IDMIR: identification of dysregulated miRNAs associated with disease based on a miRNA-miRNA interaction network constructed through gene expression data.

Micro ribonucleic acids (miRNAs) play a pivotal role in governing the human transcriptome in various biological phenomena. Hence, the accumulation of miRNA expression dysregulation frequently assumes a noteworthy role in the initiation and progression of complex diseases. However, accurate identification of dysregulated miRNAs still faces challenges at the current stage. Several bioinformatics tools have recently emerged for forecasting the associations between miRNAs and diseases. Nonetheless, the existing reference tools mainly identify the miRNA-disease associations in a general state and fall short of pinpointing dysregulated miRNAs within a specific disease state. Additionally, no studies adequately consider miRNA-miRNA interactions (MMIs) when analyzing the miRNA-disease associations. Here, we introduced a systematic approach, called IDMIR, which enabled the identification of expression dysregulated miRNAs through an MMI network under the gene expression context, where the network's architecture was designed to implicitly connect miRNAs based on their shared biological functions within a particular disease context. The advantage of IDMIR is that it uses gene expression data for the identification of dysregulated miRNAs by analyzing variations in MMIs. We illustrated the excellent predictive power for dysregulated miRNAs of the IDMIR approach through data analysis on breast cancer and bladder urothelial cancer. IDMIR could surpass several existing miRNA-disease association prediction approaches through comparison. We believe the approach complements the deficiencies in predicting miRNA-disease association and may provide new insights and possibilities for diagnosing and treating diseases. The IDMIR approach is now available as a free R package on CRAN (https://CRAN.R-project.org/package=IDMIR).

Fast fiber nonlinearity compensation method for PDM coherent optical transmission systems based on the Fourier neural operator.

Fiber nonlinearity compensation (NLC) is likely to become an indispensable component of coherent optical transmission systems for extending the transmission reach and increasing capacity per fiber. In this work, we introduce what we believe to be a novel fast black-box neural network model based on the Fourier neural operator (FNO) to compensate for the chromatic dispersion (CD) and nonlinearity simultaneously. The feasibility of the proposed approach is demonstrated in uniformly distributed as well as probabilistically-shaped 32GBaud 16/32/64-ary quadrature amplitude modulation (16/32/64QAM) polarization-division-multiplexed (PDM) coherent optical communication systems. The experimental results demonstrate that about 0.31 dB Q-factor improvement is achieved compared to traditional digital back-propagation (DBP) with 5 steps per span for PDM-16QAM signals after 1600 km standard single-mode fiber (SSMF) transmission at the optimal launched power of 4 dBm. While, the time consumption is reduced from 6.04 seconds to 1.69 seconds using a central processing unit (CPU), and from 1.54 seconds to only 0.03 seconds using a graphic processing unit (GPU), respectively. This scheme also reveals noticeable generalization ability in terms of launched power and modulation format.

Unveiling the Metal Incorporation Effect of Steady-Active FeP Hydrogen Evolution Nanocatalysts for Water Electrolyzer.

Metal phosphides are promising noble metal-free electrocatalysts for hydrogen evolution reaction (HER), but they usually suffer from inferior stability and thus are far from the device applications. We reported a facile and controllable synthetic method to prepare metal-incorporated M-FeP nanoparticles (M=Cr, Mn, Co, Fe, Ni, Cu, and Mo) with the guide of the density functional theory (DFT). The evaluated HER activity sequence was consistent with the DFT predictions, and cobalt was revealed to be the appropriate dopant. With the optimization of the Co/Fe ratio, the Fe0.67 Co0.33 P/C only required overpotentials of 67 mV and 129 mV to obtain the cathodic current density of 10 and 100 mA cm-2, respectively. It maintained the initial activity in the 10 h stability test, surpassing the other Co-FeP/C catalysts. Ex situ experiments demonstrated that the decreased element leaching and the increased surface phosphide content contributed to the high stability of the Fe0.67 Co0.33 P/C. A proton exchange membrane water electrolyzer was assembled using the Fe0.67 Co0.33 P/C as the cathodic catalyst. It showed a current density of 0.8 A cm-2 at the applied voltage of 2.0 V and retained the initial activity in the 1000 cycles' stability test, suggesting the potential application of the catalysts.

Angiotensin II-induced vascular endothelial cells ferroptosis via P53-ALOX12 signal axis.

OBJECTIVES: The present study aimed to investigate the effect and mechanism of angiotensin II-induced ferroptosis in vascular endothelial cells. METHODS: In vitro, HUVECs were treated with AngII, AT1/2 R antagonist, P53 inhibitor, or their combinations. MDA and intracellular iron content were evaluated using an ELISA assay. The expression of ALOX12, P53, P21, and SLC7A11 were determined by western blotting in HUVECs and then confirmed through RT-PCR. RESULTS: As the concentration of Ang II (0, 0.1,1,10,100, and 1000uM for 48 h) increased, the level of MDA and intracellular iron content increased in HUVECs. Compared with the single AngII group, ALOX12, p53, MDA, and intracellular iron content in AT1/2R antagonist group decreased significantly. In pifithrin-α hydrobromide-treated, ALOX12, P21,MDA, and intracellular iron content decreased significantly as compared to the single AngII group. Similarly, the effect of combined use of blockers is stronger than that of blockers alone. CONCLUSIONS: AngII can induce ferroptosis of vascular endothelial cells. The mechanism of AngII-induced ferroptosis may be regulated through the signal axis of p53-ALOX12.

PLAGL2 promotes the stemness and is upregulated by transcription factor E2F1 in human lung cancer.

This study mainly focuses on revealing the role of PLAGL2 in lung cancer stemness. In vitro and in vivo experiments were performed to evaluate the effects of PLAGL2 on lung cancer cell stemness. Mechanistic analysis using luciferase reporter and ChIP assays were implemented to reveal the underlying mechanisms. The transcriptional factor E2F1 transcriptionally activated PLAGL2 expression via directly binding to PLAGL2 promoter in lung cancer cells. Moreover, PLAGL2 promoted the stemness of lung cancer cells dependent on E2F1-mediated transcriptional activation. This study provides a potential target for lung cancer progression.

Insights into the Effect of Precursors on the FeP-Catalyzed Hydrogen Evolution Reaction.

Iron phosphide nanoparticles (NPs) are promising noble metal-free electrocatalysts for the hydrogen evolution reaction (HER), but they usually show inferior activity due to the limited surface area and oxidative passivation. We reported a facile synthetic method to prepare FeP hollow NPs (HNPs) with various precursors. It was proven that the structural parameters (i.e., size, phosphating temperature, phase, and surfactant) of oxide precursors were correlated to the electrochemically active surface area (ECSA), phase purity, surface oxidation, and hollow morphology of FeP HER catalysts, thus affecting the HER activity. Among the three FeP HNPs, the 9 nm FeP HNPs prepared using the Fe3O4 precursor exhibited the highest overall activity with the lowest overpotential of 76 mV to drive a cathodic current density of 10 mA·cm-2 due to the highest ECSA, while 25 nm FeP prepared using the Fe2O3 precursor showed the highest turnover frequency because of the high phase purity and low surface oxidation degree.

Association between Ankle Brachial Index, Brachial-Ankle Pulse Wave Velocity, and Mild Cognitive Impairment in Patients with Acute Lacunar Infarction.

BACKGROUND: The link between arterial stiffness and mild cognitive impairment (MCI) is receiving increasing attention, and the goal of this study was to explore the relationship among the ankle brachial index (ABI), brachial-ankle pulse wave velocity (Ba-PWV), and MCI in patients with acute lacunar infarction (ALI). METHODS: A total of 103 hospitalized patients with ALI were divided into a non-MCI group (n = 41) and an MCI group (n = 62) according to their Montreal Cognitive Assessment (MoCA) scores. A binary logistic regression model was used to assess the association among ABI, Ba-PWV, and MCI after adjusting for confounding factors. Spearman correlation was utilized to analyse the correlations between ABI, Ba-PWV, and MoCA total scores and sub-scores in ALI patients. RESULTS: Participants with cognitive impairment had significantly higher Ba-PWV and lower ABI than those with normal cognition. Correlation analysis suggested that Ba-PWV (r = -0.854, p < 0.05) and ABI (r = 0.734, p < 0.05) were correlated with MoCA total scores; of all MoCA sub-scores, visuospatial/executive function was the most strongly correlated with the vascular variables. In the binary logistic regression analysis, Ba-PWV (odds ratio [OR] = 4.507, 95% confidence interval [CI] = 2.152-9.441) and ABI (OR = 1.124, 95% CI = 1.015-1.254) were significantly associated with MCI, even after adjusting for lipoprotein (a) and systolic and diastolic blood pressure. CONCLUSION: The present study suggested that a higher Ba-PWV and a lower ABI were independent risk factors for MCI in patients with ALI.

Clinical characteristics, risk factors, immune status and prognosis of secondary infection of sepsis: a retrospective observational study.

BACKGROUND: Secondary infection has a higher incidence in septic patients and affects clinical outcomes. This study aims to investigate the clinical characteristics, risk factors, immune status and prognosis of secondary infection of sepsis. METHODS: A four-year retrospective study was carried out in Zhongshan Hospital, Fudan University, enrolling septic patients admitted between January, 2014 and January, 2018. Clinical data were acquired from medical records. CD14+ monocyte human leukocyte antigen-D related (HLA-DR) expression and serum cytokines levels were measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: A total of 297 septic patients were enrolled, 92 of whom developed 150 cases of secondary infections. Respiratory tract was the most common site of secondary infection (n = 84, 56%) and Acinetobacter baumanii the most commonly isolated pathogen (n = 40, 31%). Urinary and deep venous catheterization increased the risk of secondary infection. Lower HLA-DR expression and elevated IL-10 level were found in secondary infection group. The expected prolonged in-hospital stay owing to secondary infection was 4.63 ± 1.87 days. Secondary infection was also associated with higher in-hospital, 30-day and 90-day mortality. Kaplan-Meier survival analysis and Log-rank test revealed that secondary infection group had worse survival between day 15 and day 90. CONCLUSIONS: Urinary and deep venous catheterization increased the risk of secondary infection, in which underlying immunosuppression might also play a role. Secondary infection affected the prognosis of septic patients and prolonged in-hospital length of stay.

T-cell subsets are associated with serum homocysteine concentration in patients with essential hypertension.

OBJECTIVE: To explore the association between serum homocysteine (Hcy) concentration and T-cell subsets from patients with essential hypertension. PATIENTS AND METHODS: A total of 218 essential hypertension patients were recruited, of which 170 were H-type essential hypertensive and 48 were non-H-type essential hypertensive. H-type essential hypertensive patients were divided into three groups by concentration of serum Hcy. The peripheral blood T-cell subsets (CD3+%, CD4+%, CD8+ T%, CD4+/CD8+) and clinical features including age, sex, serum creatinine, uric acid, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were recorded and analyzed with T-cell subsets which were counted by fluorescence activated cytometry. RESULTS: Compared with non-H-type hypertensive patients, CD4+ T-cell percentage in peripheral blood was significantly decreased in H-type hypertensive patients. Because of the increase of Hcy level, CD4+ T-cell percentage decreased. Linear regression analysis showed that Hcy level was negatively correlated with CD4+ T-cell percentage; however, it was positively correlated with CD3+ T-cell percentage. CONCLUSION: A direct association between serum Hcy concentrations and T-cell percentage was observed in patients with essential hypertension. This observation indicates that T-cell subsets might play an important role in hypertension.

Leptin is associated with heart rate recovery in Chinese hypertensive patients.

Elevated serum leptin concentrations are closely related to sympathetic nervous system activation in essential hypertension (EH); however, it is not clear whether or not they are associated with parasympathetic nervous system impairment in EH. Heart rate recovery (HRR) is a reproducible method used to assess parasympathetic activity. This study aimed to investigate the relationship between serum leptin and HRR in Chinese untreated EH patients. This was a cross-sectional study enrolling 471 Chinese EH patients (205 men, 266 women; mean age 63.1 years). HRR was calculated during an incremental cardiopulmonary exercise test. Simple and multiple regression analyses were used to assess the correlation between serum leptin level and HRR value. Serum leptin levels elevated with increasing BP values. Moreover, univariate analysis revealed that the HRR value was negatively correlated with serum leptin (r = -0.037, P < 0.01). In multiple regression analysis, the age-adjusted serum leptin level was negatively correlated with HRR (ß = -0.268, P < 0.01). Serum leptin remained negatively associated with HRR (ß = -0.017, P < 0.01) after further adjustments for factors including age, systolic blood pressure, total cholesterol, and several factors that correlated with HRR. Our findings demonstrated that a raised serum leptin concentration is related to HRR blunt, which suggests that the role of leptin in the development of EH might be associated with impairment of the parasympathetic nervous system as well.

Echocardiographic assessment of hypertensive patients with or without hyperhomocysteinemia.

The study was designed to assess left ventricular (LV) systolic and diastolic function in hypertensive patients with or without Hhcy. The study participants consisted of 40 hypertensive patients with Hhcy, 40 hypertensive patients without Hhcy and 40 age-matched healthy control participants. Cardiac functions were determined using echocardiography and the Tei index was calculated for analysis. LAVI (left atrial volume index), IVST (interventricular septum thickness in diastole), PVST (posterior ventricular septum thickness in diastole), LVMI (left ventricular mass index), E/A (peak early and late diastolic transmitral filling flow velocities ratio), DT (deceleration time of the E wave), IRT (isovolumic relaxation time), and the Tei index were different in the hypertensive patient groups (hypertension with Hhcy and hypertension without Hhcy) compared with the controls. The Tei index was significantly higher in the hypertensive groups compared with the controls (0.62 ± 0.05, 0.51 ± 0.04, and 0.40 ± 0.04, respectively, p < 0.01). Significant differences were also observed between the hypertensive patients with Hhcy and the hypertensive patients without Hhcy regarding LAVI (25.6 ± 4.7 versus 22.9 ± 3.5 ml/m(2)), E/A (0.73 ± 0.22 versus 0.92 ± 0.14), DT (93.1 ± 6.9 versus 84.3 ± 8.1 ms), IRT (93.1 ± 6.9 versus 84.3 ± 8. ms) and the Tei index. Significant correlations were observed between serum homocysteine levels and LV diastolic function parameters (LAVI: r = 0.39, E/A: r = -0.32, DT: r = 0.47, IRT: r = 0.51, p < 0.05). We found that Hhcy had contributory effects on myocardial impairment induced by hypertension. Moreover, there were strong relationships between homocysteine level and LV diastolic dysfunction parameters.

Effects of angiotensin-converting enzyme inhibitory peptide LAP on vascular remodeling.

The aim of this article is to study the efficiency of an angiotensin-converting enzyme (ACE)-inhibitory peptide LAP on the blood pressure (BP) and the vascular remodeling in spontaneously hypertensive rats (SHRs). Ten-week-old male SHRs were divided into four groups with 10 animals in each group and treated for 2 months: blank, pseudo-experimental (NS), enalapril (ENA), and LAP. The alterations of BP, plasma angiotensin II (AngII) levels, and morphological changes of left common carotid artery and the third level of superior mesenteric artery were investigated. After 2 weeks of treatment, LAP and ENA significantly decreased BP and the antihypertensive effects lasted till the end of experiment. After 2 months, LAP and ENA also significantly lowered plasma AngII levels. LAP and enalapril significantly lowered vascular medial thickness, media thickness/lumen diameter, medial cross-sectional area, and mean nuclear area of smooth muscle cells in left common carotid artery. When compared to the blank group, LAP and ENA significantly lowered the percentages of collagen fibers in the vascular area of left common carotid artery with 24.84 ± 0.53, 23.36 ± 0.99 versus 31.82 ± 0.57 (blank), respectively, and those of the third level of superior mesenteric artery with 15.82 ± 0.60, 15.15 ± 0.71 versus 23.42 ± 0.72, respectively. LAP had a beneficial effect on BP and vascular remodeling in SHRs. These findings suggest the potential therapeutic value of LAP in the treatment of hypertension.

Epigenetic inhibition of lncRNA GMDS-AS1 by methyltransferase ESET promoted cell viability and metastasis of hepatocellular carcinoma.

BACKGROUND: Long noncoding RNA (lncRNAs) GMDS-AS1 has been reported as a tumor regulator in tumor growth and metastasis, but its effect in hepatocellular carcinoma (HCC) remains unclear. ESET, a histone H3K9 methyl-transferase, is involved in epigenomic regulation of tumor progression in multiple cancers. However, the correlation between ESET and lncRNA in HCC is less reported. METHODS: Quantitative real-time PCR (qRT-PCR) was taken to determine the expression of ESET and GMDS-AS1. Western blot was taken to determine the target protein levels of ESET and GMDS-AS1. Online database and bioinformatics analysis were used to screen abnormally expressed genes. Luciferase assay was performed to confirm the binding of GMDS-AS1 and PSMB1. Ki67 and Edu were used for evaluated the proliferation of tumor cells. ChIP assay was performed to verify the relationship between H3K9me1 and lncRNA GMDS-AS1 promoter. Transwell was taken to determine the migration and invasion ability of tumor cells. CCK-8 was used for determining the viability of tumor cells. Flow cytometry was performed to detect the cell cycle of tumor cells. RESULTS: The expression of GMDS-AS1 was decreased and the expression of ESET was increased in HCC. GMDS-AS1 inhibition contributed to tumor development, and this effect was closely related to epigenetic inhibition of GMDS-AS1 by ESET. PSMB1, a downstream target of GMDS-AS1, promoted the tumor proliferation and was negatively regulated by GMDS-AS1. CONCLUSION: Our result demonstrates anti-tumorigenic traits of lncRNA GMDS-AS1 in HCC and explains its pattern of regulation mediated by ESET. Our work unmasked an essential role of GMDS-AS1 in HCC progression and detected a novel pathway for ESET to promote HCC.

miRNA-103-3p-Hlf regulates apoptosis and autophagy by targeting hepatic leukaemia factor in heart failure.

AIMS: Cardiomyocyte apoptosis is an important factor leading to the occurrence and development of heart failure (HF), which is associated with high mortality of patients with cardiovascular diseases. This study aims to investigate the underlying mechanisms of HF in terms of expression and regulation patterns using bioinformatics and experimental validation. METHODS AND RESULTS: Two HF datasets were collected: a dataset GSE112056 downloaded from the GEO database (including mRNA and miRNA sequencing data) and another is the laboratory-owned mRNA dataset. Differential mRNAs and miRNAs in the two datasets were screened using the raw Bayesian approach method. Gene Ontology was used to perform functional enrichment analysis of the differential mRNAs and co-expression network analysis of the differential mRNAs, combined with nuclear transcription factors in the differential miRNAs and mRNAs for target gene prediction. A HF cell model was constructed using mouse cardiomyocytes (HL-1), and the role and mechanism of miRNA-103-3p-Hlf (hepatic leukaemia factor) in the process of HF was verified by cell transfection, luciferase reporter gene, WB, and qPCR. We found that Hlf gene expression was decreased in the HF model group and strongly correlated with FYCO1 (FYVE and coiled-coil domain-containing protein 1) gene, a phenomenon enriched in apoptotic autophagy-related pathways. MiR-103-3p expression was up-regulated in the HF model group, and its targeting correlation with Hlf was confirmed by luciferase activity assay. In the HL-1 cell model, miR-103-3p significantly promoted apoptosis and inhibited autophagy in HL-1 cells (all P < 0.05), and overexpression of the Hlf gene reversed this phenomenon, inhibiting apoptosis and promoting autophagy in HL-1 cells (all P < 0.05). CONCLUSIONS: MiR-103-3p affects myocardial cells apoptosis and autophagy by targeting Hlf, playing as a potential therapeutic biomarker for HF progression.

miR-129-5p/FGF2 axis is associated with homocysteine-induced human umbilical vein endothelial cell injury.

PURPOSE: Homocysteine (Hcy)-induced endothelial cell injury is a key event in atherosclerosis pathogenesis. In this study, we aimed to explore the mechanisms underlying Hcy-induced endothelial injury by assessing the effects of Hcy on endothelial cell proliferation and the microRNA (miR)-129-5p/fibroblast growth factor 2 (FGF2) axis. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with Hcy to construct an endothelial cell injury model. Expression levels of FGF2 in Hcy-induced HUVECs were determined using quantitative real-time polymerase chain reaction and western blotting. An FGF2 overexpression lentiviral vector was constructed to upregulate FGF2 expression in HUVECs via lentivirus transduction. A cell counting kit-8 assay was used to explore the effects of FGF2 overexpression on HUVEC proliferation. An upstream regulatory miRNA was predicted, and its target-binding relationship with FGF2 was evaluated using a dual-luciferase reporter assay. RESULTS: We found that FGF2 expression in HUVECs was inhibited by Hcy treatment. Lentivirus transduction led to the overexpression of FGF2 in HUVECs, which significantly reversed the effect of Hcy on endothelial cell proliferation. miR-129-5p was experimentally validated as an upstream regulator of FGF2, and its decreased levels in HUVECs led to increased FGF2 expression. In addition, HUVEC proliferation was enhanced by the knockdown of miR-129-5p, and this effect was reversed by Hcy treatment. CONCLUSION: Taken together, the results of this study revealed that Hcy inhibits FGF2 expression in HUVECs, and FGF2 is regulated by upstream miR-129-5p to improve the effect of Hcy on endothelial cell proliferation.

Construction of steady-active self-supported porous Ir-based electrocatalysts for the oxygen evolution reaction.

Developing highly active and stable oxygen evolution reaction (OER) catalysts for water electrolysis remains a great challenge. A self-supported Ir nanocatalyst was prepared via a self-assembly method. Its porous structure and residual metal incorporation contributed to its high activity and stability for the OER in acid.

FAM3D inhibits gluconeogenesis in high glucose environment via DUSP1/ZFP36/SIK1 axis.

Hyperglycemia is the most important factor leading to the complications of type 2 diabetes mellitus (T2DM). The primary condition for the treatment of T2DM is to change the glucose and lipid metabolism disorders in the liver and other insulin-sensitive tissues. The current study aims to unearth the potential molecular mechanism of inhibiting liver gluconeogenesis to provide a new theoretical basis for the treatment of T2DM. High glucose (HG) induction of HepG2 cells followed by treatment with sequence-similar family 3 member D (FAM3D). Dual specificity phosphatases 1 (DUSP1), zinc finger protein 36 (ZFP36), salt-induced kinase 1 (SIK1), p-SIK1, posphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene and protein expression level were detected by quantitative real-time polymerase chain reaction and western blot. The PEPCK and G6Pase activities were detected by enzyme linked immunosorbent assay. Glucose production assay to determine glucose content. The RNA binding protein immunoprecipitation assay was used to detect the binding of ZFP36 to SIK1. FAM3D facilitated the expression of DUSP1 but suppressed the expression of gluconeogenesis-related factors in an HG environment. The expression of ZFP36 was up-regulated in an HG environment. ZFP36 could reverse the inhibition of gluconeogenesis caused by FAM3D. HG-induced upregulation of ZFP36 was downregulated by overexpression of DUSP1. ZFP36 bound to SIK1, and downregulation of ZFP36 promoted SIK1 expression and inhibits gluconeogenesis. Our study demonstrated FAM3D inhibited gluconeogenesis through the DUSP1/ZFP36/SIK1 axis in an HG environment, which provided a new theoretical basis for exploring the pathogenesis and treatment strategy of T2DM.

DTSEA: A network-based drug target set enrichment analysis method for drug repurposing against COVID-19.

The Coronavirus Disease 2019 (COVID-19) pandemic is still wreaking havoc worldwide. Therefore, the urgent need for efficient treatments pushes researchers and clinicians into screening effective drugs. Drug repurposing may be a promising and time-saving strategy to identify potential drugs against this disease. Here, we developed a novel computational approach, named Drug Target Set Enrichment Analysis (DTSEA), to identify potent drugs against COVID-19. DTSEA first mapped the disease-related genes into a gene functional interaction network, and then it used a network propagation algorithm to rank all genes in the network by calculating the network proximity of genes to disease-related genes. Finally, an enrichment analysis was performed on drug target sets to prioritize disease-candidate drugs. It was shown that the top three drugs predicted by DTSEA, including Ataluren, Carfilzomib, and Aripiprazole, were significantly enriched in the immune response pathways indicating the potential for use as promising COVID-19 inhibitors. In addition to these drugs, DTSEA also identified several drugs (such as Remdesivir and Olumiant), which have obtained emergency use authorization (EUA) for COVID-19. These results indicated that DTSEA could effectively identify the candidate drugs for COVID-19, which will help to accelerate the development of drugs for COVID-19. We then performed several validations to ensure the reliability and validity of DTSEA, including topological analysis, robustness analysis, and prediction consistency. Collectively, DTSEA successfully predicted candidate drugs against COVID-19 with high accuracy and reliability, thus making it a formidable tool to identify potential drugs for a specific disease and facilitate further investigation.

PathwayTMB: A pathway-based tumor mutational burden analysis method for predicting the clinical outcome of cancer immunotherapy.

Immunotherapy has become one of the most promising therapy methods for cancer, but only a small number of patients are responsive to it, indicating that more effective biomarkers are urgently needed. This study developed a pathway analysis method, named PathwayTMB, to identify genomic mutation pathways that serve as potential biomarkers for predicting the clinical outcome of immunotherapy. PathwayTMB first calculates the patient-specific pathway-based tumor mutational burden (PTMB) to reflect the cumulative extent of mutations for each pathway. It then screens mutated survival benefit-related pathways to construct an immune-related prognostic signature based on PTMB (IPSP). In a melanoma training set, IPSP-high patients presented a longer overall survival and a higher response rate than IPSP-low patients. Moreover, the IPSP showed a superior predictive effect compared with TMB. In addition, the prognostic and predictive value of the IPSP was consistently validated in two independent validation sets. Finally, in a multi-cancer dataset, PathwayTMB also exhibited good performance. Our results indicate that PathwayTMB could identify the mutation pathways for predicting immunotherapeutic survival, and their combination may serve as a potential predictive biomarker for immune checkpoint inhibitor therapy.

MicroRNA-17-5p Promotes Vascular Calcification by Targeting ANKH.

BACKGROUND: MicroRNAs (miRNAs) may participate in the process of vascular calcification. However, the role of microRNA-17-5p in vascular calcification has not been clarified. In this study, we showed the effects of microRNA-17-5p on vascular calcification. MATERIALS AND METHODS: Vascular smooth muscle cells (VSMCs) were transfected with miR-17-5p mimics, a miR-17-5p inhibitor or negative control (NC) using Lipofectamine 2000. Then the cells were induced by an osteogenic medium. Alkaline phosphatase (ALP) activity and mineralization were determined. Osteocalcin (OC), bone morphogenetic protein 2(BMP-2), Collagen Ia (Colla), Runx2, and ankylosis protein homolog (ANKH) gene expressions were determined by reverse transcription-polymerase chain reaction. Vascular calcification was developed using a renal failure model. RESULTS: The ALP activity was increased when miR-17-5p mimics were transfected, whereas the miR-17-5p inhibitor reduced ALP activity (p < 0.05). The number and average area of mineral nodes in the miR-17-5p mimic group was larger than those in the corresponding control and NC groups (p < 0.05). The number and average area of the mineral nodes in the miR-17-5p inhibitor group were smaller than those in the corresponding control and NC groups (p < 0.05). Bmp2, OC, Col1a and Runx2 were higher in the miR-17-5p mimics group compared to those in the control and NC groups. ANKH expression was decreased in VSMCs with the miR-17-5p mimics and increased in VSMCs with miR-17-5p inhibitor. ANKH siRNA intervention also promoted mineralization. The miR-17-5p expression was upregulated and ANKH was down-regulated in the aortic arteries with calcification. CONCLUSION: Our data showed that miR-17-5p may promote vascular calcification by inhibiting ANKH expression.