Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant carcinomas and its molecular mechanisms remain unclear. Long noncoding RNA (lncRNA) could bind sites of miRNA which affect ...the expression of mRNA according to the competing endogenous (ceRNA) theory. The aim of the present study was to construct a ceRNA network and to identify key lncRNA to predict survival prognosis. We identified differentially expressed mRNA, lncRNA and miRNA between tumor tissues and normal tissues from The Cancer Genome Atlas database. Then, using bioinformatics tools, we explored the connection of 89 lncRNA, 10 miRNA and 22 mRNA, and we constructed the ceRNA network. Furthermore, we analyzed the functions and pathways of 22 differentially expressed mRNA. Then, univariate and multivariate Cox regression analyses of these 89 lncRNA and overall survival were explored. Nine lncRNA were finally screened out in the training group. The patients were divided into high‐risk and low‐risk groups according to the 9 lncRNA and low‐risk scores having better clinical overall survival (P < .01). Furthermore, the receiver operating characteristic curve demonstrates the predicted role of the 9 lncRNA. The 9‐lncRNA signature was successfully proved in the testing group and the entire group. Finally, multivariate Cox regression analysis and stratification analysis further proved that the 9‐lncRNA signature was an independent factor to predict survival. In summary, the present study provides a deeper understanding of the lncRNA‐related ceRNA network in ccRCC and suggests that the 9‐lncRNA signature could serve as an independent biomarker to predict survival in ccRCC patients.
The lncRNA‐miRNA‐mRNA ceRNA network.
Machine-learning techniques have shown their capability for studying phase transitions in condensed matter physics. Here, we employ machine-learning techniques to study the nuclear liquid-gas phase ...transition. We adopt an unsupervised learning and classify the liquid and gas phases of nuclei directly from the final-state raw experimental data of heavy-ion reactions. Based on a confusion scheme which combines the supervised and unsupervised learning, we obtain the limiting temperature of the nuclear liquid-gas phase transition. Its value 9.24±0.04MeV is consistent with that obtained by the traditional caloric curve method. Our study explores the paradigm of combining machine-learning techniques with heavy-ion experimental data, and it is also instructive for studying the phase transition of other uncontrollable systems, such as QCD matter.
•High initial BDG may be a predictor of satisfactory caspofungin and TMP/SMZ response to PJP.•A better choice of caspofungin and TMP/SMZ therapy in PJP when BDG≥800pg/ml.•Low lymphocyte counts and ...high LDH levels at the diagnosis of PJP are risk factors for death.•Continuous monitoring of lymphocyte count is important in immunosuppressed individuals.•Progression to shock in PJP is an independent risk factor for death.
The aim of this study was to investigate the efficacy of combination therapy of caspofungin and TMP/SMZ (trimethoprim/sulfamethoxazole) in moderate to severe pneumocystis jirovecii pneumonia (PJP) in patients without human immunodeficiency virus infection (HIV) and the relationship between therapeutic effect and plasma (1, 3) Beta-d-Glucan (BDG) levels.
We retrospectively reviewed HIV-negative patients with PJP diagnosed in our department, who were treated with combination therapy of caspofungin and TMP/SMZ or monotherapy of TMP/SMZ during a six and a half year period.
A total of 126 moderate to severe PJP patients were enrolled in the study. In the multivariate analysis, low lymphocyte counts, high serum lactate dehydrogenase levels at the diagnosis of PJP and progression to shock were significant risk factors for death. In all patients, there was no significant difference in risk of death at 3 months. In the group of BDG≥800pg/m, patients receiving combination therapy was associated with a significantly decreased risk of death at 3 months, whereas in the group of BDG<800pg/ml, there were no statistically significant difference in survival rate between the two treatment regimens.
High initial plasma (1, 3) Beta-d-Glucan concentration may be a predictor of satisfactory caspofungin response to HIV-negative patients with PJP. Based on our findings, we suggest the choice of combination therapy with caspofungin and TMP/SMZ as the initial treatment when BDG≥800pg/ml in moderate to severe HIV-negative patients with PJP.
Abstract
MicroRNAs regulate post-transcriptional gene expression and play important roles in multiple cellular processes. In this study, we found that miR-421 suppresses kelch-like ECH-associated ...protein 1(KEAP1) expression by targeting its 3′-untranslated region (3′UTR). A Q-PCR assay demonstrated that miR-421 is overexpressed in non-small cell lung cancer (NSCLC), especially in A549 cells. Consistently, the level of miR-421 was higher in clinical blood samples from lung cancer patients than in those from normal healthy donors, suggesting that miR-421 is an important lung cancer biomarker. Interestingly, overexpression of miR-421 reduced the level of KEAP1 expression, which further promoted lung cancer cell migration and invasion, as well as inhibited cell apoptosis both in vivo and in vitro. Furthermore, knockdown of miR-421 expression with an antisense morpholino oligonucleotide (AMO) increased ROS levels and treatment sensitivity to paclitaxel in vitro and in vivo, indicating that high miR-421 expression may at least partly account for paclitaxel tolerance in lung cancer patients. To find the upstream regulator of miR-421, one of the candidates, β-catenin, was knocked out via the CRISPR/Cas9 method in A549 cells. Our data showed that inhibiting β-catenin reduced miR-421 levels in A549 cells. In addition, β-catenin upregulation enhanced miR-421 expression, indicating that β-catenin regulates the expression of miR-421 in lung cancer. Taken together, our findings reveal the critical role of miR-421 in paclitaxel drug resistance and its upstream and downstream regulatory mechanisms. Therefore, miR-421 may serve as a potential molecular therapeutic target in lung cancer, and AMOs may be a potential treatment strategy.
In this paper, we propose a T-Y-type microchannel heat sink (MCHS), which is designed based on T-shaped and Y-shaped channels. First, we perform numerical simulations and experiments to calculate the ...equivalent heat-transfer coefficients and pressure drop-values of the proposed T-Y-type MCHS for six different entrance velocities. The simulated equivalent heat-transfer coefficients and pressure drop-values agree well with the experimental results. Further, by performing Fluent-3D numerical simulations, we perform a systematic investigation of the heat-transfer performance of the proposed T-Y-type heat sink using a liquid GaInSn coolant for different values of the entrance mass flow rate and other structural parameters. The MCHS has excellent heat-transfer and temperature-evenness performances, the equivalent heat-transfer coefficient is up to 4.7 × 104 W/m2K for a pressure drop of 2.21 × 104 Pa. In addition, the temperature difference can decrease to 27 K when the heat flux is 106 W/m2. The use of all inlets with the same mass flow rate is more practical in engineering. The performance of the heat sink can be effectively improved by increasing the number of inlets and employing an interlaced placement mode. We determine that the optimal bifurcation angle is approximately 60°. Finally, compared to the water coolant, the use of the GaInSn coolant can enhance the heat-transfer performance of the heat sink.
•A new kind of T-Y type microchannel heat sink is presented.•Heat transfer characteristics are discussed using thermal resistance and filed synergy principle.•Heat transfer and pressure drop characteristics in the MCHS are studied by simulation and experiment.•Interlaced microchannel leads to better heat transfer performance.•Pressure drop of the T-Y type microchannel is low.
Delayed diagnosis of HIV infection is associated with advanced immunosuppression and increased risk of onward transmission. Little data exists regarding factors associated with diagnostic delays ...among patients presenting with advanced HIV disease in China. Medical records of patients with HIV/AIDS hospitalized at a 2000-bed tertiary hospital in Beijing, China between 1997 and 2012 were retrospectively reviewed. Demographic and clinical data of patients newly diagnosed with HIV at the hospital were abstracted. Patient characteristics, disease parameters, and the time interval between the first medical visit and the visit leading to HIV diagnosis were compared among three periods: 1997-2002, 2003-2008 and 2009-2012. Chi-square, Kruskal-Wallis and logistic regression analyses were used as appropriate. A quarter of patients (72/279) were newly diagnosed with HIV at the hospital, consisting of 11, 29 and 32 patients in 1997-2002, 2003-2008 and 2009-2012 respectively. The median time delay between the first medical visit and the visit leading to HIV diagnosis decreased over time from 91 days among patients diagnosed before 2002, to 75 days between 2003 to 2008, and 39 days after 2009 (p = 0.036). However, the median CD4+T cell count at diagnosis was 26 cells/μL interquartile range 3-132 cells/μL in 1997-2002, and remained unchanged across time intervals. Forty-one (57%) patients had AIDS-defining conditions and Pneumocystis jiroveci pneumonia was the most common opportunistic infection (31 cases). These results reveal persistent missed opportunities for timely HIV testing among patients with advanced disease. Strategies for promoting early HIV testing in healthcare settings are needed in China.
ABSTRACT
Hypoxia, a unique and essential environmental stress, evokes highly coordinated cellular responses, and hypoxia‐inducible factor (HIF) 1 in the hypoxia signaling pathway, an evolutionarily ...conserved cellular signaling pathway, acts as a master regulator of the transcriptional response to hypoxic stress. MicroRNAs (miRNAs), a major class of posttranscriptional gene expression regulators, also play pivotal roles in orchestrating hypoxia‐mediated cellular adaptations. Here, global miRNA expression profiling and quantitative real‐time PCR indicated that the up‐regulation of the miR‐462/miR‐731 cluster in zebrafish larvae is induced by hypoxia. It was further validated that miR‐462 and miR‐731 are upregulated in a Hif‐1α‐mediated manner under hypoxia and specifically target ddx5 and ppm1da, respectively. Overexpression of miR‐462 and miR‐731 represses cell proliferation through blocking cell cycle progress of DNA replication, and induces apoptosis. In situ detection revealed that the miR‐462/miR‐731 cluster is highly expressed in a consistent and ubiquitous manner throughout the early developmental stages. Additionally, the transcripts become restricted to the notochord, pharyngeal arch, liver, and gut regions from postfertiliztion d 3 to 5. These data highlight a previously unidentified role of the miR‐462/miR‐731 cluster as a crucial signaling mediator for hypoxia‐mediated cellular adaptations and provide some insights into the potential function of the cluster during embryonic development.—Huang, C.‐X., Chen, N., Wu, X.‐J., Huang, C.‐H., He, Y., Tang, R., Wang, W.‐M., Wang, H.‐L. The zebrafish miR‐462/miR‐731 cluster is induced under hypoxic stress via hypoxia‐inducible factor 1α and functions in cellular adaptations. FASEB J. 29, 4901–4913 (2015). www.fasebj.org
Antimicrobial peptides are small, cationic, and amphiphilic peptides found in most organisms, and many of these peptides have broad antimicrobial activity against Gram-negative, -positive bacteria ...and fungi. In the present study, a derivative of antimicrobial peptide Tatritin, 6His-Tatritin, was designed and expressed by Pichia pastoris using a constitutive vector pGAPZαA with the promoter of pGAP. The 6His-Tatritin had a broad-spectrum antibacterial activity based on the Oxford cup method and the micro broth dilution test. In addition, to explore the role of 6His-Tatritin in vivo, grass carps (Ctenopharyngodon idellus) were infected with Aeromonas hydrophila after they were fed with 6His-Tatritin as feed additives for 28 days. The results revealed that 6His-Tatritin could significantly up-regulate the expression levels of Hepcidin, Leap-2b, Nrf-2, CuZn-SOD and LZM (P < 0.05). In addition, 6His-Tatritin could significantly reduce the mortality (P < 0.05) and the intestinal injury of grass carps infected with bacteria. The 16S sequencing analysis showed that the structure of microbial community in intestine of fish was more diversified compared with control after treatment with 6His-Tatritin. In summary, the peptide of 6His-Tatritin could promote antimicrobial defense via regulating immune ability and intestinal microbial community in grass carp. This study provides an effective method and approach for the application of antimicrobial peptide Tatritin in aquaculture, and also provides insights into the function of antimicrobial peptides in immunity against pathogens in fish.
•The derivative of a new antimicrobial peptide Tatritin, 6His-Tatritin, was designed and expressed by Pichia pastoris.•The 6His-Tatritin had a broad-spectrum antibacterial activity similar to Tatritin in vitro.•6His-Tatritin can significantly reduce the intestinal injury and mortality of fish infected with Aeromonas hydrophila.
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