Development of clinical phenotypes and biological profiles via proteomic analysis of trauma patients.

BACKGROUND: Trauma is a heterogeneous condition, and specific clinical phenotypes may identify target populations that could benefit from certain treatment strategies. In this retrospective study, we determined clinical phenotypes and identified new target populations of trauma patients and their treatment strategies. METHODS: We retrospectively analyzed datasets from the Japan Trauma Data Bank and determined trauma death clinical phenotypes using statistical machine learning techniques and evaluation of biological profiles. RESULTS: The analysis included 71,038 blunt trauma patients [median age, 63 (interquartile range [IQR], 40-78) years; 45,479 (64.0%) males; median Injury Severity Score, 13 (IQR, 9-20)], and the derivation and validation cohorts included 42,780 (60.2%) and 28,258 (39.8%) patients, respectively. Of eight derived phenotypes (D-1-D-8), D-8 (n = 2178) had the highest mortality (48.6%) with characteristic severely disturbed consciousness and was further divided into four phenotypes: D-8α, multiple trauma in the young (n = 464); D-8ß, head trauma with lower body temperature (n = 178); D-8γ, severe head injury in the elderly (n = 957); and D-8δ, multiple trauma, with higher predicted mortality than actual mortality (n = 579). Phenotype distributions were comparable in the validation cohort. Biological profile analysis of 90 trauma patients revealed that D-8 exhibited excessive inflammation, including enhanced acute inflammatory response, dysregulated complement activation pathways, and impaired coagulation, including downregulated coagulation and platelet degranulation pathways, compared with other phenotypes. CONCLUSIONS: We identified clinical phenotypes with high mortality, and the evaluation of the molecular pathogenesis underlying these clinical phenotypes suggests that lethal trauma may involve excessive inflammation and coagulation disorders.

A platform for in silico modeling of physiological systems III.

Physiome and systems biology have been recognized as emerging and important research areas that can integrate quantitatively growing knowledge about biological structure and physiological functions at multiple scales of time and space. For the integration, it is important to build physiologically plausible and sharable mathematical models that can be used for dynamic simulations of functions at multi-scale and multi-level. Here we describe new features of our open platform insilicoML (ISML) and insilicoIDE (ISIDE) that have been presented previously. The platform can support reuse existing mathematical models of physiological functions in the model databases, to construct brand new models, and to simulate models. The major new features of the platform include improvement of the capabilities to incorporate experimentally obtained data such as time-series and morphological data with dynamic simulation of models that may be driven by the data, and extension of variety of model types that can be described by ISML and simulated on ISIDE, such as multi agent systems and models described by partial differential equations that are solved by the finite element method.

A method for efficient execution of bioinformatics workflows.

Efficient execution of data-intensive workflows has been playing an important role in bioinformatics as the amount of data has been rapidly increasing. The execution of such workflows must take into account the volume and pattern of communication. When orchestrating data-centric workflows, a centralized workflow engine can become a bottleneck to performance. To cope with the bottleneck, a hybrid approach with choreography for data management of workflows is proposed. However, when a workflow includes many repetitive operations, the approach might not gain good performance because of the overheads of its additional mechanism. This paper presents and evaluates an improvement of the hybrid approach for managing a large amount of data. The performance of the proposed method is demonstrated by measuring execution times of example workflows.

Specifications of insilicoML 1.0: a multilevel biophysical model description language.

An extensible markup language format, insilicoML (ISML), version 0.1, describing multi-level biophysical models has been developed and available in the public domain. ISML is fully compatible with CellML 1.0, a model description standard developed by the IUPS Physiome Project, for enhancing knowledge integration and model sharing. This article illustrates the new specifications of ISML 1.0 that largely extend the capability of ISML 0.1. ISML 1.0 can describe various types of mathematical models, including ordinary/partial differential/difference equations representing the dynamics of physiological functions and the geometry of living organisms underlying the functions. ISML 1.0 describes a model using a set of functional elements (modules) each of which can specify mathematical expressions of the functions. Structural and logical relationships between any two modules are specified by edges, which allow modular, hierarchical, and/or network representations of the model. The role of edge-relationships is enriched by key words in order for use in constructing a physiological ontology. The ontology is further improved by the traceability of history of the model's development and by linking between different ISML models stored in the model's database using meta-information. ISML 1.0 is designed to operate with a model database and integrated environments for model development and simulations for knowledge integration and discovery.

Rational design of conformationally restricted quinazolinone inhibitors of poly(ADP-ribose)polymerase.

A successful design of conformationally restricted novel quinazolinone derivatives linked via a cyclopentene moiety as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors has been developed. One selected member of the new series, 8-chloro-2-[(3S)-3-(4-phenylpiperidin-1-yl)cyclopent-1-en-1-yl]quinazolin-4(3H)-one (S-16d), was found to be highly potent with IC(50)=8.7 nM and good brain penetration.

Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling.

We disclose herein our efforts aimed at discovery of selective PARP-1 and PARP-2 inhibitors. We have recently discovered several novel classes of quinazolinones, quinazolidinones, and quinoxalines as potent PARP-1 inhibitors, which may represent attractive therapeutic candidates. In PARP enzyme assays using recombinant PARP-1 and PARP-2, the quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2, and the quinazolidinone derivatives did not have selectivity for PARP-1/2. Structure-based drug design analysis via a combination of X-ray structural study utilizing the complexes of inhibitors and human PARP-1 catalytic domain, and homology modeling using murine PARP-2 suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2.

Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP-ribose) polymerase-1/2 inhibitors.

Two classes of quinazolinone derivatives and quinoxaline derivatives were identified as potent and selective poly(ADP-ribose) polymerase-1 and 2 (PARP-1) and (PARP-2) inhibitors, respectively. In PARP enzyme assays using recombinant PARP-1 and PARP-2, quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2. SBDD analysis via a combination of X-ray structural study and homology modeling suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2.

Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase.

A novel class of quinazolinone derivatives as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors has been discovered. Key to success was application of a rational discovery strategy involving structure-based design, combinatorial chemistry, and classical SAR for improvement of potency and bioavailability. The new inhibitors were shown to bind to the nicotinamide-ribose binding site (NI site) and the adenosine-ribose binding site (AD site) of NAD+.

Inhibitor-induced structural change of the active site of human poly(ADP-ribose) polymerase.

The crystal structure of human recombinant poly(ADP-ribose) polymerase (PARP) complexed with a potent inhibitor, FR257517, was solved at 3.0 A resolution. The fluorophenyl part of the inhibitor induces an amazing conformational change in the active site of PARP by motion of the side chain of the amino acid, Arg878, which forms the bottom of the active site. Consequently, a corn-shaped hydrophobic subsite, which consists of the side chains of Leu769, Ile879, Pro881, and the methylene chain of Arg878, newly emerges from the well-known active site.

Architecture of a grid-enabled research platform with location-transparency for bioinformatics.

The recent advance in information technologies has bought about the borderlessness in every field of both science and business. The borderlessness has increasingly made activities in interdisciplinary field more important. This current situation produces a strong demand that people want to establish a virtual group, organization and society for their business and scientific purposes irrespective of the actual structure formed by organizations. Remarkably, bio sciences require a research platform that satisfies such demand for further development. In this paper, we present a research platform for bioinformatics in detail. The prominent feature of the research platform is the use of Grid and its location transparency, which means that bio scientists and researchers are able to utilize a large amount of computational power for their analysis and to access data of their interest without being aware of where data and computational resources are located. The usefulness and feasibility of the architecture of the research platform is shown as well as future issues to achieve toward the final goal of our research in this paper.

Equatorial preference in the C[bond]H activation of cycloalkanes: GaCl3-catalyzed aromatic alkylation reaction.

GaCl(3) catalyzes the aromatic alkylation of naphthalene or phenanthrene using cycloalkanes. The C[bond]C formation predominantly takes place at the least hindered positions of the substrates, and equatorial isomers regarding the cycloalkane moiety are generally obtained. The reaction of bicyclo[4.4.0]decane and naphthalene occurs at the 2-position of naphthalene and at the 2- or 3-carbons of the cycloalkane, and the products possess a trans configuration at the junctures and an equatorial configuration at the naphthyl groups. Notably, cis-bicyclo[4.4.0]decane turns out to be much more reactive than the trans isomer, and a turnover number "TON" up to 20 based on GaCl(3) is attained. 1,2-Dimethylcyclohexane reacts similarly, and the cis isomer is more reactive than the trans isomer. Monoalkylcycloalkanes react at the secondary carbons provided that the alkyl group is smaller than tert-butyl. Adamantanes react at the tertiary 1-position. The alkylation reaction is considered to involve the C[bond]H activation of cycloalkanes with GaCl(3) at the tertiary center followed by the migration of carbocations and electrophilic aromatic substitution yielding thermodynamically stable products. The stereochemistry of the reaction reveals that GaCl(3) activates the equatorial tertiary C[bond]H rather than the axial tertiary C[bond]H.