Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole. coadministrated 13 1 3 1/ practice CYPC CYP C CYP2C1 drugdrug drug interactionsDDIs interactions interactions(DDIs (PBPK error AUC024, AUC024 AUC AUC0 24, 24 AUC0-24 tmax population 146h h PMs, PMs , (PMs) IMs (IMs metabolizersEMs, metabolizersEMs EMs metabolizers(EMs) respectively CYP2C AUC02 2 AUC0-2 (PMs metabolizers(EMs AUC0-

Abstract Introduction: This study investigated the correlation between the levels of long noncoding ribonucleic acids (lncRNAs) AF131217.1 and coronary slow flow (CSF). Methods: A total of 22 patients in the high-sensitivity C-reactive protein (hsCRP) group diagnosed with CSF from January 2018 to December 2018 were enrolled in this study. Coronary flow velocity was determined using the thrombolysis in myocardial infarction frame count (TFC) method. Results: LncRNA AF131217.1 expression in the CSF model was activated. Mean TFC was positively correlated with lncRNA AF131217.1 levels and hsCRP levels. LncRNA AF131217.1 induced inflammation factor levels in the in vitro model. Micro ribonucleic acid (miR)-128-3p is a target spot of lncRNA AF131217.1 on the inflammation in vitro model via Kruppel-like factor (KLF) 4. MiR-128-3p reduced inflammation factor levels (tumor necrosis factor alpha, interleukin [IL]-6, IL-1β, and IL-18). Conclusion: Thus, lncRNA AF131217.1 promoted inflammation in the regulated CSF via KLF4 by miR-128-3p. Introduction lncRNAs (lncRNAs AF1312171 AF AF131217 1 AF131217. CSF. . (CSF) Methods 2 highsensitivity high sensitivity Creactive C reactive (hsCRP 201 (TFC method Results activated miR1283p miRp miR 128 3p p Kruppellike Kruppel like KLF (KLF 4 MiR1283p MiRp MiR tumor alpha IL6, IL6 IL 6, 6 [IL]-6 IL1β, IL1β ILβ 1β, 1β β IL-1β IL18. IL18 18 IL-18) Conclusion Thus miR1283p. 3p. miR-128-3p AF13121 (CSF 20 12 [IL]- IL1 IL-18 AF1312 [IL] IL-1 AF131 [IL IL- AF13 AF1

Abstract Objectives To explore the role and possible mechanisms of action of apolipoprotein O (APOO) in autophagy in Myocardial Infarction (MI) in vivo and in vitro. Methods Differential gene expression and single Gene Set Enrichment Analysis (GSEA) were used to evaluate MI-related candidate genes. Animal and cell MI models were established. Sh-APOO, si-APOO, and SB203580 were used to inhibit the expression of APOO or p38MAPK. Western blot and qRT-PCR were used to analyze the expression levels of the target protein or mRNA. Apoptosis was observed using the TUNEL assay. The plasma concentrations of CK-MB and cTn-I in humans and mice were determined. Results In the GSE23294 dataset, APOO mRNA was highly expressed in the left ventricle of mice with MI; GSEA revealed that APOO was positively correlated with p38MAPK, autophagy, and apoptosis. The plasma concentration of APOO in patients with MI was significantly higher than that in healthy subjects. The expression of APOO, Beclin-1, LC3, and Bax in mouse and AC16 cell MI models increased, while the level of Bcl-2 decreased. After silencing the APOO gene, the expression of APOO was downregulated; meanwhile, changes in autophagy, apoptosis and myocardial cell injury were reversed in vivo and in vitro. Furthermore, autophagy was alleviated after AC16 cells were treated with SB203580. Conclusions The increased APOO expression in mouse and cell MI models may activate autophagy and apoptosis by regulating the p38MAPK signaling pathway, thus aggravating the myocardial injury. HIGHLIGHTS APOO was highly expressed in the left ventricle of mice with myocardial infarction. Increasing of APOO may activate autophagy and apoptosis in myocardial infarction. The regulation of APOO in autophagy and apoptosis was regulated by p38MAPK signaling pathway.

Abstract Objectives Accurate prognosis assessment across the heterogeneous population of brain metastases is very important, which may facilitate clinical decision-making and appropriate stratification of future clinical trials. Previous studies have shown the L1 Cell Adhesion Molecule (L1CAM) is potentially involved in human malignancies of multiple different samples and unfavorable survival. However, no data of L1CAM are available for the brain metastases from lung adenocarcinoma, especially for the one with neurosurgical resection. Method The authors investigated the L1CAM expression in cranial metastatic lesions for patients with brain metastases from lung adenocarcinoma after neurosurgical resection using tissue microarrays that were obtained from the Department of Neurosurgery at the Cancer Hospital of the Chinese Academy of Medical Sciences. Furthermore, the relationship between L1CAM expression and clinic-pathological parameters, including overall survival time, was analyzed to assess the prognostic value of L1CAM. Results L1CAM high expression was found in 62.30% of brain metastases from lung adenocarcinoma and significantly correlated with brain metastasis number (p = 0.028) and Lung-molGPA score (p = 0.042). Moreover, L1CAM expression was an independent predictor of survival for brain metastases after neurosurgical resection in a multivariate analysis. Patients with L1CAM high expression had unfavorable overall survival time (p = 0.016). In addition, the multivariate analysis also showed age and extracranial transfer were also the independent prognostic factors for this type of patient with brain metastases. Conclusions A subset of brain metastases from lung adenocarcinoma aberrantly expresses L1CAM. L1CAM is a novel independent prognostic factor for brain metastasis from lung adenocarcinoma after neurosurgical resection.

Abstract MicroRNAs (miRNAs) dysregulation is tightly related to diseases including tumor, neuro disease and cardiovascular disease. In this study, we investigated the potential biological effects of miR-34a and its target CXCR3 in phenotypic modulation of vascular smooth muscle cells (VSMCs) of intracranial aneurysms (IAs). MiR-34a was found to be down-regulated in IAs patients tested by Real-time PCR and decreased in GEO data. Meanwhile, our study also showed miR-34a inhibited matrix metalloproteinases (MMPs) and migration of VSMCs. Besides, CXCR3 is a direct target of miR-34a identified via luciferase assay. CXCR3 showed inhibitory effect on SM-MHC, SM22 while promoted MMPs expression, cell proliferation and migration in VSMCs. MiR-34a reversed the effect of CXCR3 in VSMCs. In addition, MMP-2 is a competitive endogenous RNA (ceRNA) of CXCR3 sharing common miR-34a target. CXCR3 increased MMP-2 level through competitive endogenous RNA regulation by sponging endogenous miR-34a. In conclusion, miR-34a is down-regulated in IAs while CXCR3 is the direct target of miR-34a that regulates phenotypic modulation of VSMCs. CXCR3 increased MMP-2 level through competitive endogenous RNA regulation by sharing common miR-34a targets.

Stereotactic biopsies for lesions in the brainstem and deep brain are rare. This study aimed to summarize our 6-year experience in the accurate diagnosis of lesions in the brain stem and deep brain and to discuss the technical note and strategies. From December 2011 to January 2018, 72 cases of intracranial lesions in the brainstem or deep in the lobes undergoing stereotactic biopsy were retrospectively reviewed. An individualized puncture path was designed based on the lesion's location and the image characteristics. The most common biopsy targets were deep in the lobes (43 cases, 59.7%), including frontal lobe (33 cases, 45.8%), temporal lobe (4 cases, 5.6%), parietal lobe (3 cases, 4.2%), and occipital lobe (3 cases, 4.2 %). There were 12 cases (16.7%) of the brainstem, including 8 cases (11.1%) of midbrain, and 4 cases (5.6%) of pons or brachium pontis. Other targets included internal capsule (2 cases, 2.8%), thalamus (3 cases, 4.2%), and basal ganglion (12 cases, 16.7%). As for complications, one patient developed acute intracerebral hemorrhage in the biopsy area at 2 h post-operation, and one patient had delayed intracerebral hemorrhage at 7 days post-operation. The remaining patients recovered well after surgery. There was no surgery-related death. The CT-MRI-guided stereotactic biopsy of lesions in the brainstem or deep in the brain has the advantages of high safety, accurate diagnosis, and low incidence of complications. It plays a crucial role in the diagnosis of atypical, microscopic, diffuse, multiple, and refractory lesions.

This study aimed to explore gene expression profiles that drive malignancy from low- to high-grade head and neck carcinomas (HNC), as well as to analyze their correlations with survival. Gene expressions and clinical data of HNC were downloaded from the Gene Expression Omnibus (GEO) repository. The significantly differential genes (SDGs) between low- and high-grade HNC were screened. Cox regressions were performed to identify prognostic SDGs of progression-free survival (PFS) and disease-specific survival (DSS). The genes were experimentally validated by RT-PCR in clinical tissue specimens. Thirty-five SDGs were identified in 47 low-grade and 30 high-grade HNC samples. Cox regression analyses showed that CXCL14, SLC44A1, and UBD were significantly associated with DSS, and PPP2R2C and SLC44A1 were associated with PFS. Patients were grouped into high-risk or low-risk groups for prognosis based on gene signatures. High-risk patients had significantly shorter DSS and PFS than low-risk patients (P=0.033 and P=0.010, respectively). Multivariate Cox regression showed HPV (P=0.033), lymph node status (P=0.032), and residual status (P<0.044) were independent risk factors for PFS. ROC curves showed the risk score had better efficacy to predict survival both for DSS and PFS (AUC=0.858 and AUC=0.901, respectively). The results showed CXCL14 and SLC44A1 were significantly overexpressed in the low-grade HNC tissues and the UBD were overexpressed in the high-grade HNC tissues. Our results suggested that SDGs had different expression profiles between the low-grade and high-grade HNC, and these genes may serve as prognostic biomarkers to predict survival.

The detection of vitamin D in complex samples is challenging because of the instability of vitamin D in sample preparation. To resolve this problem, packed-fiber solid-phase extraction (PFSPE) has been successfully developed for the pre-treatment of samples containing vitamin D2 (D2) and vitamin D3 (D3) in dairy products. Based on PFSPE, vitamin D could avoid oxidation because of the shorter extraction time. The adsorbent materials, polystyrene/polypyrrole (PS/PPy) nanofibers, were prepared by electrospinning of PS and in situ polymerization of PPy on the surface of PS nanofibers. The linearity was within the range of 1-2000 ng mL−1 in dairy solution, and the recoveries were 91.9-109.1% with a relative standard deviation (RSD) < 13.6%. Therefore, the prepared method could be used for the detection of D2 and D3 in dairy products.

Abstract: The three-dimensional and networked SBA-15 (3D-SBA-15) supported phosphotungstic acid (PW) was used as heterogeneous catalyst for the one-pot three-components Mannich reaction at room temperature. The H3PW12O40/3D-SBA-15 catalyst was prepared using an impregnation method and confirmed by series of characterizations such as Fourier-transform infrared spectra (FT-IR), scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), N2 physisorption and thermogravimetric (TG) analysis. 50PW/3D-SBA-15 catalyst with H3PW12O40 loading of 50 wt% showed the highest yield of 93% in 1.8 h for the Mannich reaction of benzaldehyde, aniline and acetophenone under solvent-free condition. A series of β-aminoketone derivatives were synthesized successfully in the presence of this catalyst. In addition, H3PW12O40/3D-SBA-15 catalyst can be easily recovered and reused four times without significant decrease of the activity. This work provides an improved modification of the three-component Mannich reaction in terms of mild reaction conditions, clean reaction profiles, small quantity of catalyst and a simple workup procedure.

Resumen: El ácido fosfotungstico (PW) se soportó en sílice SBA-15 (3D-SBA-15) y se usó como catalizador heterogéneo en la reacción de Mannich en un solo paso de tres componentes a temperatura ambiente. El catalizador H3PW12O40/3D-SBA-15 se preparó mediante impregnación y se caracterizó por espectroscopia de infrarrojo (FT-IR), microscopia electrónica de barrido (SEM), microscopía electrónica de transmisión (TEM), difracción de rayos-X (XRD) fisisorción de N2 y análisis termogravimétrico (TG). El catalizador 50PW/3D-SBA-15, con una carga de H3PW12O40 del 50% en peso, mostró el rendimiento más alto del 93% en 1.8 h para la reacción de Mannich entre benzaldehído, anilina y acetofenona, sin disolvente. Se sintetizó una serie de derivados de β-aminocetona en presencia de éste catalizador. Además, el catalizador H3PW12O40/3D-SBA-15 puede recuperarse fácilmente y reutilizarse cuatro veces sin pérdida significativa de la actividad. Este trabajo reporta una modificación de la reacción de Mannich de tres componentes bajo condiciones de reacción suaves, perfiles de reacción limpios, pequeña cantidad de catalizador y un procedimiento de tratamiento simple.

Abstract Laboratory and field culture experiments have been carried out at two sites which show that temperature and soil moisture significantly affected nitrogen mineralization in the soil in a tobacco field. Intermittent leaching under aerobic incubation conditions was adopted to develop dynamic simulation models of organic nitrogen mineralization under different temperature regimes (10, 15, 20, 25, 30, 35, 30, 25, and 20 °C) and soil gravimetric moisture content (0.1, 7%, 13%, 20%, 27%, 33%, 40%, 47%, and 53%). The results show that the highest N mineralization rate appeared at 35°C and the lowest was 10°C. Soil N mineralization rate, as affected by soil moisture, is a single peak curve with a peak at 40%. The interaction of temperature and moisture on soil N mineralization is significant. Based on the results of a field trial, the combined model given by governing equation: has been established to simulate the dynamics of soil N mineralization under tobacco field conditions. A validation experiment showed that the measured values of mineralized N accumulation in the two experimental sites had a good correlation with the simulated values, indicating the practical value of the proposed model.

Abstract The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) technology has recently emerged as a powerful genomic editing tool with great potential for crop breeding. However, commonly used protocols for screening of CRISPR/Cas9-induced mutations are laborious, time-consuming, and costly. In the present study we examined the applicability of high resolution melting (HRM) analysis fast screening CRISPR/Cas9-induced mutations in T0 plants and subsequent genotyping of T1 populations. Comparative analysis demonstrated that HRM analysis could identify mutant T0 plants carrying various types of mutation, including single nucleotide substitutions and short insertion/deletions, with false positive/negative rates of 0-2.78%. Furthermore, T1 plants derived from single T0 plants could be correctly genotyped by HRM analysis using WT parents and T0 plants as controls. We hence recommend the adoption of HRM analysis in CRISPR/Cas9 mediated genetic studies and breeding in rice and other crop species.

Propofol is an intravenous sedative hypnotic agent of which the growth-inhibitory effect has been reported on various cancers. However, the roles of propofol in endometrial cancer (EC) remain unclear. This study aimed to explore the effects of propofol on EC in vitro and in vivo. Different concentrations of propofol were used to treat Ishikawa cells. Colony number, cell viability, cell cycle, apoptosis, migration, and invasion were analyzed by colony formation, MTT, flow cytometry, and Transwell assays. In addition, the pcDNA3.1-Sox4 and Sox4 siRNA plasmids were transfected into Ishikawa cells to explore the relationship between propofol and Sox4 in EC cell proliferation. Tumor weight in vivo was measured by xenograft tumor model assay. Protein levels of cell cycle-related factors, apoptosis-related factors, matrix metalloproteinases 9 (MMP9), matrix metalloproteinases 2 (MMP2) and Wnt/β-catenin pathway were examined by western blot. Results showed that propofol significantly decreased colony numbers, inhibited cell viability, migration, and invasion but promoted apoptosis in a dose-dependent manner in Ishikawa cells. Moreover, propofol reduced the expression of Sox4 in a dose-dependent manner. Additionally, propofol significantly suppressed the proportions of Ki67+ cells, but Sox4 overexpression reversed the results. Furthermore, in vivo assay results showed that propofol inhibited tumor growth; however, the inhibitory effect was abolished by Sox4 overexpression. Moreover, propofol inhibited Sox4 expression via inactivation of Wnt/β-catenin signal pathway. Our study demonstrated that propofol inhibited cell proliferation, migration, and invasion but promoted apoptosis by regulation of Sox4 in EC cells. These findings might indicate a novel treatment strategy for EC.

Background/Aim. To describe the epidemiological profile of nasal carriage of Staphylococcus aureus (S. aureus) strains, its antibiotic resistance and mecA and Panton Valentine leukocidin (PVL) genes presence, in school children residing in high altitude areas of Southwestern China. Methods. The cross sectional study screened nasal swabs taken from students for S. aureus. PCR was performed to identify mecA and PVL genes. Results. Of the total 314 children 5.10% (16/314) was detected S. aureus. The resistance of isolated strains to penicillin, erythromycin, clindamycin, rifampicin and cefoxitin was 100%, 81.3%, 81.3%, 0.0%, and 6.3% respectively. No strains demonstrated resistance to vancomycin; expression of mecA gene was detected in 3 isolates and 10 isolates were PVL-positive. Conclusion. S. aureus was detected in 5.10% (16/314) of the study population; 0.96% (3/314) had methicillin resistant S. aureus (MRSA); expression of the mecA and PVL genes were detected in 3 and 10 isolates respectively.

Antecedentes/Objetivo. Describir el perfil epidemiológico de la portación nasal de cepas de Staphylococcus aureus (S. aureus), su resistencia a antibióticos y la presencia de los genes de leucocidina de Panton-Valentine (LPV) y mecA en niños en edad escolar que viven en zonas de gran altitud del sudoeste de China. Métodos. En el estudio transversal, se analizaron hisopados nasales de estudiantes a fin de detectar S. aureus. Se realizó la prueba de la reacción en cadena de la polimerasa (RCP) para identificar los genes de LPV y mecA. Resultados. Del total de 314 niños, se detectó S. aureus en el 5,10% (16/314). La resistencia de las cepas aisladas a la penicilina, eritromicina, clindamicina, rifampicina y cefoxitina fue del 100%, 81,3%, 81,3%, 0,0% y 6,3%, respectivamente. Ninguna de las cepas mostró resistencia a la vancomicina. Se detectó la expresión del gen mecA en 3 cepas aisladas, y 10 cepas aisladas dieron resultado positivo para el gen de LPV. Conclusión. Se detectó S. Aureus en el 5,10% (16/314) de la población del estudio; el 0,96% (3 /314) presentó S. Aureus resistente a la meticilina (SARM). Además, se detectó la expresión de los genes de LPV y mecA en 10 y 3 cepas aisladas, respectivamente.

Abstract Purpose: To evaluate the effects of HBO (Hyperbaric oxygen) and NGF (Nerve growth factor) on the long-term neural behavior of neonatal rats with HIBD (Neonatal hypoxic ischemic brain damage). Methods: The HIBD model was produced by ligating the right common carotid artery of 7 days old SD (Sprague-Dawley) rats followed by 8% O2 + 92% N2 for 2h. Totally 40 rats were randomly divided into 5 groups including sham-operated group, HIBD control group, HBO treated group, NGF treated group and NGF + HBO treated group. The learning and memory ability of these rats was evaluated by Morris water maze at 30 days after birth, and sensory motor function was assessed by experiments of foot error and limb placement at 42 days after birth. Results: The escape latency of HBO treated group, NGF treated group and NGF + HBO treated group was shorter than that of HIBD control group (p<0.01) and longer than that of sham-operated group. The piercing indexes of 3 treated groups were higher than that of HIBD control group (p<0.01). Conclusion: Hyperbaric oxygen and nerve growth factor treatments may improve learning and memory ability and sensory motor function in neonatal rats after hypoxic ischemic brain damage.

Abstract Wax deposition behavior was investigated in a set of one-inch experiment flow loops, using a local crude oil with high wax content. The temperature of the oil phase is chosen as a variable parameter while the temperature of the coolant media is maintained constant. Detailed composition of the deposit is characterized using High Temperature Gas Chromatography. It was found that the magnitude of the diffusion of the heavier waxy components (C35-C50) decreases when the oil temperature decreases, but the magnitude of the diffusion of the lighter waxy components increases. This result means that the diffusion of wax molecules shifts towards lower carbon number, which further proves the concept of molecular diffusion. Meanwhile, a meaningful phenomenon is that the mass of the deposit increases with the oil temperature decrease, which definitely proves the influence of wax solubility on deposition, while the formation of an incipient gel layer reflects the fact that an increase in the mass of the deposit does not mean a larger wax percentage fraction at lower oil temperature.