NCACO-score: An effective main-chain dependent scoring function for structure modeling

<p>Abstract</p> <p>Background</p> <p>Development of effective scoring functions is a critical component to the success of protein structure modeling. Previously, many efforts have been dedicated to the development of scoring functions. Despite these efforts, development of an effective scoring function that can achieve both good accuracy and fast speed still presents a grand challenge.</p> <p>Results</p> <p>Based on a coarse-grained representation of a protein structure by using only four main-chain atoms: N, Cα, C and O, we develop a knowledge-based scoring function, called NCACO-score, that integrates different structural information to rapidly model protein structure from sequence. In testing on the Decoys'R'Us sets, we found that NCACO-score can effectively recognize native conformers from their decoys. Furthermore, we demonstrate that NCACO-score can effectively guide fragment assembly for protein structure prediction, which has achieved a good performance in building the structure models for hard targets from CASP8 in terms of both accuracy and speed.</p> <p>Conclusions</p> <p>Although NCACO-score is developed based on a coarse-grained model, it is able to discriminate native conformers from decoy conformers with high accuracy. NCACO is a very effective scoring function for structure modeling.</p

Systematic elucidation of the traditional Chinese medicine prescription Danxiong particles via network pharmacology and molecular docking

Purpose: To investigate the pharmacological effect of the traditional Chinese medicine (TCM) prescription Danxiong particles (TDX105) and its mechanism of action.Methods: The active compound and targets of TDX105 were investigated via network pharmacology. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were enriched, and protein-protein interaction network (PPI) was constructed. A network of ‘components-targets-pathways’ was developed with Cytoscape 3.8.0 software, while the formation of molecular docking analysis was conducted using Autodock vina software.Results: There were 304 compounds and 482 targets identified in total. Genes with degree ≥ mean node values were selected as the crucial targets, and string database was to be combined to 64 targets identified with cytoscape so as to draw a protein interaction map. A total of 137 pathways were enriched from 64 targets involving mainly 10 pathways, for example, PI3K-Akt signaling pathway, pathways in cancer, human cytomegalovirus infection and focal adhesion. Then, compound-target and compoundtarget- pathways were constructed using cytoscape (3.8.0). Finally, the five most active compounds, viz, quercetin, myricetin, luteolin, ellagic acid and kaempferol, and the top ten targets AKT1, GAPDH, TP53, ALB, EGFR, MAPK3, JUN, MAPK1, SRC and ESR1 were selected for molecular docking. These targets and compounds had strong interactions through a combination of hydrogen bonds and hydrophobic forces.Conclusion: The mechanism of action of TDX105 has been successfully explained using the combination of network pharmacology and molecular docking. This may offer a solid foundation to the clinical use of TDX105, and further strengthen the prospects of its development for clinical use

Potential distributions of seven sympatric sclerophyllous oak species in Southwest China depend on climatic, non-climatic, and independent spatial drivers

Key message An ensemble modelling approach was performed to predict the distributions of seven sympatric sclerophyllous oak species in the Hengduan Mountains of Southwest China. Spatial eigenvector filters revealed missing factors in addition to commonly used environmental variables, thus effectively improved predictive accuracy for the montane oak species. This study identified a richness center of sclerophyllous oaks, which provides a reference for proper conservation and utilization of oak resources. Context As key species and important trees for construction- and fuel-wood, montane sclerophyllous oaks (Quercus sect. Heterobalanus) in the Hengduan Mountains of Southwest China are threatened by climate change, habitat fragmentation, and human activities. Aims This study aims to simulate the potential distributions of seven sympatric sclerophyllous oak species with an emphasis on exploring the relative importance of climatic, non-climatic, and additional spatial factors. Methods We performed an ensemble modelling approach of six ecological niche models in combination with spatial eigenvector filters to predict the potential distributions of seven oak species. Results The results elucidated that temperature seasonality, followed by land use/cover and the human influence index were the most critical variables controlling oak species distributions. Regardless of the selected algorithm, the best performing models for most oaks combined climatic and non-climatic factors as well as additional spatial filters. Conclusion It is necessary to strengthen the conservation of oak species at the junction of Sichuan and Yunnan Province where we found the richness center of the studied oaks. Our research provides essential insights for the rational conservation and management of sclerophyllous oak species, suggesting that spatial constraints might reflect limited ability of migration under future climate change.Peer reviewe

Photoinduced coupled twisted intramolecular charge transfer and excited-state proton transfer via intermolecular hydrogen bonding: a DFT/TD-DFT study

We discuss theoretically the geometric and electronic structure properties of the thiazolidinedione derivative A and its hydrogen-bonded complex in dimethylformamide (DMF) solution in the S0 and S1 states. To gain insight into the photoinduced coupled excited-state proton transfer (ESPT) and twisted intramolecular charge transfer (TICT) associated with intermolecular hydrogen bonding, the potential energy profiles are provided along the Osingle bondH bond and the twisted angle. It is predicted that TICT in S1 can facilitate ESPT initiated by intermolecular hydrogen-bond strengthening in the S1 state. The coupling of ESPT and TICT is energetically preferable

Efficacy of using cancer stem cell markers in isolating and characterizing liver cancer stem cells

Recent evidence suggests that a subset of hepatocellular carcinomas (HCCs) are derived from liver cancer stem cells (LCSCs). In order to isolate and characterize LCSCs, reliable markers that are specific to these cells are required. We evaluated the efficacy of a range of cancer stem cell (CSC) markers in isolating and characterizing LCSCs. We show that the most widely used CSC markers are not specific to LCSCs. By western analysis, protein expression of the common markers showed no significant difference between HCC tumor tissues and adjacent non-cancerous liver. Further, isolation of LCSCs from common HCC cell lines using FACScan and microbeads showed no consistent marker expression pattern. We also show that LCSCs have unique subtypes. Immunohistochemistry of HCC tissues showed that different HCCs express unique combinations of LCSC markers. Quantitative real-time polymerase chain reaction analysis showed that LCSCs isolated using different markers in the same HCC phenotype had different expression profiles. Likewise, LCSCs isolated from different HCC phenotypes with the same marker also had unique expression profiles and displayed varying resistance profiles to Sorafenib. Thus, using a range of commonly used CSC markers in HCCs and cell lines, we demonstrate that currently available markers are not specific for LCSCs. LCSCs have unique subtypes that express distinctive combinations of LCSC markers and altered drug resistance profiles, making their identification problematic

Improvement of protein production in baculovirus expression vector system by removing a total of 10 kb of nonessential fragments from Autographa californica multiple nucleopolyhedrovirus genome

Baculovirus expression vector system (BEVS) is a powerful and versatile platform for recombinant protein production in insect cells. As the most frequently used baculovirus, Autographa californica multiple nucleopolyhedrovirus (AcMNPV) encodes 155 open reading frames (ORFs), including a considerable number of non-essential genes for the virus replication in cell culture. Studies have shown that protein production in BEVS can be improved by removing some viral dispensable genes, and these AcMNPV vectors also offer the possibility of accommodating larger exogenous gene fragments. In this study, we, respectively, deleted 14 DNA fragments from AcMNPV genome, each of them containing at least two contiguous genes that were known nonessential for viral replication in cell culture or functionally unknown. The effects of these fragment-deletions on virus replication and exogenous protein production were examined. The results showed that 11 of the 14 fragments, containing 43 genes, were dispensable for the virus replication in cultured cells. By detecting the expression of intracellularly expressed and secreted reporter proteins, we demonstrated that nine of the fragment-deletions benefited protein production in Sf9 cells and/or in High Five cells. After combining the deletion of some dispensable fragments, we obtained two AcMNPV vectors shortened by more than 10 kb but displayed an improved capacity for recombinant protein production. The deletion strategies used in this study has the potential to further improve the BEVS

Improving the Efficacy of Conventional Therapy by Adding Andrographolide Sulfonate in the Treatment of Severe Hand, Foot, and Mouth Disease: A Randomized Controlled Trial

Background. Herb-derived compound andrographolide sulfonate (called Xiyanping injection) recommended control measure for severe hand, foot, and mouth disease (HFMD) by the Ministry of Health (China) during the 2010 epidemic. However, there is a lack of good quality evidence directly comparing the efficacy of Andrographolide Sulfonate combination therapy with conventional therapy. Methods. 230 patients were randomly assigned to 7–10 days of Andrographolide Sulfonate 5–10 mg/Kg/day and conventional therapy, or conventional therapy alone. Results. The major complications occurred less often after Andrographolide Sulfonate (2.6% versus 12.1%; risk difference [RD], 0.94; 95% CI, 0.28–1.61; P=0.006). Median fever clearance times were 96 hours (CI, 80 to 126) for conventional therapy recipients and 48 hours (CI, 36 to 54) for Andrographolide Sulfonate combination-treated patients (χ2=16.57, P<0.001). The two groups did not differ in terms of HFMD-cause mortality (P=1.00) and duration of hospitalization (P=0.70). There was one death in conventional therapy group. No important adverse event was found in Andrographolide Sulfonate combination therapy group. Conclusions. The addition of Andrographolide Sulfonate to conventional therapy reduced the occurrence of major complications, fever clearance time, and the healing time of typical skin or oral mucosa lesions in children with severe HFMD

Microbiome-derived bile acids contribute to elevated antigenic response and bone erosion in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, disabling and incurable autoimmune disease. It has been widely recognized that gut microbial dysbiosis is an important contributor to the pathogenesis of RA, although distinct alterations in microbiota have been associated with this disease. Yet, the metabolites that mediate the impacts of the gut microbiome on RA are less well understood. Here, with microbial profiling and non-targeted metabolomics, we revealed profound yet diverse perturbation of the gut microbiome and metabolome in RA patients in a discovery set. In the Bacteroides-dominated RA patients, differentiation of gut microbiome resulted in distinct bile acid profiles compared to healthy subjects. Predominated Bacteroides species expressing BSH and 7a-HSDH increased, leading to elevated secondary bile acid production in this subgroup of RA patients. Reduced serum fibroblast growth factor-19 and dysregulated bile acids were evidence of impaired farnesoid X receptor-mediated signaling in the patients. This gut microbiota-bile acid axis was correlated to ACPA. The patients from the validation sets demonstrated that ACPA-positive patients have more abundant bacteria expressing BSH and 7a-HSDH but less Clostridium scindens expressing 7a-dehydroxylation enzymes, together with dysregulated microbial bile acid metabolism and more severe bone erosion than ACPA-negative ones. Mediation analyses revealed putative causal relationships between the gut microbiome, bile acids, and ACPA-positive RA, supporting a potential causal effect of Bacteroides species in increasing levels of ACPA and bone erosion mediated via disturbing bile acid metabolism. These results provide insights into the role of gut dysbiosis in RA in a manifestation-specific manner, as well as the functions of bile acids in this gut-joint axis, which may be a potential intervention target for precisely controlling RA conditions.Comment: 38 pages, 6 figure