of identifying/determining unknown coefficients for a class of coupled PDE systems by measuring the average flux data on part of the underlying boundary. In these coupled systems, we mainly consider the non-negative solutions of the coupled equations, which are consistent with realistic settings in biology and ecology. There are several salient features of our inverse problem study: the drastic reduction of the measurement/observation data due to averaging effects, the nonlinear coupling of multiple equations, and the non-negative constraints on the solutions, which pose significant challenges to the inverse problems. We develop a new and effective scheme to tackle the inverse problems and achieve unique identifiability results by properly controlling the injection of different source terms to obtain multiple sets of mean flux data. The approach relies on certain monotonicity properties which are related to the intrinsic structures of the coupled PDE system. We also connect our study to biological applications of practical interest.

Elabela, a Novel Peptide, Exerts Neuroprotective Effects Against Ischemic Stroke Through the APJ/miR-124-3p/CTDSP1/AKT Pathway.

Elabela (ELA), which is the second endogenous peptide ligand of the apelin receptor (APJ) to be discovered, has been widely studied for potential use as a therapeutic peptide. However, its role in ischemic stroke (IS), which is a leading cause of disability and death worldwide and has limited therapeutic options, is uncertain. The aim of the present study was to investigate the beneficial effects of ELA on neuron survival after ischemia and the underlying molecular mechanisms. Primary cortical neurons were isolated from the cerebral cortex of pregnant C57BL/6J mice. Flow cytometry and immunofluorescence showed that ELA inhibited oxygen-glucose deprivation (OGD) -induced apoptosis and axonal damage in vitro. Additionally, analysis of the Gene Expression Omnibus database revealed that the expression of microRNA-124-3p (miR-124-3p) was decreased in blood samples from patients with IS, while the expression of C-terminal domain small phosphatase 1 (CTDSP1) was increased. These results indicated that miR-124-3p and CTDSP1 were related to ischemic stroke, and there might be a negative regulatory relationship between them. Then, we found that ELA significantly elevated miR-124-3p expression, suppressed CTDSP1 expression, and increased p-AKT expression by binding to the APJ receptor under OGD in vitro. A dual-luciferase reporter assay confirmed that CTDSP1 was a direct target of miR-124-3p. Furthermore, adenovirus-mediated overexpression of CTDSP1 exacerbated neuronal apoptosis and axonal damage and suppressed AKT phosphorylation, while treatment with ELA or miR-124-3p mimics reversed these effects. In conclusion, these results indicated that ELA could alleviate neuronal apoptosis and axonal damage by upregulating miR-124-3p and activating the CTDSP1/AKT signaling pathway. This study, for the first time, verified the protective effect of ELA against neuronal injury after ischemia and revealed the underlying mechanisms. We demonstrated the potential for the use of ELA as a therapeutic agent in the treatment of ischemic stroke.

Static and dynamic mechanical properties and deterioration of bedding sandstone subjected to freeze-thaw cycles: considering bedding structure effect.

The bedding rock widely exists in nature and its mechanical properties are complex. In this study, the Φ100 mm split Hopkinson pressure bar (SHPB), freeze-thaw(F-T) cycle test system joint with scanning electron microscope and other facilities are applied to investigate the static characteristics, impact characteristics, and damage microstructure of the bedding rock under freezing and thawing conditions. Our experimental results show that under the F-T cycle conditions, the peak point deteriorating path of the static stress-strain curve and the post-peak strain softening curve of the vertical and parallel bedding sandstone specimens have obvious anisotropic characteristics. Parallel bedding specimens have a "pressure bar" effect when loaded. Under the dynamic mechanical test, the peak stress of the vertical bedding specimen is always larger than that of the parallel bedding specimen, and the difference between the two becomes larger while the impact velocity increases. Finally, our microscopic analysis indicates that the main reason for the formation of fissures in the bedding sandstone under the F-T cycle is the cracking of the cement and the shedding of the mineral particles, while the fracture of the mineral particles rarely occurs. The results can provide theoretical guidance for geotechnical engineering in alpine regions.

Longitudinal Analysis of Risk Factors for Clinical Outcomes of Enterobacteriaceae Meningitis/Encephalitis in Post-Neurosurgical Patients: A Comparative Cohort Study During 2014-2019.

PURPOSE: Our study is a retrospective observational study conducted in one of the largest clinical centers of neurosurgery in China. We aimed to investigate the antimicrobial susceptibility patterns of the Enterobacteriaceae isolates responsible for nosocomial meningitis/encephalitis in post-neurosurgical patients. Meanwhile, we tried to evaluate the risk factors for mortality following Enterobacteriaceae meningitis/encephalitis. PATIENTS AND METHODS: Medical data on clinical characteristics, antibiotic susceptibilities, and mortality were reviewed until patients' discharge or death in the hospital. Data for a total of 164 cerebrospinal fluid (CSF) infection cases due to Enterobacteriaceae after neurosurgery were collected between January 2014 and November 2019 in order to identify risk factors affecting the outcome. Kaplan-Meier survival analysis and multivariable Cox proportional hazard models were applied. RESULTS: In this study, a total of 2416 neurosurgical meningitis/encephalitis cases were reported between 2014 and 2019. Enterobacteriaceae accounted for 7.3% (176/2416) of all the bacterial infections. Of them, 164 Enterobacteriaceae isolates were available to divide into two groups according to the final outcome of whether the patient died or survived. In total, 38 patients died (23.2%) and 126 patients survived (76.8%). The most frequent infecting species was Klebsiella pneumoniae (47.0%, 77/164). Fourteen-day and 30-day mortality rates were 7.9% (13/164) and 15.2% (25/164). Kaplan-Meier survival analysis revealed that the risk factors of Enterobacteriaceae meningitis/encephalitis that resulted in poor outcomes included comorbidities, Glasgow Coma Scale (GCS) score, sepsis, intensive care unit (ICU) admission, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, and ventilation. A GCS score of less than or equal to 8 (P=0.04, HR 2.562) was identified to be a significant risk factor for mortality according to the multivariable Cox proportional hazards model. CONCLUSION: In-hospital mortality caused by Enterobacteriaceae meningitis/encephalitis in neurosurgery was high. A GCS score of ≤8 was an independent risk factor for mortality following Enterobacteriaceae meningitis/encephalitis in post-neurosurgical patients.

DPP-4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic/high-glucose conditions, potentially through the SIRT1/HIF-1/VEGF pathway.

BACKGROUND: Vascular disease in diabetes, for example, stroke, presents a significant public health burden. Recently, the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin has been found to counteract stroke among diabetic patients, showing great promise in drug repurposing and indication expansion. However, the molecular basis of this protection mechanism remains unknown. METHODS: The expression and localization of DPP-4 in rat brain microvascular endothelial cells (rBMVECs) were assessed with immunofluorescent staining and Western blotting. The effects of DPP-4 inhibitors on cell proliferation and migration of rBMVECs were determined using MTT and transwell assays, separately. The influence of DPP-4 inhibition on the expression of molecular markers (eg, VEGF, eNOS, HIF-1α. SIRT1) was examined at both mRNA and protein levels with qRT-PCR and Western blotting, individually. RESULTS: DPP-4 inhibitors (40 nmol/L linagliptin, 30 µmol/L berberine) offer protection from hypoxia/high glucose induced impairments in the proliferation and migration of rBMVECs. Treatment with DPP-4 inhibitors counteracted the attenuating effects of hypoxic/high-glucose conditions on the expression of VEGF, eNOS, HIF-1α, and SIRT1, which can be completely eliminated by the inhibition of SIRT1 with 1 mmol/L nicotinamide. CONCLUSIONS: The protection of rBMVECs from hypoxia/high-glucose induced impairment by DPP-4 inhibitors may be mediated by the SIRT1/HIF-1α/VEGF pathway.

Design and Synthesis of Cajanine Analogues against Hepatitis C Virus through Down-Regulating Host Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1.

There still remains a need to develop new anti-HCV agents with distinct mechanism of action (MOA) due to the occurrence of resistance to direct-acting antiviral agents (DAAs). Cajanine, a stilbenic component isolated from Cajanus cajan L., was identified as a potent HCV inhibitor by phenotypic screening in this work (EC50 = 3.17 ± 0.75 µM). The intensive structure optimization provided significant insights into the structure-activity relationships. Furthermore, the MOA study revealed that cajanine inhibited HCV replications via down-regulating a cellular protein chondroitin sulfate N-acetylgalactosaminyltransferase 1. In consistency with this host-targeting mechanism, cajanine showed the similar magnitude of inhibitory activity against both drug-resistant and wild-type HCV and synergistically inhibited HCV replication with approved DAAs. Taken together, our study not only presented cajanine derivatives as a novel class of anti-HCV agents but also discovered a promising anti-HCV target to combat drug resistance.

[Estimating Soil Iron Content Based on Reflectance Spectra].

In recent decades, the application of spectral technology in soil science is getting more and more attention. Soil information can be obtained quickly by using soil reflectance spectra to understand the physical and chemical properties of soil and to estimate soil iron content. In previous studies, the surface soil always is selected for the estimation of soil iron content by using spectroscopy. It needs to estimate total iron and, the different forms of soil iron is ignored, therefore, the estimation result is not ideal. In order to gets a different form of soil iron processing method of optimal model to evaluate the accuracy of models, as well as discuss the organic matter content and soil depth on the influence of different forms of soil iron estimation accuracy. A total of 160 soil samples were collected from 20 sites in Dongtai city, Jiangsu province. These samples were ground to 10 meshes and 100 meshes. In the use of 8 different methods for the pretreatment of the same time each method will be selected by a variety of parameters, using partial least squares regression method to model the total reflection band and the total iron, free iron, amorphous iron content in the soil respectively, then evaluation model precision. The results showed that: (1) the optimal model of three kinds of soil iron was all ground to 100 meshes and the best pretreatment method was MSC. The prediction accuracy of total iron was acceptable and R2 was less than 0.6. The results of free iron and amorphous iron inversion were better and the R2 was 0.77 and 0.69, respectively. The errors were small and the models were stable. (2) Because the ferric metasilicate in total iron is easily affected by external environment, the organic matter and soil depth are of great influence on the estimate precision of total iron the most. But the estimation accuracy of free iron is the least affected. Because of the low content of amorphous iron, the estimated model is also susceptible to the influence of organic matter and soil depth.

A Mechanism Study of Reflectance Spectroscopy for Predicting Soil Total Nitrogen.

Reflectance spectroscopy has been widely used for predicting soil properties due to its rapidity and convenience. In past decades, the application of soil spectroscopy on soil science studies has increased exponentially. The total nitrogen (TN) content in soil is an important index for soil fertility and the rapid prediction of TN content with spectroscopy serves an important function in precision agriculture. However, whether the TN content in soil is predicted through its relationship with soil organic carbon (SOC) or on its specific absorption is still debatable. The objective of this study was to explore the mechanism of reflectance spectroscopy for predicting TN in soils. Soils used for calibration were sampled from coastal soil in the north of Jiangsu province. Partial least squares regression (PLSR) analysis was used for the calibration datasets with different TN content when the sample number is the same in every dataset. In order to explore the mechanism of reflectance spectroscopy for predicting total nitrogen in soil, the changes of model accuracies and the correlation of TN and SOC were analyzed. The results indicated that the contents of TN and SOC in soil were relatively lower because the soil was derived from coastal sediments in the past 1 000 years and formed during cultivation. There was strong correlation between TN and SOC (R=0.98). The prediction accuracy of TN increased at first and then decreased slightly with the increase of mean, standard deviation of TN content. Meanwhile, the changes of prediction accuracy comply well with coefficients of variation. In conclusion, when the TN content is relatively low (mean TN<0.27 g·kg-1), the correlation coefficient between TN and SOC was moderately-high and TN was predicted on the basis of N absorbers. When the TN content is relatively high (mean TN>0.29 g·kg-1), strong correlation coefficients were obtained for TN and SOC and the model accuracy of SOC were better than TN. The effect of SOC to spectroscopy enhanced with the increase of SOC content, which masked the spectral features of N. Therefore, TN was predicted through the correlation with SOC when the TN content is high. This study revealed the mechanism of reflectance spectroscopy for predicting TN in soil and it could provide a theoretical basis for predicting soil TN content rapidly using reflectance spectroscopy.

Design, synthesis and in vitro and in vivo antitumour activity of 3-benzylideneindolin-2-one derivatives, a novel class of small-molecule inhibitors of the MDM2-p53 interaction.

A novel class of small-molecule inhibitors of MDM2-p53 interaction with a (E)-3-benzylideneindolin-2-one scaffold was identified using an integrated virtual screening strategy that combined both pharmacophore- and structure-based approaches. The hit optimisation identified several compounds with more potent activity than the hit compound and the positive drug nutlin-3a, especially compound 1b, which exhibited both the highest binding affinity to MDM2 (Ki = 0.093 µM) and the most potent antiproliferative activity against HCT116 (wild type p53) cells (GI50 = 13.42 µM). Additionally, 1b dose-dependently inhibited tumour growth in BALB/c mice bearing CT26 colon carcinoma, with no visible sign of toxicity. In summary, compound 1b represents a novel and promising lead structure for the development of anticancer drugs as MDM2-p53 interaction disruptors.

Synthesis and anti-influenza virus activities of a novel class of gastrodin derivatives.

A series of substituted aryl glycoside analogues of gastrodin have been identified as potential anti-influenza agents. The most potent inhibitor 1a exhibited moderate inhibitory activity against the A/Hanfang/359/95(H3N2) and A/FM/1/47(H1N1) strains of the influenza A virus (IC(50) values of 44.40 and 34.45 µM, respectively) and the oseltamivir-null B/Jifang/13/97 strain of influenza B (IC(50) value of 33.01 µM). In this article, multiple doses of compound 1a (80 mg/kg/day, oral administration) were used for the treatment of mice infected with influenza A/FM/1/47-MA (H1N1), and surprisingly we found that compound 1a significantly increased the number of survivors and prolonged the mean survival time. The preliminary studies on the mechanism of antiviral activity showed no interaction between compound 1a and the neuraminidase or the M2 protein. The novel target to overcome drug resistance combined with its good in vivo profile support compound 1a to be a new lead for further development of antiviral agents.

[Prediction of As in soil with reflectance spectroscopy].

In the present study, visible-near infrared reflectance spectroscopy (VNIR) measured in laboratory was evaluated for prediction of the content of As in soils. Calibrations between As and reflectance were developed using cross-validation under partial least squares regression (PLSR). Prediction accuracy was tested via separate validation samples. The reflectance was pre-processed by several techniques like smoothing, multiplicative scatter correction (MSC), Log(1/R), first/second derivative (F/ SD) and continuum removal (CR). The accuracy of prediction was evaluated with three statistics: coefficients of determination (R2), ratio of performance to deviation (RPD), and root mean square error of prediction (RMSEP). The results of calibration, cross-validation and prediction of different pre-processing techniques, spectral resolution and OM content were compared. MSC provided better prediction (Prediction R2 = 0.711, RPD = 1.827, RMSEP = 1.613) than other methods because it removed the effects of light scattering and sample thickness. All the results of different resolution are acceptable (Prediction 0.678 < R2 < 0.711, 1.750 < RPD < 1.827, 1.613 < RMSEP < 1.685). The prediction accuracy of subsets with lower OM content(Prediction R2 = 0.694, RPD = 1.697, RMSEP = 1.644) was better than that with higher content. The study indicates that it is feasible to predict As element in soils using reflectance spectroscopy and the prediction accuracy can be improved by pre-processing. Thus this new rapid and cost-effective technique can be used in the monitoring of soil contamination.