DrugRep: an automatic virtual screening server for drug repurposing.

Computationally identifying new targets for existing drugs has drawn much attention in drug repurposing due to its advantages over de novo drugs, including low risk, low costs, and rapid pace. To facilitate the drug repurposing computation, we constructed an automated and parameter-free virtual screening server, namely DrugRep, which performed molecular 3D structure construction, binding pocket prediction, docking, similarity comparison and binding affinity screening in a fully automatic manner. DrugRep repurposed drugs not only by receptor-based screening but also by ligand-based screening. The former automatically detected possible binding pockets of the receptor with our cavity detection approach, and then performed batch docking over drugs with a widespread docking program, AutoDock Vina. The latter explored drugs using seven well-established similarity measuring tools, including our recently developed ligand-similarity-based methods LigMate and FitDock. DrugRep utilized easy-to-use graphic interfaces for the user operation, and offered interactive predictions with state-of-the-art accuracy. We expect that this freely available online drug repurposing tool could be beneficial to the drug discovery community. The web site is http://cao.labshare.cn/drugrep/ .

Controlled Construction of Heteroleptic [Pd2 (LA )2 (LB )(LC )]4+ Cages: A Facile Approach for Site-Selective endo-Functionalization of Supramolecular Cavities.

Construction of supramolecular structures with internal functionalities is a promising approach to build enzyme-like cavities. The endo-functionalized [Pd12 L24 ] and [Pd2 L4 ] coordination cages represent the most successful systems in this regard. However, these systems mainly contain one type of endo-moiety. We herein provide a solution for the controlled endo-functionalization of [Pd2 L4 ] cages. Site-selective introduction of the endo-functional group was achieved through the formation of heteroleptic [Pd2 (LA )2 (LB )(LC )] cages. Using two orthogonal steric control elements is the key for the selective formation of the hetero-assemblies. We demonstrated the construction of two hetero-cages with a single internal functional group as well as a hetero-cage with two distinct endohedral functionalities. The endo-functionalized hetero-cages bound sulfonate guests with fast-exchange dynamics. This strategy provides a new solution for the controlled endo-functionalization of supramolecular cavities.

CB-Dock: a web server for cavity detection-guided protein-ligand blind docking.

As the number of elucidated protein structures is rapidly increasing, the growing data call for methods to efficiently exploit the structural information for biological and pharmaceutical purposes. Given the three-dimensional (3D) structure of a protein and a ligand, predicting their binding sites and affinity are a key task for computer-aided drug discovery. To address this task, a variety of docking tools have been developed. Most of them focus on docking in the preset binding sites given by users. To automatically predict binding modes without information about binding sites, we developed a user-friendly blind docking web server, named CB-Dock, which predicts binding sites of a given protein and calculates the centers and sizes with a novel curvature-based cavity detection approach, and performs docking with a popular docking program, Autodock Vina. This method was carefully optimized and achieved ~70% success rate for the top-ranking poses whose root mean square deviation (RMSD) were within 2 Å from the X-ray pose, which outperformed the state-of-the-art blind docking tools in our benchmark tests. CB-Dock offers an interactive 3D visualization of results, and is freely available at http://cao.labshare.cn/cb-dock/.

The Epidemiological Characteristics of Beijing Lineage Mycobacterium tuberculosis from a National Referral Center in China.

Our study was to investigate the epidemiological characteristics of M.tuberculosis from a national tuberculosis referral center in China. All strains isolated from TB patients, were genotyped by the RD105 deletion, 8 and 51 SNP loci and VNTR. The high differentiation SNPs of modern Beijing strains were analyzed for protein function and structure. 413 M. tuberculosis were included. Of 379 Beijing lineage M. tuberculosis, 'modern' and 'ancient' strains respectively represented 85.5% (324/379) and 14.5% (55/379). Rv2494 (V48A) and Rv0245 (S103F) were confirmed as high differentiation SNPs associated with modern strains. In a word, Modern Beijing lineage M.tuberculosis was dominant and the structural models suggested that modern sub-lineage may more easily survive in 'extreme' host condition.

Predicting the Risk of Postoperative Delirium in Elderly Patients Undergoing Hip Arthroplasty: Development and Assessment of a Novel Nomogram.

OBJECTIVE: To construct and internally validate a nomogram that predicts the likelihood of postoperative delirium in a cohort of elderly individuals undergoing hip arthroplasty. METHODS: Data for a total of 681 elderly patients underwent hip arthroplasty were retrospectively collected and divided into a model (n = 477) and a validation cohort (n = 204) according to the principle of 7:3 distribution temporally. The assessment of postoperative cognitive function was conducted through the utilization of The Confusion Assessment Method (CAM). The nomogram model for postoperative cognitive impairments was established by a combination of Lasso regression and logistic regression. The receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA) were used to evaluate the performance. RESULTS: The nomogram utilized various predictors, including age, body mass index (BMI), education, preoperative Barthel Index, preoperative hemoglobin level, history of diabetes, and history of cerebrovascular disease, to forecast the likelihood of postoperative delirium in patients. The area under the ROC curves (AUC) for the nomogram, incorporating the aforementioned predictors, was 0.836 (95% CI: 0.797-0.875) for the training set and 0.817 (95% CI: 0.755-0.880) for the validation set. The calibration curves for both sets indicated a good agreement between the nomogram's predictions and the actual probabilities. CONCLUSION: The use of this novel nomogram can help clinicians predict the likelihood of delirium after hip arthroplasty in elderly patients and help prevent and manage it in advance.

Magnesium sulfate enhances non-depolarizing muscle relaxant vecuronium action at adult muscle-type nicotinic acetylcholine receptor in vitro.

AIM: To investigate the effect of magnesium sulfate and its interaction with the non-depolarizing muscle relaxant vecuronium at adult muscle-type acetylcholine receptors in vitro. METHODS: Adult muscle-type acetylcholine receptors were expressed in HEK293 cells. Drug-containing solution was applied via a gravity-driven perfusion system. The inward currents were activated by brief application of acetylcholine (ACh), and recorded using whole-cell voltage-clamp technique. RESULTS: Magnesium sulfate (1-100 mmol/L) inhibited the inward currents induced ACh (10 µmol/L) in a concentration-dependent manner (IC(50)=29.2 mmol/L). The inhibition of magnesium sulfate was non-competitive. In contrast, vecuronium produced a potent inhibition on the adult muscle-type acetylcholine receptor (IC(50)=8.7 nmol/L) by competitive antagonism. Magnesium sulfate at the concentrations of 1, 3, and 6 mmol/L markedly enhanced the inhibition of vecuronium (10 nmol/L) on adult muscle-type acetylcholine receptors. CONCLUSION: Clinical enhancement of vecuronium-induced muscle relaxation by magnesium sulfate can be attributed partly to synergism between magnesium sulfate and non-depolarizing muscle relaxants at adult muscle-type acetylcholine receptors.

Advances in RNA Epigenetic Modifications in Hepatocellular Carcinoma and Potential Targeted Intervention Strategies.

The current interventions for hepatocellular carcinoma (HCC) are not satisfactory, and more precise targets and promising strategies need to be explored. Recent research has demonstrated the non-negligible roles of RNA epigenetic modifications such as N6-methyladenosine (m6A) and 5-methylcytosine (m5C) in various cancers, including HCC. However, the specific targeting mechanisms are not well elucidated. In this review, we focus on the occurrence and detailed physiopathological roles of multiple RNA modifications on diverse RNAs closely related to the HCC process. In particular, we highlight fresh insights into the impact mechanisms of these posttranscriptional modifications on the whole progression of HCC. Furthermore, we analyzed the possibilities and significance of these modifications and regulators as potential therapeutic targets in HCC treatment, which provides the foundation for exploring targeted intervention strategies. This review will propel the identification of promising therapeutic targets and novel strategies that can be translated into clinical applications for HCC treatment.

[Characteristics of surface electromyography and work load of the forearm extensors in repetitive wrist extending].

OBJECTIVE: To evaluate the influence of the frequency, the weight and the motion angle on the stress and the fatigue of the forearm extensors in repetitive wrist extending at low force loading level with surface electromyography (SEMG). METHODS: Sixteen male college student volunteers were recruited for the experiment. Eight tasks of wrist extending were performed for 20 minutes respectively in given weight (1.96, 4.90 N), frequency (8.0, 33.3 moves/minute) and motion angle (45 degrees, 90 degrees). The static wrist extending at the level of 20% maximum voluntary contraction (MVC) were performed before and after each task for 2 up to 3 seconds, and the SEMG signals of extensor carpi ulnaris muscle (ECU) and extensor digitorum (ED) were recorded and analyzed. RESULTS: The weight loading level was approximately equal to 1.40% or 3.50% of the MVC force. The mean power frequency (MPF) and the median frequency (MF) were decreased with the increase of 3 kinds of loading levels. The decrease of MPF of the muscle ED was significant (P < 0.05 or P < 0.01). The MF was decreased with the increase of angle and weight loading levels (P < 0.05 or P < 0.01). The root mean square (RMS) value of SEMG could be divided into 3 or 4 groups with significant difference. All three kinds of loads had positive correlation with amplitude of SEMG according to the stepwise regression analysis. CONCLUSION: The fatigue level of ED is the highest. The primary load factor for the forearm extensors is the frequency followed by the weight and the angle. MF, MPF and RMS can be used as sensitive indexes for evaluating the stress and the fatigue of the forearm extensors during repetitive performance at lower force loading level.

The human disease network in terms of dysfunctional regulatory mechanisms.

BACKGROUND: Elucidation of human disease similarities has emerged as an active research area, which is highly relevant to etiology, disease classification, and drug repositioning. In pioneer studies, disease similarity was commonly estimated according to clinical manifestation. Subsequently, scientists started to investigate disease similarity based on gene-phenotype knowledge, which were inevitably biased to well-studied diseases. In recent years, estimating disease similarity according to transcriptomic behavior significantly enhances the probability of finding novel disease relationships, while the currently available studies usually mine expression data through differential expression analysis that has been considered to have little chance of unraveling dysfunctional regulatory relationships, the causal pathogenesis of diseases. METHODS: We developed a computational approach to measure human disease similarity based on expression data. Differential coexpression analysis, instead of differential expression analysis, was employed to calculate differential coexpression level of every gene for each disease, which was then summarized to the pathway level. Disease similarity was eventually calculated as the partial correlation coefficients of pathways' differential coexpression values between any two diseases. The significance of disease relationships were evaluated by permutation test. RESULTS: Based on mRNA expression data and a differential coexpression analysis based method, we built a human disease network involving 1326 significant Disease-Disease links among 108 diseases. Compared with disease relationships captured by differential expression analysis based method, our disease links shared known disease genes and drugs more significantly. Some novel disease relationships were discovered, for example, Obesity and cancer, Obesity and Psoriasis, lung adenocarcinoma and S. pneumonia, which had been commonly regarded as unrelated to each other, but recently found to share similar molecular mechanisms. Additionally, it was found that both the type of disease and the type of affected tissue influenced the degree of disease similarity. A sub-network including Allergic asthma, Type 2 diabetes and Chronic kidney disease was extracted to demonstrate the exploration of their common pathogenesis. CONCLUSION: The present study produces a global view of human diseasome for the first time from the viewpoint of regulation mechanisms, which therefore could provide insightful clues to etiology and pathogenesis, and help to perform drug repositioning and design novel therapeutic interventions.

Differential network analysis reveals dysfunctional regulatory networks in gastric carcinogenesis.

Gastric Carcinoma is one of the most common cancers in the world. A large number of differentially expressed genes have been identified as being associated with gastric cancer progression, however, little is known about the underlying regulatory mechanisms. To address this problem, we developed a differential networking approach that is characterized by including a nascent methodology, differential coexpression analysis (DCEA), and two novel quantitative methods for differential regulation analysis. We first applied DCEA to a gene expression dataset of gastric normal mucosa, adenoma and carcinoma samples to identify gene interconnection changes during cancer progression, based on which we inferred normal, adenoma, and carcinoma-specific gene regulation networks by using linear regression model. It was observed that cancer genes and drug targets were enriched in each network. To investigate the dynamic changes of gene regulation during carcinogenesis, we then designed two quantitative methods to prioritize differentially regulated genes (DRGs) and gene pairs or links (DRLs) between adjacent stages. It was found that known cancer genes and drug targets are significantly higher ranked. The top 4% normal vs. adenoma DRGs (36 genes) and top 6% adenoma vs. carcinoma DRGs (56 genes) proved to be worthy of further investigation to explore their association with gastric cancer. Out of the 16 DRGs involved in two top-10 DRG lists of normal vs. adenoma and adenoma vs. carcinoma comparisons, 15 have been reported to be gastric cancer or cancer related. Based on our inferred differential networking information and known signaling pathways, we generated testable hypotheses on the roles of GATA6, ESRRG and their signaling pathways in gastric carcinogenesis. Compared with established approaches which build genome-scale GRNs, or sub-networks around differentially expressed genes, the present one proved to be better at enriching cancer genes and drug targets, and prioritizing disease-related genes on the dataset we considered. We propose this extendable differential networking framework as a promising way to gain insights into gene regulatory mechanisms underlying cancer progression and other phenotypic changes.

The genetic basis of white tigers.

The white tiger, an elusive Bengal tiger (Panthera tigris tigris) variant with white fur and dark stripes, has fascinated humans for centuries ever since its discovery in the jungles of India. Many white tigers in captivity are inbred in order to maintain this autosomal recessive trait and consequently suffer some health problems, leading to the controversial speculation that the white tiger mutation is perhaps a genetic defect. However, the genetic basis of this phenotype remains unknown. Here, we conducted genome-wide association mapping with restriction-site-associated DNA sequencing (RAD-seq) in a pedigree of 16 captive tigers segregating at the putative white locus, followed by whole-genome sequencing (WGS) of the three parents. Validation in 130 unrelated tigers identified the causative mutation to be an amino acid change (A477V) in the transporter protein SLC45A2. Three-dimensional homology modeling suggests that the substitution may partially block the transporter channel cavity and thus affect melanogenesis. We demonstrate the feasibility of combining RAD-seq and WGS to rapidly map exotic variants in nonmodel organisms. Our results identify the basis of the longstanding white tiger mystery as the same gene underlying color variation in human, horse, and chicken and highlight its significance as part of the species' natural polymorphism that is viable in the wild.

[Comparative study of the replication difference of HearNPV in infected exponential and stationary host cells].

Real-time quantitative PCR was used to characterize HearNPV DNA replication in exponential and stationary phases of HzAM1 cells. Results showed that the doubling time of HzAM1 cells was 22 h in exponential phases. Most of the exponential cells were in S phase (48.6%), and most of the stationary cells in G2/M phase (72.6%). The replication of viral DNA was completed within 60 h post infection (h p. i.) in different phases of HzAM1 cells. During 14 to 20 h p. i., the doubling time of HearNPV replica-tion was 1.8 h in exponential cells and 1.9 h in stationary cells, and no significant difference was found between them. But the amounts of BV entering and releasing, the final progeny virions and viral protein products in the infected exponential phase cells were obviously higher than that in the stationary phase cells. 25% of the total synthesized viral DNAs were released from infected exponential phase cells, but on-ly 13% from the infected stationary phase cells. Viral DNA started to be replicated from 7-8 h p. i. both in infected exponential phase and in stationary phase cells. But in infected exponential phase cells, BVs were started to release from 18-20 h p. i., and BVs were started to release from 22-25 h p. i. from infected sta-tionary phase cells. During 30-60 h p. i., the BV releasing rate was about 483 copies/cell/h in the expo-nential phase cells, but was 100 copies/cell/h in the stationary-phase cells. The initial viral DNA entering into exponential phase cells was much more than that entered into the stationary phase cells. The data of cell membrane fluidity at exponential and stationary phases suggested that the fluidity of cell membrane played an important role during virus entry.