Microstructured Polyelectrolyte Elastomer-Based Ionotronic Sensors with High Sensitivities and Excellent Stability for Artificial Skins.

High-performance flexible pressure sensors are highly demanded for artificial tactile sensing. Using ionic conductors as the dielectric layer has enabled ionotronic pressure sensors with high sensitivities owing to giant capacitance of the electric double layer (EDL) formed at the ionic conductor/electronic conductor interface. However, conventional ionotronic sensors suffer from leakage, which greatly hinders long-term stability and practical applications. Herein, a leakage-free polyelectrolyte elastomer as the dielectric layer for ionotronic sensors is synthesized. The mechanical and electrical properties of the polyelectrolyte elastomer are optimized, a micropyramid array is constructed, and it is used as the dielectric layer for an ionotronic pressure sensor with marked performances. The obtained sensor exhibits a sensitivity of 69.6 kPa-1 , a high upper detecting limit on the order of 1 MPa, a fast response/recovery speed of ≈6 ms, and excellent stability under both static and dynamic loads. Notably, the sensor retains a high sensitivity of 4.96 kPa-1 at 500 kPa, and its broad sensing range within high-pressure realm enables a brand-new coding strategy. The applications of the sensor as a wearable keyboard and a quasicontinuous controller for a robotic arm are demonstrated. Durable and highly sensitive ionotronic sensors potentialize high-performance artificial skins for soft robots, human-machine interfaces, and beyond.

Rational Design of Hollow Structural Materials for Sodium-Ion Battery Anodes.

The development of sodium-ion battery (SIB) anodes is still hindered by their rapid capacity decay and poor rate capabilities. Although there have been some new materials that can be used to fabricate stable anodes, SIBs are still far from wide applications. Strategies like nanostructure construction and material modification have been used to prepare more robust SIB anodes. Among all the design strategies, the hollow structure design is a promising method in the development of advanced anode materials. In the past decade, research efforts have been devoted to modifying the synthetic route, the type of templates, and the interior structure of hollow structures with high capacity and stability. A brief introduction is made to the main material systems and classifications of hollow structural materials first. Then different morphologies of hollow structural materials for SIB anodes from the latest reports are discussed, including nanoboxes, nanospheres, yolk shells, nanotubes, and other more complex shapes. The most used templates for the synthesis of hollow structrual materials are covered and the perspectives are highlighted at the end. This review offers a comprehensive discussion of the synthesis of hollow structural materials for SIB anodes, which could be potentially of use to research areas involving hollow materials design for batteries.

Screening Power of End-Point Free-Energy Calculations in Cucurbituril Host-Guest Systems.

End-point free-energy methods as an indispensable component in virtual screening are commonly recognized as a tool with a certain level of screening power in pharmaceutical research. While a huge number of records could be found for end-point applications in protein-ligand, protein-protein, and protein-DNA complexes from academic and industrial reports, up to now, there is no large-scale benchmark in host-guest complexes supporting the screening power of end-point free-energy techniques. A good benchmark requires a data set of sufficient coverage of pharmaceutically relevant chemical space, a long-time sampling length supporting the trajectory approximation of the ensemble average, and a sufficient sample size of receptor-acceptor pairs to stabilize the performance statistics. In this work, selecting a popular family of macrocyclic hosts named cucurbiturils, we construct a large data set containing 154 host-guest pairs, perform extensive end-point sampling of several hundred nanosecond lengths for each system, and extract the free-energy estimates with a variety of end-point free-energy techniques, including the advanced three-trajectory dielectric-constant-variable regime proposed in our recent work. The best-performing end-point protocol employs GAFF2 for solute descriptions, the three-trajectory end-point sampling regime, and the MM/GBSA Hamiltonian in free-energy extraction, achieving a high ranking metrics of Kendall τ > 0.6, a Pearlman predictive index of ∼0.8, and a high scoring power of Pearson r > 0.8. The current project as the first large-scale systematic benchmark of end-point methods in host-guest complexes in academic publications provides solid evidence of the applicability of end-point techniques and direct guidance of computational setups in practical host-guest systems.

Light-Mediated Electrochemical Synthesis of Manganese Oxide Enhances Its Stability for Water Oxidation.

New methods are needed to increase the activity and stability of earth-abundant catalysts for electrochemical water splitting to produce hydrogen fuel. Electrodeposition has been previously used to synthesize manganese oxide films with a high degree of disorder and a mixture of oxidation states for Mn, which has led to electrocatalysts with high activity but low stability for the oxygen evolution reaction (OER) at high current densities. In this study, we show that multipotential electrodeposition of manganese oxide under illumination produces nanostructured films with significantly higher stability for the OER compared to films grown under otherwise identical conditions in the dark. Manganese oxide films grown by multipotential deposition under illumination sustain a current density of 10 mA/cm2 at 2.2 V versus reversible hydrogen electrode for 18 h (pH 13). Illumination does not enhance the activity or stability of manganese oxide films grown using a constant potential, and films grown by multipotential deposition in the dark undergo a complete loss of activity within 1 h of electrolysis. Electrochemical and structural characterization indicate that photoexcitation of the films during growth reduces Mn ions and changes the content and structure of intercalated potassium ions and water molecules in between the disordered layers of birnessite-like sheets of MnOx, which stabilizes the nanostructured film during electrocatalysis. These results demonstrate that combining multiple external stimuli (i.e., light and an external potential) can induce structural changes not attainable by either stimulus alone to make earth-abundant catalysts more active and stable for important chemical transformations such as water oxidation.

Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host-Guest Binding: III. Force-Field Comparison, Three-Trajectory Realization and Further Dielectric Augmentation.

Host-guest binding, despite the relatively simple structural and chemical features of individual components, still poses a challenge in computational modelling. The extreme underperformance of standard end-point methods in host-guest binding makes them practically useless. In the current work, we explore a potentially promising modification of the three-trajectory realization. The alteration couples the binding-induced structural reorganization into free energy estimation and suffers from dramatic fluctuations in internal energies in protein-ligand situations. Fortunately, the relatively small size of host-guest systems minimizes the magnitude of internal fluctuations and makes the three-trajectory realization practically suitable. Due to the incorporation of intra-molecular interactions in free energy estimation, a strong dependence on the force field parameters could be incurred. Thus, a term-specific investigation of transferable GAFF derivatives is presented, and noticeable differences in many aspects are identified between commonly applied GAFF and GAFF2. These force-field differences lead to different dynamic behaviors of the macrocyclic host, which ultimately would influence the end-point sampling and binding thermodynamics. Therefore, the three-trajectory end-point free energy calculations are performed with both GAFF versions. Additionally, due to the noticeable differences between host dynamics under GAFF and GAFF2, we add additional benchmarks of the single-trajectory end-point calculations. When only the ranks of binding affinities are pursued, the three-trajectory realization performs very well, comparable to and even better than the regressed PBSA_E scoring function and the dielectric constant-variable regime. With the GAFF parameter set, the TIP3P water in explicit solvent sampling and either PB or GB implicit solvent model in free energy estimation, the predictive power of the three-trajectory realization in ranking calculations surpasses all existing end-point methods on this dataset. We further combine the three-trajectory realization with another promising modified end-point regime of varying the interior dielectric constant. The combined regime does not incur sizable improvements for ranks and deviations from experiment exhibit non-monotonic variations.

Development and validation of a DNA damage repair-related gene-based prediction model for the prognosis of lung adenocarcinoma.

Background: Lung cancer is the leading cause of morbidity and mortality among all cancer types, with lung adenocarcinoma (LUAD) being the most prevalent subtype. DNA damage repair (DDR)-related genes are closely associated with cancer progression and treatment, with emerging evidence highlighting their correlation with tumor development. However, the relationship between LUAD prognosis and DDR-related genes remains unclear. Methods: RNA sequencing (RNA-seq) data and clinical information were obtained from The Cancer Genome Atlas (TCGA) database. The GSE31210 dataset, utilized for external validation, was retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed DDR genes were identified, and a DDR-related prognostic model was established and validated using Kaplan-Meier (KM) survival analysis, time-dependent receiver operating characteristic (ROC) curves, gene set enrichment analysis (GSEA), tumor mutational burden (TMB) analysis, and immune cell infiltration. A P value of less than 0.05 was considered statistically significant. Results: A total of 514 patients with LUAD from TCGA database were divided into distinct subtypes to characterize the diversity within the DDR pathway. DDR-activated and DDR-suppressed subgroups showed distinct clinical characteristics, molecular characteristics, and immune profiles. Nine genes were identified as hub DDR-related genes, including CASP14, DKK1, ECT2, FLNC, HMMR, IGFBP1, KRT6A, TYMS, and FCER2. By using the expression levels of these selected genes, the corresponding risk scores for each sample was predicted. In the training group, KM survival analysis revealed that the high-risk group exhibited significantly diminished overall survival (OS) [hazard ratio (HR) =3.341, P=1.38e-08]. The corresponding area under the curve (AUC) values for the 1-year follow-up periods was 0.767, respectively. Upon validation in the external cohort, patients with higher risk scores manifested significantly reduced OS (HR =2.372, P=1.87e-03). The AUC values of the ROC curves for the 1-year OS in the validation cohort was 0.87, respectively. Moreover, advanced DDR risk score was correlated with increased TMB scores, a heightened frequency of TP53 mutations, an increased abundance of cancer-testicular antigens (CTAs), and a lower tumor immune dysfunction and exclusion (TIDE) score in patients with LUAD (P<0.05). Conclusions: A nine-gene risk signature associated with DDR in LUAD was effectively developed, demonstrating its potential as a robust and reliable classification tool for clinical practice. This model exhibited the capability to accurately predict the prognosis and survival outcomes of LUAD patients.

Advances in platinum-based and platinum-free oxygen reduction reaction catalysts for cathodes in direct methanol fuel cells.

Direct methanol fuel cells (DMFCs) have been the focus of future research because of their simple structure, abundant fuel sources, high energy conversion efficiency and low cost. Among the components in DMFC, the activity and stability of the cathode catalyst is the key to the performance and lifetime of the DMFCs. Oxygen reduction reaction (ORR) is an important electrode reaction on DMFC cathode. It is known that Pt is widely used in the fabrication of ORR catalysts, but the limited earth storage of Pt and its high price limit the use of Pt-based commercial catalysts in DMFCs. To overcome these problems, advances have been made on new low Pt-based catalysts and Pt-free catalysts in recent years. In this article, the development of novel ORR catalysts and the carbon supports is reviewed and discussed.

High expression of glycolysis-related PGM2 gene in relation to poor prognosis and deficient immune cells infiltration in lung adenocarcinoma: a study based on bioinformatics analysis.

Background: Lung adenocarcinoma (LUAD) is the most important subtype of lung cancer and usually metastasizes. Patients with LUAD usually had a poor prognosis. Identifying viable molecular markers for diagnostic and prognostic prediction among individuals with LUAD is critical for the future management of this disease. This study aimed to determine and verify a correlation between the glycolysis-related phosphoglucomutase 2 (PGM2) gene and dissatisfactory results and deficient infiltration of immune cells in LUAD. Methods: The expression of PGM2 in LUAD and adjoining normal tissues was screened from The Cancer Genome Atlas (TCGA) data and human protein atlas (HPA), and validatied by quantative reverse transcription polymerase chain reaction (qRT-PCR). We examined the correlation between PGM2 expression and clinicopathologic characteristics (including pathological stage, gender, M stage, smoker, age, N stage, race, and number pack years smoked) by multivariable approaches and Kaplan-Meier survival curves. The proteins network with PGM2 was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The correlation between PGM2 expression and infiltration of immune cells, along with the corresponding gene marker sets, was investigated through the Gene Expression Profiling Interactive Analysis (GEPIA) and Tumor Immune Estimation Resource (TIMER) databases. We evaluated the possible correlation between PGM2 expression and progression-free interval (PFI), disease-specific survival (DSS), and overall survival (OS) in LUAD patients. Results: Expression of PGM2 was up-regulated in LUAD tissues (P=0.003). According to the multivariate logistic regression analysis, the elevated expression level of PGM2 exhibited a remarkable correlation with advanced tumor-node-metastasis (TNM) stage, high-grade malignancy, and primary therapeutic outcome . Overexpression of PGM2 was shown to be correlated with an unfavorable prognosis including OS (P=0.004, HR =1.54), DSS (P=0.003, HR =1.77), and PFI (P=0.003, HR =1.5) in LUAD. The proteins PGM1 and UGP2 were shown to have a significant correlation with PGM2. Additionally, PGM2 was associated with the lack of infiltrating immune cells as well as their associated gene marker sets in LUAD. Conclusions: Overexpression of PGM2 was shown to be associated with the progression and an unfavorable prognosis of LUAD, as well as with inefficient immune cell infiltration. PGM2 was expected to be a potential biological marker for predicting the prognosis of patients with LUAD.

Comprehensive evaluation of end-point free energy techniques in carboxylated-pillar[6]arene host-guest binding: I. Standard procedure.

Despite the massive application of end-point free energy methods in protein-ligand and protein-protein interactions, computational understandings about their performance in relatively simple and prototypical host-guest systems are limited. In this work, we present a comprehensive benchmark calculation with standard end-point free energy techniques in a recent host-guest dataset containing 13 host-guest pairs involving the carboxylated-pillar[6]arene host. We first assess the charge schemes for solutes by comparing the charge-produced electrostatics with many ab initio references, in order to obtain a preliminary albeit detailed view of the charge quality. Then, we focus on four modelling details of end-point free energy calculations, including the docking procedure for the generation of initial condition, the charge scheme for host and guest molecules, the water model used in explicit-solvent sampling, and the end-point methods for free energy estimation. The binding thermodynamics obtained with different modelling schemes are compared with experimental references, and some practical guidelines on maximizing the performance of end-point methods in practical host-guest systems are summarized. Further, we compare our simulation outcome with predictions in the grand challenge and discuss further developments to improve the prediction quality of end-point free energy methods. Overall, unlike the widely acknowledged applicability in protein-ligand binding, the standard end-point calculations cannot produce useful outcomes in host-guest binding and thus are not recommended unless alterations are performed.

Rapid death due to pulmonary epithelioid haemangioendothelioma in several weeks: A case report.

A 49-year-old woman was admitted to our hospital because of haemoptysis for 6 days. This patient claimed no medical history except high blood sugar. Chest computed tomography (CT) showed infection and multiple nodules on both sides of the lung. Blood tests showed no obvious abnormalities. Tracheoscopy showed haemorrhagic discharge in the left upper lobe and an old thrombus obstructing the lumen in the anterior basal segment of the right lower lobe. Then, CT-guided percutaneous lung biopsy was performed. The pathological results suggested multiple nodular-like lesions in the submitted tissues, and tumour cells were round or short fusiform, forming a solid nest structure, visible mitosis, and a vascular cavity-like structure containing red blood cells. Immunohistochemistry revealed positive staining for Vimentin, Bcl-2, CD31, and CD34; negative staining for CD68, SMA, CR, and D2-40; and 40% Ki67+ positivity. Based on the earlier data, the patient was diagnosed with pulmonary epithelioid haemangioendothelioma. This patient did not receive any treatment for several reasons. Unfortunately, the patient died 8 weeks after diagnosis. In conclusion, we present a case featuring the rapid death due to PEH.

Hypermethylation of the Nrf2 Promoter Induces Ferroptosis by Inhibiting the Nrf2-GPX4 Axis in COPD.

BACKGROUND: Nuclear factor E2-related factor 2 (Nrf2) is involved in oxidative stress and lung inflammation and regulates the etiology of chronic obstructive pulmonary disease (COPD). Ferroptosis is characterized by the accumulation of lipid reactive oxygen species (ROS) via ferrous ion-dependent Fenton reactions and is involved in COPD. However, the role of Nrf2 in ferroptosis and its epigenetic regulation in the pathogenesis of COPD remain unclear. METHODS: Ferroptosis was detected by 4-HNE, MDA, C11BODIPY, DCFH-DA, Peals' staining and CCK-8 assays. qPCR and Western blotting were performed to examine the Nrf2 levels in peripheral lung tissues, primary epithelial cells collected from patients with COPD and subjects with normal pulmonary function (never-smoker [control-NS]; smoker [control-S]), and cigarette smoke extract (CSE)-treated human bronchial epithelial (HBE) cells. ELISA was used to quantify IL-8 and IL-1ß levels. Methylation of the Nrf2 promoter was analyzed by bisulfite sequencing and pyrosequencing. RESULTS: Ferroptosis was involved in COPD and glutathione peroxidase 4 (GPX4) expression was downregulated in the COPD group. Reactive oxygen species (ROS), lipid peroxides and MDA were increased, but GPX4 and SOD were exhausted in CSE-treated HBE cells. The production of IL-1ß and IL-8 was promoted in HBE cells in response to CSE but could be reversed by the ferroptosis inhibitor fer-1. The Nrf2 level was significantly decreased in the COPD group compared with the control-S and control-NS groups. Increased Nrf2 expression enhanced GPX4 and SOD levels and inhibited ferroptosis and proinflammatory cytokines in the supernatant. Inhibition of GPX4 reversed the effect of Nrf2 overexpression and promoted ferroptosis. Two specific CpG sites within the Nrf2 promoter were hypermethylated in the COPD group. Similarly, CSE-treated HBE cells exhibited hypermethylation of the Nrf2 gene. CONCLUSION: Nrf2 expression was downregulated in the lungs of COPD patients due to hypermethylation of the Nrf2 promoter, inhibiting Nrf2/GPX4 and ferroptosis, which is related to the initiation and progression of COPD. Targeting Nrf2/GPX4 may inhibit ferroptosis, which could provide strategies to delay or treat COPD.

Circular RNA 0006349 Augments Glycolysis and Malignance of Non-small Cell Lung Cancer Cells Through the microRNA-98/MKP1 Axis.

Background: The involvement of dysregulated circular RNAs (circRNAs) in human diseases has been increasingly recognized. In this study, we focused on the function of a newly screened circRNA, circ_0006349, in the progression of non-small-cell lung cancer (NSCLC) and the molecules of action. Methods: The NSCLC circRNA dataset GSE101684, microRNA (miRNA) dataset GSE29250, and mRNA dataset GSE51852 obtained from the GEO database were used to identify the differentially expressed genes in NSCLC samples. Tumor and normal tissues were collected from 59 patients with NSCLC. The expression of circ_0006349, miR-98, and MAP kinase phosphatase 1 (MKP1) in collected tissue samples and in acquired cells was determined. The binding relationships between miR-98 and circ_0006349/MKP1 were predicted and validated. Altered expression of circ_0006349, miR-98, and MKP1 was introduced in NSCLC cells to examine their roles in cell growth, apoptosis, and glycolysis. Results: Circ_0006349 and MKP1 were upregulated, and miR-98 was poorly expressed in the collected tumor tissues and the acquired NSCLC cell lines. Circ_0006349 was identified as a sponge for miR-98 to elevate MKP1 expression. Silencing of circ_0006349 suppressed proliferation and increased apoptosis of Calu-3 and H1299 cells, and it reduced glycolysis, glucose uptake, and the production of lactate in cells. Upon circ_0006349 knockdown, further downregulation of miR-98 or upregulation of MKP1 restored the malignant behaviors of cells. Conclusion: This research demonstrated that circ_0006349 derepressed MKP1 expression by absorbing miR-98, which augmented the proliferation and glycolysis of NSCLC cells and promoted cancer development.

Clinical Utility of Central and Peripheral Airway Nitric Oxide in Aging Patients with Stable and Acute Exacerbated Chronic Obstructive Pulmonary Disease.

PURPOSE: Exhaled nitric oxide has been used as a marker of airway inflammation. The NO concentration in the central and peripheral airway/alveolar can be measured by a slow and fast exhalation flow rate to evaluate inflammation in different divisions within the respiratory tract. We hypothesized that FeNO200 (exhaled NO at a flow rate of 200mL/s) could be used as an evaluation tool for peripheral airway/alveolar inflammation and corticosteroid therapy in chronic obstructive pulmonary disease (COPD) patients. METHODS: We recruited 171 subjects into the study: 73 healthy controls, 59 stable COPD patients, and 39 acute exacerbations of COPD (AECOPD) patients. Exhaled nitric oxide (FeNO50 (exhaled NO at a flow rate of 50mL/s)), FeNO200 and CaNO (peripheral concentration of NO/alveolar NO) and clinical variables including pulmonary function, COPD Assessment Test (CAT), C-reactive protein concentration (CRP) and circulating eosinophil count were measured among the recruited participants. FeNO50, FeNO200 and CaNO were repeatedly evaluated in 39 AECOPD patients after corticosteroid treatment. RESULTS: FeNO200 was significantly higher in stable COPD and AECOPD patients than in healthy controls. Nevertheless, CaNO could not differentiate COPD from healthy controls. No correlation was found between circulating eosinophil counts or FEV1 and exhaled nitric oxide (FeNO50, FeNO200, CaNO) in COPD patients. For AECOPD patients, 64% of patients had eosinophil counts >100 cells/µL; 59% of patients had FeNO200 >10 ppb; only 31% of patients had FeNO50 > 25 ppb. Among AECOPD patients, the high FeNO50 and FeNO200 groups' levels were significantly lower than their baseline levels, and significant improvements in CAT were seen in the two groups after corticosteroid treatment. These implied a good corticosteroid response in AECOPD patients with FeNO200>10ppb. CONCLUSION: FeNO200 is a straightforward and feasible method to evaluate the peripheral NO concentration in COPD. FeNO200 can be a type 2 inflammation biomarker and a useful tool for predicting corticosteroid therapy in COPD.

Let-7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL-6.

BACKGROUND: Myofibroblast differentiation and extracellular matrix (ECM) deposition are observed in chronic obstructive pulmonary disease (COPD). However, the mechanisms of regulation of myofibroblast differentiation remain unclear. MATERIALS AND METHODS: We detected let-7 levels in peripheral lung tissues, serum and primary bronchial epithelial cells of COPD patients and cigarette smoke (CS)-exposed mice. IL-6 mRNA was explored in lung tissues of COPD patients and CS-exposed mice. IL-6 protein was detected in cell supernatant from primary epithelial cells by ELISA. We confirmed the regulatory effect of let-7 on IL-6 by luciferase reporter assay. Western blotting assay was used to determine the expression of α-SMA, E-cadherin and collagen I. In vitro, cell study was performed to demonstrate the role of let-7 in myofibroblast differentiation and ECM deposition. RESULTS: Low expression of let-7 was observed in COPD patients, CS-exposed mice and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. Increased IL-6 was found in COPD patients, CS-exposed mice and CSE-treated HBE cells. Let-7 targets and silences IL-6 protein coding genes through binding to 3' untranslated region (UTR) of IL-6. Normal or CSE-treated HBE cells were co-cultured with human embryonic lung fibroblasts (MRC-5 cells). Reduction of let-7 in HBE cells caused myofibroblast differentiation and ECM deposition, while increase of let-7 mimics decreased myofibroblast differentiation phenotype and ECM deposition. CONCLUSION: We demonstrate that CS reduced let-7 expression in COPD and, further, identify let-7 as a regulator of myofibroblast differentiation through the regulation of IL-6, which has potential value for diagnosis and treatment of COPD.

Downregulation of PTEN mediates bleomycin-induced premature senescence in lung cancer cells by suppressing autophagy.

OBJECTIVE: Bleomycin is an important chemotherapeutic drug that activates premature senescence to decrease the tumorigenic process. We aimed to investigate the role of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in bleomycin-induced premature senescence in lung cancer cells. METHODS: Human lung cancer A549 cells were incubated in the presence of different concentrations of bleomycin for 5 days. A lentivirus vector was used to silence the PTEN gene, followed by stimulation with bleomycin (1 µg/mL). Changes were evaluated by senescence-associated ß-galactosidase staining, reverse transcription-polymerase chain reaction, and western blot. RESULTS: Treatment with bleomycin induced premature senescence. PTEN expression was decreased and key downstream molecules in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway were gradually activated following bleomycin treatment. Silencing PTEN reduced autophagy and accelerated senescence of A549 cells. Autophagy levels were also increased and senescence markers were reduced after inhibiting mTOR. CONCLUSIONS: Downregulation of PTEN mediates bleomycin-induced premature senescence in lung cancer cells by suppressing autophagy via the PI3K/Akt/mTOR pathway. These findings provide new insights into the potential role of PTEN as a molecular target for cancer chemotherapy.

Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics.

Knowledge of therapeutic targets and early drug candidates is useful for improved drug discovery. In particular, information about target regulators and the patented therapeutic agents facilitates research regarding druggability, systems pharmacology, new trends, molecular landscapes, and the development of drug discovery tools. To complement other databases, we constructed the Therapeutic Target Database (TTD) with expanded information about (i) target-regulating microRNAs and transcription factors, (ii) target-interacting proteins, and (iii) patented agents and their targets (structures and experimental activity values if available), which can be conveniently retrieved and is further enriched with regulatory mechanisms or biochemical classes. We also updated the TTD with the recently released International Classification of Diseases ICD-11 codes and additional sets of successful, clinical trial, and literature-reported targets that emerged since the last update. TTD is accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp. In case of possible web connectivity issues, two mirror sites of TTD are also constructed (http://db.idrblab.org/ttd/ and http://db.idrblab.net/ttd/).

Close Relationship between cIAP2 and Human ARDS Induced by Severe H7N9 Infection.

BACKGROUND: cIAP2 is involved in necroptosis as a key upstream regulation factor. We aimed to investigate the role of cIAP2 in ARDS/ALI induced by H7N9 virus through regulating the RIPK1/3 necroptosis pathway. METHODS: Lung tissues of 11 patients who died from ARDS-complicated H7N9 infection between 2013 and 2016 were obtained as the H7N9-ARDS group. Lung tissues near benign lung nodules were acquired as the control group. Histological changes were evaluated by H&E staining. Protein levels of cIAP2, RIPK1, RIPK3, p-RIPK3, MLKL, and p-MLKL in the lung tissues were detected by Western Blot. The mRNA levels of cIAP2, RIPK1, and RIPK3 were detected by real-time PCR. RESULTS: H7N9 virus infection had a high mortality, with ARDS being the leading cause of death. The protein level of cIAP2 in the experimental group was lower than that in the control group (P<0.05). However, the experimental group showed higher RIPK1, RIPK3, and p-RIPK3 protein levels than the control group (P<0.05), as well as the expression level of MLKL and p-MLKL protein, which is a key downstream protein in necroptosis (P<0.05). CONCLUSION: In tissues from patients with fatal H7N9, downregulation of cIAP2 and induction of necroptosis was observed. We could speculate that necroptosis of the pulmonary epithelium is associated with severe H7N9 infection leading to ARDS. Thus, necroptosis inhibition may be a novel therapy for H7N9 influenza virus.

CMAUP: a database of collective molecular activities of useful plants.

The beneficial effects of functionally useful plants (e.g. medicinal and food plants) arise from the multi-target activities of multiple ingredients of these plants. The knowledge of the collective molecular activities of these plants facilitates mechanistic studies and expanded applications. A number of databases provide information about the effects and targets of various plants and ingredients. More comprehensive information is needed for broader classes of plants and for the landscapes of individual plant's multiple targets, collective activities and regulated biological pathways, processes and diseases. We therefore developed a new database, Collective Molecular Activities of Useful Plants (CMAUP), to provide the collective landscapes of multiple targets (ChEMBL target classes) and activity levels (in 2D target-ingredient heatmap), and regulated gene ontologies (GO categories), biological pathways (KEGG categories) and diseases (ICD blocks) for 5645 plants (2567 medicinal, 170 food, 1567 edible, 3 agricultural and 119 garden plants) collected from or traditionally used in 153 countries and regions. These landscapes were derived from 47 645 plant ingredients active against 646 targets in 234 KEGG pathways associated with 2473 gene ontologies and 656 diseases. CMAUP (http://bidd2.nus.edu.sg/CMAUP/) is freely accessible and searchable by keywords, plant usage classes, species families, targets, KEGG pathways, gene ontologies, diseases (ICD code) and geographical locations.

LncRNA-MEG3 functions as a competing endogenous RNA to regulate Treg/Th17 balance in patients with asthma by targeting microRNA-17/ RORγt.

BACKGROUND: Treg/Th17 imbalance plays an essential role in the pathogenesis of asthma. Disordered LncRNAs were observed in asthma, however, whether LncRNAs can regulate the Treg/Th17 balance and its mechanism still needs to be investigated. METHODS: Microarrays were performed to identify the differentially expressed lncRNAs and microRNAs in peripheral blood CD4 + T cells from patients with asthma and healthy controls. Bioinformatical evidence was used to select candidate lncRNAs and microRNAs which may involve in regulation of Treg/Th17 balance. The function of LncRNA-MEG3 and microRNA-17 on the alteration of the CD4 + T cell population were determined in vitro experiments. Meanwhile, the regulatory effect of LncRNA-MEG3 and microRNA-17 on RORγt or Foxp3 was estimated. The interaction of LncRNA-MEG3 with microRNA-17 was confirmed by dual luciferase reporter assay and RNA pull-down. RESULTS: 25 lncRNAs and 19 microRNAs were selected as candidate genes which differentially expressed in CD4 + T cells from patients with asthma compared with healthy controls and had potential to control Treg/Th17 balance by regulating RORγt or Foxp3. Alternation of LncRNA-MEG3 changed the function and increased the percentage of Th17. LncRNA-MEG3 could regulate the RORγt mRNA and protein level. LncRNA-MEG3 could inhibit the level of microRNA-17 as a competing endogenous RNA (ceRNA). microRNA-17 suppressed Th17 though targeting RORγt directly. CONCLUSION: LncRNA-MEG3 can sponge microRNA-17 as a ceRNA, thereby regulating RORγt and ultimately affecting Treg/Th17 balance in asthma. The lncRNA/microRNA axis may have potential application in clinical treatment and diagnosis of the disease.

NPASS: natural product activity and species source database for natural product research, discovery and tool development.

There has been renewed interests in the exploration of natural products (NPs) for drug discovery, and continuous investigations of the therapeutic claims and mechanisms of traditional and herbal medicines. In-silico methods have been employed for facilitating these studies. These studies and the optimization of in-silico algorithms for NP applications can be facilitated by the quantitative activity and species source data of the NPs. A number of databases collectively provide the structural and other information of ∼470 000 NPs, including qualitative activity information for many NPs, but only ∼4000 NPs are with the experimental activity values. There is a need for the activity and species source data of more NPs. We therefore developed a new database, NPASS (Natural Product Activity and Species Source) to complement other databases by providing the experimental activity values and species sources of 35 032 NPs from 25 041 species targeting 5863 targets (2946 proteins, 1352 microbial species and 1227 cell-lines). NPASS contains 446 552 quantitative activity records (e.g. IC50, Ki, EC50, GI50 or MIC mainly in units of nM) of 222 092 NP-target pairs and 288 002 NP-species pairs. NPASS, http://bidd2.nus.edu.sg/NPASS/, is freely accessible with its contents searchable by keywords, physicochemical property range, structural similarity, species and target search facilities.