Using workflows to explore and optimise named entity recognition for chemistry

Chemistry text mining tools should be interoperable and adaptable regardless of system-level implementation, installation or even programming issues. We aim to abstract the functionality of these tools from the underlying implementation via reconfigurable workflows for automatically identifying chemical names. To achieve this, we refactored an established named entity recogniser (in the chemistry domain), OSCAR and studied the impact of each component on the net performance. We developed two reconfigurable workflows from OSCAR using an interoperable text mining framework, U-Compare. These workflows can be altered using the drag-&-drop mechanism of the graphical user interface of U-Compare. These workflows also provide a platform to study the relationship between text mining components such as tokenisation and named entity recognition (using maximum entropy Markov model (MEMM) and pattern recognition based classifiers). Results indicate that, for chemistry in particular, eliminating noise generated by tokenisation techniques lead to a slightly better performance than others, in terms of named entity recognition (NER) accuracy. Poor tokenisation translates into poorer input to the classifier components which in turn leads to an increase in Type I or Type II errors, thus, lowering the overall performance. On the Sciborg corpus, the workflow based system, which uses a new tokeniser whilst retaining the same MEMM component, increases the F-score from 82.35% to 84.44%. On the PubMed corpus, it recorded an F-score of 84.84% as against 84.23% by OSCAR.     

Systemic CD8+ T Cell-Mediated Tumoricidal Effects by Intratumoral Treatment of Oncolytic Herpes Simplex Virus with the Agonistic Monoclonal Antibody for Murine Glucocorticoid-Induced Tumor Necrosis Factor Receptor

Oncolytic virotherapy combined with immunomodulators is a novel noninvasive strategy for cancer treatment. In this study, we examined the tumoricidal effects of oncolytic HF10, a naturally occurring mutant of herpes simplex virus type-1, combined with an agonistic DTA-1 monoclonal antibody specific for the glucocorticoid-induced tumor necrosis factor receptor. Two murine tumor models were used to evaluate the therapeutic efficacies of HF10 virotherapy combined with DTA-1. The kinetics and immunological mechanisms of DTA-1 in HF10 infection were examined using flow cytometry and immunohistochemistry. Intratumoral administration of HF10 in combination with DTA-1 at a low dose resulted in a more vigorous attenuation of growth of the untreated contralateral as well as the treated tumors than treatment with either HF10 or DTA-1 alone. An accumulation of CD8⁺ T cells, including tumor- and herpes simplex virus type-1-specific populations, and a decrease in the number of CD4⁺ Foxp3⁺ T regulatory cells were seen in both HF10- and DTA-1-treated tumors. Studies using Fc-digested DTA-1 and Fcγ receptor knockout mice demonstrated the direct participation of DTA-1 in regulatory T cell depletion by antibody-dependent cellular cytotoxicity primarily via macrophages. These results indicated the potential therapeutic efficacy of a glucocorticoid-induced tumor necrosis factor receptor-specific monoclonal antibody in oncolytic virotherapy at local tumor sites.     

Effect of antigen-dependent clearance on pharmacokinetics of anti-heparin-binding EGF-like growth factor (HB-EGF) monoclonal antibody

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family and is an important therapeutic target in some types of human cancers. KM3566 is a mouse anti-HB-EGF monoclonal antibody that neutralizes HB-EGF activity by inhibiting the binding of HB-EGF to its receptors. Based on the results of our pharmacokinetics study, a humanized derivative antibody, KHK2866, is rapidly cleared from serum and shows nonlinear pharmacokinetics in cynomolgus monkeys. In this study, we examined the antigen-dependent clearance of an anti-HB-EGF monoclonal antibody in vivo and in vitro in order to pharmacokinetically explain the rapid elimination of KHK2866. We revealed tumor size-dependent clearance of KM3566 in in vivo studies and obtained good fits between the observed and simulated concentrations of KM3566 based on the two-compartment with a saturable route of clearance model. Furthermore, in vivo imaging analyses demonstrated tumor-specific distribution of KM3566. We then confirmed rapid internalization and distribution to lysosome of KM3566 at a cellular level. Moreover, we revealed that the amounts of HB-EGF on cell surface membrane were maintained even while HB-EGF was internalized with KM3566. Recycled or newly synthesized HB-EGF, therefore, may contribute to a consecutive clearance of KM3566, which could explain a rapid clearance from serum. These data suggested that the rapid elimination in pharmacokinetics of KM3566 is due to antigen-dependent clearance. Given that its antigen is expressed in a wide range of normal tissue, it is estimated that the rapid elimination of KHK2866 from cynomolgus monkey serum is caused by antigen-dependent clearance.     

Sphingosine-1-phosphate signaling controlling osteoclasts and bone homeostasis

Bone is a dynamic organ that is continuously turned over during growth, even in adults. During bone remodeling, homeostasis is regulated by the balance between bone formation by osteoblasts and bone resorption by osteoclasts. However, in pathological conditions such as osteoporosis, osteopetrosis, arthritic joint destruction, and bone metastasis, this equilibrium is disrupted. Since osteoclasts are excessively activated in osteolytic diseases, the inhibition of osteoclast function has been a major therapeutic strategy. It has recently been demonstrated that sphingosine-1-phosphate (S1P), a biologically active lysophospholipid that is enriched in blood, controls the trafficking of osteoclast precursors between the circulation and bone marrow cavities via G protein-coupled receptors, S1PRs. While S1PR1 mediates chemoattraction toward S1P in bone marrow, where S1P concentration is low, S1PR2 mediates chemorepulsion in blood, where the S1P concentration is high. The regulation of precursor recruitment may represent a novel therapeutic strategy for controlling osteoclast-dependent bone remodeling. By means of intravital multiphoton imaging of bone tissues, we have recently revealed that the reciprocal action of S1P controls the migration of osteoclast precursors between bone tissues and blood stream. Imaging technologies have enabled us to visualize the in situ behaviors of different cell types in intact tissues. In this review we also discuss future perspectives on this new method in the field of bone biology and medical sciences in general. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

Cloning and nucleotide sequence of the mono- and diacylglycerol lipase gene (mdlB) of Aspergillus oryzae

Abstract Aspergillus oryzae IFO4202 produces at least two extracellular lipolytic enzymes L1 and L2 (cutinase, and mono- and diacylglycerol lipase, respectively). Southern hybridization of restriction enzyme-digested genomic DNA fragments with 23mer oligonucleotides synthesized according to the amino acid sequence of the L2 as probe suggested the presence of the L2 gene (tentatively designated as mdlB ) and an additional weakly hybridizing region. A fragment containing the genomic mdlB gene was cloned in Escherichia coli . Nucleotide sequencing of the fragment revealed an open reading frame, comprising 1021 nucleotides, which contains two introns (51 and 52 nucleotides). Putative polyadenylation signals were found 182 and 287 bp downstream of the stop codon. The deduced amino acid sequence of the mdlB gene corresponds to 306 amino acid residues including a leader sequence of 28 amino acids and is highly similar to that of the mdlA gene of Penicillium camembertii . Three residues presumed to form the catalytic triad (serine, aspartic acid and histidine) of lipases were also conserved.     

Different consequences of reactions with hydrogen peroxide and t-butyl hydroperoxide in the hyperoxidative inactivation of rat peroxiredoxin-4

Eukaryotic typical 2-Cys type peroxiredoxin (Prx) is inactivated by hyperoxidation of the peroxidatic cysteine to a sulphinic acid in a catalytic cycle-dependent manner. This inactivation process has been well documented for cytosolic isoforms of Prx. However, such a hyperoxidative inactivation has not fully been investigated in Prx-4, a secretable endoplasmic reticulum-resident isoform, in spite of being a typical 2-Cys type, and details of this process are reported herein. As has been observed in many peroxiredoxins, the peroxidase activity of Prx-4 was almost completely inhibited in the reaction with t-butyl hydroperoxide. On the other hand, when H(2)O(2) was used as the substrate, the peroxidase activity significantly remained after oxidative damage. In spite of these different consequences, mass spectrometric analyses indicated that both reactions resulted in the same oxidative damage, i.e. sulphinic acid formation at the peroxidatic cysteine, suggesting that another cysteine in the active site confers the peroxidase activity. As suggested by the analyses using cysteine-substituted mutants sulphinic acid formation at the peroxidatic cysteine may play a role in the development of the possible alternative mechanism, thereby sustaining the peroxidase activity that prefers H(2)O(2).     

The role of sphingosine 1-phosphate in migration of osteoclast precursors; an application of intravital two-photon microscopy

Sphingosine-1-phosphate (S1P), a biologically active lysophospholipid that is enriched in blood, controls the trafficking of osteoclast precursors between the circulation and bone marrow cavities via G protein-coupled receptors, S1PRs. While S1PR1 mediates chemoattraction toward S1P in bone marrow, where S1P concentration is low, S1PR2 mediates chemorepulsion in blood, where the S1P concentration is high. The regulation of precursor recruitment may represent a novel therapeutic strategy for controlling osteoclast-dependent bone remodeling. Through intravital multiphoton imaging of bone tissues, we reveal that the bidirectional function of S1P temporospatially regulates the migration of osteoclast precursors within intact bone tissues. Imaging technologies have enabled in situ visualization of the behaviors of several players in intact tissues. In addition, intravital microscopy has the potential to be more widely applied to functional analysis and intervention.     

Ab initio simulation of a 57-residue protein in explicit solvent reproduces the native conformation in the lowest free-energy cluster

An enhanced conformational sampling method, multicanonical molecular dynamics (McMD), was applied to the ab intio folding of the 57-residue first repeat of human glutamyl- prolyl-tRNA synthetase (EPRS-R1) in explicit solvent. The simulation started from a fully extended structure of EPRS-R1 and did not utilize prior structural knowledge. A canonical ensemble, which is a conformational ensemble thermodynamically probable at an arbitrary temperature, was constructed by reweighting the sampled structures. Conformational clusters were obtained from the canonical ensemble at 300 K, and the largest cluster (i.e., the lowest free-energy cluster), which contained 34% of the structures in the ensemble, was characterized by the highest similarity to the NMR structure relative to all alternative clusters. This lowest free-energy cluster included native-like structures composed of two anti-parallel α-helices. The canonical ensemble at 300 K also showed that a short Gly-containing segment, which adopts an α-helix in the native structure, has a tendency to be structurally disordered. Atomic-level analyses demonstrated clearly that inter-residue hydrophobic interactions drive the helix formation of the Gly-containing segment, and that increasing the hydrophobic contacts accompanies exclusion of water molecules from the vicinity of this segment. This study has shown, for the first time, that the free-energy landscape of a structurally well-ordered protein of about 60 residues is obtainable with an all atom model in explicit water without prior structural knowledge.     

External and internal flavonoids from Madagascarian Uncarina species (Pedaliaceae)

External and internal flavonoids were isolated from 12 Uncarina taxa (Pedaliaceae), endemic to Madagascar. Four flavone aglycones, tricetin 7,3′,5′-trimethyl ether, tricetin 7,4′,5′-trimethyl ether, 5,3′-dihydroxy-6,7,4′,5′-tetramethoxyflavone and eupatorin were isolated from leaf wax of seven Uncarina taxa, Uncarina grandidieri, Uncarina decaryi, Uncarina abbreviata, Uncarina turicana, Uncarina platycarpa, Uncarina leandrii var. leandrii and Uncarina peltata, but not Uncarina stellulifera, Uncarina perrieri, Uncarina sakalava, Uncarina leptocarpa and U. leandrii var. rechbergeri. Furthermore, eight flavonoid glycosides were isolated from the leaves. Major glycosides were apigenin and luteolin 7-O-glucuronides and occurred in all the Uncarina taxa examined, except the absence of the former compound in U. peltata. Other glycosides were identified as hispidulin, jaceosidin, chrysoeriol and tricin 7-O-glucuronides, and luteolin 7,4′-di-O-glucuronide and a flavonol, isorhamnetin 3-O-diglucoside. From the results described above, methylated flavone aglycones and glucuronides were chemical characters of the leaves of Uncarina species, and also may be those of the family Pedaliaceae. Besides, an anthocyanin, two flavonols and three flavones were isolated from the flowers of U. grandidieri, and identified as cyanidin 3-O-rutinoside (anthocyanin), quercetin and isorhamnetin 7-O-glucuronides (flavonols) and apigenin, luteolin and jaceosidin 7-O-glucuronides (flavones).