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1.  DelPhi Web Server: A comprehensive online suite for electrostatic calculations of biological macromolecules and their complexes 
Here we report a web server, the DelPhi web server, which utilizes DelPhi program to calculate electrostatic energies and the corresponding electrostatic potential and ionic distributions, and dielectric map. The server provides extra services to fix structural defects, as missing atoms in the structural file and allows for generation of missing hydrogen atoms. The hydrogen placement and the corresponding DelPhi calculations can be done with user selected force field parameters being either Charmm22, Amber98 or OPLS. Upon completion of the calculations, the user is given option to download fixed and protonated structural file, together with the parameter and Delphi output files for further analysis. Utilizing Jmol viewer, the user can see the corresponding structural file, to manipulate it and to change the presentation. In addition, if the potential map is requested to be calculated, the potential can be mapped onto the molecule surface. The DelPhi web server is available from http://compbio.clemson.edu/delphi_webserver.
PMCID: PMC3966485  PMID: 24683424
DelPhi; electrostatics; proteins; continuum models; electrostatic potential; Finite-Difference Poisson-Boltzmann solver
2.  DelPhi web server v2: incorporating atomic-style geometrical figures into the computational protocol 
Bioinformatics  2012;28(12):1655-1657.
Summary: A new edition of the DelPhi web server, DelPhi web server v2, is released to include atomic presentation of geometrical figures. These geometrical objects can be used to model nano-size objects together with real biological macromolecules. The position and size of the object can be manipulated by the user in real time until desired results are achieved. The server fixes structural defects, adds hydrogen atoms and calculates electrostatic energies and the corresponding electrostatic potential and ionic distributions.
Availability and implementation: The web server follows a client–server architecture built on PHP and HTML and utilizes DelPhi software. The computation is carried out on supercomputer cluster and results are given back to the user via http protocol, including the ability to visualize the structure and corresponding electrostatic potential via Jmol implementation. The DelPhi web server is available from http://compbio.clemson.edu/delphi_webserver.
Contact: nsmith@clemson.edu, ealexov@clemson.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts200
PMCID: PMC3371833  PMID: 22531215
3.  Highly efficient and exact method for parallelization of grid-based algorithms and its implementation in DelPhi 
Journal of computational chemistry  2012;33(24):1960-1966.
The Gauss-Seidel method is a standard iterative numerical method widely used to solve a system of equations and, in general, is more efficient comparing to other iterative methods, such as the Jacobi method. However, standard implementation of the Gauss-Seidel method restricts its utilization in parallel computing due to its requirement of using updated neighboring values (i.e., in current iteration) as soon as they are available. Here we report an efficient and exact (not requiring assumptions) method to parallelize iterations and to reduce the computational time as a linear/nearly linear function of the number of CPUs. In contrast to other existing solutions, our method does not require any assumptions and is equally applicable for solving linear and nonlinear equations. This approach is implemented in the DelPhi program, which is a finite difference Poisson-Boltzmann equation solver to model electrostatics in molecular biology. This development makes the iterative procedure on obtaining the electrostatic potential distribution in the parallelized DelPhi several folds faster than that in the serial code. Further we demonstrate the advantages of the new parallelized DelPhi by computing the electrostatic potential and the corresponding energies of large supramolecular structures.
doi:10.1002/jcc.23033
PMCID: PMC3412928  PMID: 22674480
electrostatics; DelPhi; Poisson- Boltzmann equation; Gauss-Seidel iteration; parallel computing
4.  A general and Robust Ray-Casting-Based Algorithm for Triangulating Surfaces at the Nanoscale 
PLoS ONE  2013;8(4):e59744.
We present a general, robust, and efficient ray-casting-based approach to triangulating complex manifold surfaces arising in the nano-bioscience field. This feature is inserted in a more extended framework that: i) builds the molecular surface of nanometric systems according to several existing definitions, ii) can import external meshes, iii) performs accurate surface area estimation, iv) performs volume estimation, cavity detection, and conditional volume filling, and v) can color the points of a grid according to their locations with respect to the given surface. We implemented our methods in the publicly available NanoShaper software suite (www.electrostaticszone.eu). Robustness is achieved using the CGAL library and an ad hoc ray-casting technique. Our approach can deal with any manifold surface (including nonmolecular ones). Those explicitly treated here are the Connolly-Richards (SES), the Skin, and the Gaussian surfaces. Test results indicate that it is robust to rotation, scale, and atom displacement. This last aspect is evidenced by cavity detection of the highly symmetric structure of fullerene, which fails when attempted by MSMS and has problems in EDTSurf. In terms of timings, NanoShaper builds the Skin surface three times faster than the single threaded version in Lindow et al. on a 100,000 atoms protein and triangulates it at least ten times more rapidly than the Kruithof algorithm. NanoShaper was integrated with the DelPhi Poisson-Boltzmann equation solver. Its SES grid coloring outperformed the DelPhi counterpart. To test the viability of our method on large systems, we chose one of the biggest molecular structures in the Protein Data Bank, namely the 1VSZ entry, which corresponds to the human adenovirus (180,000 atoms after Hydrogen addition). We were able to triangulate the corresponding SES and Skin surfaces (6.2 and 7.0 million triangles, respectively, at a scale of 2 grids per Å) on a middle-range workstation.
doi:10.1371/journal.pone.0059744
PMCID: PMC3618509  PMID: 23577073
5.  GPU linear and non-linear Poisson–Boltzmann solver module for DelPhi 
Bioinformatics  2013;30(4):569-570.
Summary: In this work, we present a CUDA-based GPU implementation of a Poisson–Boltzmann equation solver, in both the linear and non-linear versions, using double precision. A finite difference scheme is adopted and made suitable for the GPU architecture. The resulting code was interfaced with the electrostatics software for biomolecules DelPhi, which is widely used in the computational biology community. The algorithm has been implemented using CUDA and tested over a few representative cases of biological interest. Details of the implementation and performance test results are illustrated. A speedup of ∼10 times was achieved both in the linear and non-linear cases.
Availability and implementation: The module is open-source and available at http://www.electrostaticszone.eu/index.php/downloads.
Contact: walter.rocchia@iit.it
Supplementary information: Supplementary data are available at Bioinformatics online
doi:10.1093/bioinformatics/btt699
PMCID: PMC3928518  PMID: 24292939
6.  Between algorithm and model: different Molecular Surface definitions for the Poisson-Boltzmann based electrostatic characterization of biomolecules in solution 
The definition of a molecular surface which is physically sound and computationally efficient is a very interesting and long standing problem in the implicit solvent continuum modeling of biomolecular systems as well as in the molecular graphics field. In this work, two molecular surfaces are evaluated with respect to their suitability for electrostatic computation as alternatives to the widely used Connolly-Richards surface: the blobby surface, an implicit Gaussian atom centered surface, and the skin surface. As figures of merit, we considered surface differentiability and surface area continuity with respect to atom positions, and the agreement with explicit solvent simulations. Geometric analysis seems to privilege the skin to the blobby surface, and points to an unexpected relationship between the non connectedness of the surface, caused by interstices in the solute volume, and the surface area dependence on atomic centers. In order to assess the ability to reproduce explicit solvent results, specific software tools have been developed to enable the use of the skin surface in Poisson-Boltzmann calculations with the DelPhi solver. Results indicate that the skin and Connolly surfaces have a comparable performance from this last point of view.
doi:10.4208/cicp.050711.111111s
PMCID: PMC3601494  PMID: 23519863
Molecular Surface; Connolly Surface; Blobby Surface; Skin Surface; Poisson-Boltzmann
7.  Understanding the Selectivity Mechanism of the Human Asialoglycoprotein Receptor (ASGP-R) toward Gal- and Man-type Ligands for Predicting Interactions with Exogenous Sugars 
A practical approach for addressing the computer simulation of protein-carbohydrate interactions is described here. An articulated computational protocol was set up and validated by checking its ability to predict experimental data, available in the literature, and concerning the selectivity shown by the Carbohydrate Recognition Domain (CRD) of the human asialoglycoprotein receptor (ASGP-R) toward Gal-type ligands. Some required features responsible for the interactions were identified. Subsequently the same protocol was applied to monomer sugar molecules that constitute the building blocks for alginates and ulvans. Such sugar polymers may supply a low-cost source of rare sugars with a potential impact on several industrial applications, from pharmaceutical to fine chemical industry. An example of their applicative exploitation could be given by their use in developing biomaterial with adhesion properties toward hepatocytes, through interaction with the ASGP-R. Such a receptor has been already proposed as a target for exogenous molecules, specifically in the case of hepatocytes, for diagnostic and therapeutic purposes. The DOCK5.2 program was used to search optimal locations of the above ligands of interest into CRD binding site and to roughly estimate interaction energies. Finally, the binding ΔG of theoretical protein-ligand complexes was estimated by using the DelPhi program in which the solvation free energy is accounted for with a continuum solvent model, by solving the Poisson-Boltzmann equation. The structure analysis of the obtained complexes and their ΔG values suggest that one of the sugar monomers of interest shows the desired characteristics.
PMCID: PMC3662984
human asialoglycoprotein receptor; molecular docking; DelPhi; natural sugar polymers
8.  Electrostatics of ligand binding: parameterization of the generalized Born model and comparison with the Poisson-Boltzmann approach 
The journal of physical chemistry. B  2006;110(18):9304-9313.
An accurate and fast evaluation of the electrostatics in ligand-protein interactions is crucial for computer-aided drug design. The pairwise generalized Born (GB) model, a fast analytical method originally developed for studying solvation of organic molecules, has been widely applied to macromolecular systems, including ligand-protein complexes. Yet, this model involves several empirical scaling parameters, which have been optimized for solvation of organic molecules, peptides and nucleic acids, but not for energetics of ligand binding. Studies have shown that a good solvation energy does not guarantee a correct model of solvent-mediated interactions. Thus in this study, we have used the Poisson-Boltzmann (PB) approach as a reference to optimize the GB model for studies of ligand-protein interactions. Specifically, we have employed the pairwise descreening approximation proposed by Hawkins et al [1] for GB calculations, and DelPhi for PB calculations. The AMBER all-atom force field parameters have been used in this work. Seventeen protein-ligand complexes have been used as a training database, and a set of atomic descreening parameters has been selected with which the pairwise GB model and the PB model yield comparable results on atomic Born radii, the electrostatic component of free energies of ligand binding, and desolvation energies of the ligands and proteins. The energetics of the fifteen test complexes calculated with the GB model using this set of parameters also agrees well with the energetics calculated with the PB method. This is the first time that the GB model is parameterized and thoroughly compared with the PB model for the electrostatics of ligand binding.
doi:10.1021/jp060334w
PMCID: PMC2716126  PMID: 16671749
generalized Born model; ligand-protein binding free energies; solvation
9.  Continuous development of schemes for parallel computing of the electrostatics in biological systems: Implementation in DelPhi 
Journal of computational chemistry  2013;34(22):1949-1960.
Due to the enormous importance of electrostatics in molecular biology, calculating the electrostatic potential and corresponding energies has become a standard computational approach for the study of biomolecules and nano-objects immersed in water and salt phase or other media. However, the electrostatics of large macromolecules and macromolecular complexes, including nano-objects, may not be obtainable via explicit methods and even the standard continuum electrostatics methods may not be applicable due to high computational time and memory requirements. Here, we report further development of the parallelization scheme reported in our previous work (J Comput Chem. 2012 Sep 15; 33(24):1960–6.) to include parallelization of the molecular surface and energy calculations components of the algorithm. The parallelization scheme utilizes different approaches such as space domain parallelization, algorithmic parallelization, multi-threading, and task scheduling, depending on the quantity being calculated. This allows for efficient use of the computing resources of the corresponding computer cluster. The parallelization scheme is implemented in the popular software DelPhi and results in speedup of several folds. As a demonstration of the efficiency and capability of this methodology, the electrostatic potential and electric field distributions are calculated for the bovine mitochondrial supercomplex illustrating their complex topology which cannot be obtained by modeling the supercomplex components alone.
doi:10.1002/jcc.23340
PMCID: PMC3707979  PMID: 23733490
electrostatics; DelPhi; Poisson-Boltzmann equation; parallel computing
10.  The inadvertent disclosure of personal health information through peer-to-peer file sharing programs 
Objective
There has been a consistent concern about the inadvertent disclosure of personal information through peer-to-peer file sharing applications, such as Limewire and Morpheus. Examples of personal health and financial information being exposed have been published. We wanted to estimate the extent to which personal health information (PHI) is being disclosed in this way, and compare that to the extent of disclosure of personal financial information (PFI).
Design
After careful review and approval of our protocol by our institutional research ethics board, files were downloaded from peer-to-peer file sharing networks and manually analyzed for the presence of PHI and PFI. The geographic region of the IP addresses was determined, and classified as either USA or Canada.
Measurement
We estimated the proportion of files that contain personal health and financial information for each region. We also estimated the proportion of search terms that return files with personal health and financial information. We ascertained and discuss the ethical issues related to this study.
Results
Approximately 0.4% of Canadian IP addresses had PHI, as did 0.5% of US IP addresses. There was more disclosure of financial information, at 1.7% of Canadian IP addresses and 4.7% of US IP addresses. An analysis of search terms used in these file sharing networks showed that a small percentage of the terms would return PHI and PFI files (ie, there are people successfully searching for PFI and PHI on the peer-to-peer file sharing networks).
Conclusion
There is a real risk of inadvertent disclosure of PHI through peer-to-peer file sharing networks, although the risk is not as large as for PFI. Anyone keeping PHI on their computers should avoid installing file sharing applications on their computers, or if they have to use such tools, actively manage the risks of inadvertent disclosure of their, their family's, their clients', or patients' PHI.
doi:10.1136/jamia.2009.000232
PMCID: PMC3000774  PMID: 20190057
11.  P2P Watch: Personal Health Information Detection in Peer-to-Peer File-Sharing Networks 
Background
Users of peer-to-peer (P2P) file-sharing networks risk the inadvertent disclosure of personal health information (PHI). In addition to potentially causing harm to the affected individuals, this can heighten the risk of data breaches for health information custodians. Automated PHI detection tools that crawl the P2P networks can identify PHI and alert custodians. While there has been previous work on the detection of personal information in electronic health records, there has been a dearth of research on the automated detection of PHI in heterogeneous user files.
Objective
To build a system that accurately detects PHI in files sent through P2P file-sharing networks. The system, which we call P2P Watch, uses a pipeline of text processing techniques to automatically detect PHI in files exchanged through P2P networks. P2P Watch processes unstructured texts regardless of the file format, document type, and content.
Methods
We developed P2P Watch to extract and analyze PHI in text files exchanged on P2P networks. We labeled texts as PHI if they contained identifiable information about a person (eg, name and date of birth) and specifics of the person’s health (eg, diagnosis, prescriptions, and medical procedures). We evaluated the system’s performance through its efficiency and effectiveness on 3924 files gathered from three P2P networks.
Results
P2P Watch successfully processed 3924 P2P files of unknown content. A manual examination of 1578 randomly selected files marked by the system as non-PHI confirmed that these files indeed did not contain PHI, making the false-negative detection rate equal to zero. Of 57 files marked by the system as PHI, all contained both personally identifiable information and health information: 11 files were PHI disclosures, and 46 files contained organizational materials such as unfilled insurance forms, job applications by medical professionals, and essays.
Conclusions
PHI can be successfully detected in free-form textual files exchanged through P2P networks. Once the files with PHI are detected, affected individuals or data custodians can be alerted to take remedial action.
doi:10.2196/jmir.1898
PMCID: PMC3415260  PMID: 22776692
Privacy; personal health information; natural language processing, text data mining
12.  Cross-cultural adaptation of the delphi definitions of low back pain prevalence (German DOLBaPP) 
Background
Assessed dimensions of low back pain (LBP) vary in prevalence studies. This may explain the heterogeneity in frequency estimates. To standardize definitions of LBP, an English consensus with 28 experts from 12 countries developed the “Delphi Definitions of Low Back Pain Prevalence” (DOLBaPP). The optimal definition and the shorter minimal definition with the related questionnaires for online, paper, and face-to-face use and telephone surveys are suitable for population-based studies. The definitions have to be adapted to different languages and cultures to provide comparable frequency estimates. The objective was to culturally adapt and pre-test the English definitions and corresponding Delphi DOLBaPP questionnaire forms into German.
Methods
The German DOLBaPP adaptation was conducted using the systematic approach suggested by Beaton et al. A pre-test of the Delphi DOLBaPP optimal paper questionnaire including an additional evaluation form was conducted in a sample of 121 employees (mainly office workers). In order to evaluate the comprehensibility, usability, applicability, and completeness of the adapted questionnaire, response to the questionnaire and 6 closed evaluation questions were analyzed descriptively. Qualitative methods were used for the 3 open questions of the evaluation form.
Results
The cultural adaptation of the DOLBaPP for a German-speaking audience required little linguistic adaptation. Conceptual equivalence was difficult for the expression “low back pain”. The expert committee considered the face validity of the pre-final version of the related Delphi DOLBaPP questionnaires as good. In the pre-test, most participants (95%) needed less than 5 minutes to fill in the optimal Delphi DOLBaPP questionnaire. They were generally positive regarding length, wording, diagram, and composition. All subjects with LBP (n = 61 out of 121 – 50.4%) answered the questions on functional limitation, sciatic pain, frequency and duration of symptoms as well as pain severity.
Conclusion
The results indicate that the cross-cultural German adaptation of the DOLBaPP Definitions and the corresponding questionnaires was successful. The definitions can be used in epidemiological studies to measure the prevalence of LBP. Some critical issues were raised regarding the general features of the Delphi DOLBaPP questionnaires. Future research is needed to evaluate these instruments.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2474-15-397) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2474-15-397
PMCID: PMC4258005  PMID: 25425047
Questionnaire; Validation; Low back pain; Pre-test; Cross-cultural adaptation; Prevalence; Site; Symptoms; Duration; Functional limitation
13.  Using DelPhi capabilities to mimic protein’s conformational reorganization with amino acid specific dielectric constants 
Many molecular events are associated with small or large conformational changes occurring in the corresponding proteins. Modeling such changes is a challenge and requires significant amount of computing time. From point of view of electrostatics, these changes can be viewed as a reorganization of local charges and dipoles in response to the changes of the electrostatic field, if the cause is insertion or deletion of a charged amino acid. Here we report a large scale investigation of modeling the changes of the folding energy due to single mutations involving charged group. This allows the changes of the folding energy to be considered mostly electrostatics in origin and to be calculated with DelPhi assigning residue-specific value of the internal dielectric constant of protein. The predicted energy changes are benchmarked against experimentally measured changes of the folding energy on a set of 257 single mutations. The best fit between experimental values and predicted changes is used to find out the effective value of the internal dielectric constant for each type of amino acid. The predicted folding free energy changes with the optimal, amino acid specific, dielectric constants are within RMSD=0.86 kcal/mol from experimentally measured changes.
PMCID: PMC3966310  PMID: 24683422
DelPhi; protein electrostatics; dielectric constant; Poisson-Boltzmann equation; protein flexibility; energy calculations; single point mutations
14.  On the Modeling of Polar Component of Solvation Energy using Smooth Gaussian-Based Dielectric Function 
Journal of theoretical & computational chemistry  2014;13(3):10.1142/S0219633614400021.
Traditional implicit methods for modeling electrostatics in biomolecules use a two-dielectric approach: a biomolecule is assigned low dielectric constant while the water phase is considered as a high dielectric constant medium. However, such an approach treats the biomolecule-water interface as a sharp dielectric border between two homogeneous dielectric media and does not account for inhomogeneous dielectric properties of the macromolecule as well. Recently we reported a new development, a smooth Gaussian-based dielectric function which treats the entire system, the solute and the water phase, as inhomogeneous dielectric medium (J Chem Theory Comput. 2013 Apr 9; 9(4): 2126-2136.). Here we examine various aspects of the modeling of polar solvation energy in such inhomogeneous systems in terms of the solute-water boundary and the inhomogeneity of the solute in the absence of water surrounding. The smooth Gaussian-based dielectric function is implemented in the DelPhi finite-difference program, and therefore the sensitivity of the results with respect to the grid parameters is investigated, and it is shown that the calculated polar solvation energy is almost grid independent. Furthermore, the results are compared with the standard two-media model and it is demonstrated that on average, the standard method overestimates the magnitude of the polar solvation energy by a factor 2.5. Lastly, the possibility of the solute to have local dielectric constant larger than of a bulk water is investigated in a benchmarking test against experimentally determined set of pKa's and it is speculated that side chain rearrangements could result in local dielectric constant larger than 80.
doi:10.1142/S0219633614400021
PMCID: PMC4092036  PMID: 25018579
dielectric constant; Poisson-Boltzmann equation; electrostatics; finite-difference method; protein flexibility
15.  Protein Nano-Object Integrator (ProNOI) for generating atomic style objects for molecular modeling 
Background
With the progress of nanotechnology, one frequently has to model biological macromolecules simultaneously with nano-objects. However, the atomic structures of the nano objects are typically not available or they are solid state entities. Because of that, the researchers have to investigate such nano systems by generating models of the nano objects in a manner that the existing software be able to carry the simulations. In addition, it should allow generating composite objects with complex shape by combining basic geometrical figures and embedding biological macromolecules within the system.
Results
Here we report the Protein Nano-Object Integrator (ProNOI) which allows for generating atomic-style geometrical objects with user desired shape and dimensions. Unlimited number of objects can be created and combined with biological macromolecules in Protein Data Bank (PDB) format file. Once the objects are generated, the users can use sliders to manipulate their shape, dimension and absolute position. In addition, the software offers the option to charge the objects with either specified surface or volumetric charge density and to model them with user-desired dielectric constants. According to the user preference, the biological macromolecule atoms can be assigned charges and radii according to four different force fields: Amber, Charmm, OPLS and PARSE. The biological macromolecules and the atomic-style objects are exported as a position, charge and radius (PQR) file, or if a default dielectric constant distribution is not selected, it is exported as a position, charge, radius and epsilon (PQRE) file. As illustration of the capabilities of the ProNOI, we created a composite object in a shape of a robot, aptly named the Clemson Robot, whose parts are charged with various volumetric charge densities and holds the barnase-barstar protein complex in its hand.
Conclusions
The Protein Nano-Object Integrator (ProNOI) is a convenient tool for generating atomic-style nano shapes in conjunction with biological macromolecule(s). Charges and radii on the macromolecule atoms and the atoms in the shapes are assigned according to the user’s preferences allowing various scenarios of modeling. The default output file is in PQR (PQRE) format which is readable by almost any software available in biophysical field. It can be downloaded from: http://compbio.clemson.edu/downloadDir/ProNO_integrator.tar.gz
doi:10.1186/1472-6807-12-31
PMCID: PMC3532097  PMID: 23217202
Biological macromolecules; Electrostatic calculations; Molecular modeling; Nano technology; DelPhi; Poisson-Boltzmann equation
16.  Lack of agreement between tonometric and gastric juice partial carbon dioxide tension 
Critical Care  2000;4(4):249-254.
Our goal was to compare measurement of tonometered saline and gastric juice partial carbon dioxide tension (PCO2). In this prospective observational study, 112 pairs of measurements were simultaneously obtained under various hemodynamic conditions, in 15 critical care patients. Linear regression analysis showed a significant correlation between the two methods of measuring PCO2 (r 2 = 0.43; P < 0.0001). However, gastric juice PCO2 was systematically higher (mean difference 51 mmHg). The 95% limits of agreement were 315 mmHg and the dispersion increased as the values of PCO2 increased. Tonometric and gastric juice PCO2 cannot be used interchangeably. Gastric juice PCO2 measurement should be interpreted with caution.
Introduction:
In recent years there has been growing interest in tonometric estimation of gastric intramucosal pH (pHi). More recently, attention has focused on the gradient between intraluminal and arterial PCO2. pHi appears to be a useful diagnostic and prognostic tool in critically ill patients, and may also be used as a therapeutic guide. However, intraluminal PCO2 is the parameter measured to calculate pHi, and it is assumed as equivalent to the PCO2 of the upper layers of the gastric mucosa.
Direct measurement of PCO2 in gastric juice might offer advantages over tonometry. Tonometer costs could be saved, and equilibration time would no longer be necessary. Additionally, preanalytic factors that account for poor reproducibility, such as inadequate volume of saline in the tonometer, errors in the dwell time of the sample or in the technique used to aspirate saline, mixing of the sample with tonometer dead space and delay in analysis, could be prevented. Nevertheless, to our knowledge few experimental or clinical studies have examined PCO2 in gastric juice. Moreover, no comparison with simultaneous tonometric samples has been performed. Our goal was to compare simultaneous measurement of PCO2 in gastric juice and in saline samples from a tonometer. Data from the present study show that gastric juice PCO2 is systematically higher. Furthermore, differences widen at high PCO2 values, and data dispersion becomes even more striking. Therefore, tonometric PCO2 and gastric juice PCO2 are not interchangeable.
Patients and methods:
The present study was approved by the local ethics committee, and informed consent was obtained from the next of kin of each patient.
We studied 15 consecutive mechanically ventilated patients from a medical/surgical intensive care unit, in whom tonometric monitoring was indicated by attending physicians. All patients were receiving 50 mg intravenous ranitidine every 8 h. Gastric tonometers were filled with saline, which was extracted after 90 min of equilibration time. At the same time, gastric juice was anaerobically extracted from the aspiration port of the tonometer. The initial 20 ml was discarded. PCO2 in both samples was measured using a blood gas analyzer (AVL 945; AVL List GMBH, Gratz, Austria). These measurements were taken at various time points in each patient, and under various haemodynamic and oxygen transport conditions, All measurements were performed with the patient fasted. Correlation between the two measurements was examined using the Bland-Altman technique.
We also performed an in vitro study to quantify the precision and bias for the AVL 945. For this purpose, a stable PCO2 in saline solution was achieved by bubbling 5% carbon dioxide calibration gas.
Results:
We performed 112 pairs of measurements in 15 patients. Table 1 shows clinical data and the first values of arterial, tonometered and gastric juice PCO2 for each patient. Regression analysis demonstrated a significant correlation between both methods of measuring PCO2 (r 2 =0.43; gastric juice PCO2 = -28.79 + [2.55 × tonometric PCO2]; P < 0.0001; Fig. 1). However, the bias calculated as the mean difference of gastric juice and tonometric PCO2 was 51 mmHg. The 95% limits of agreement were 315 mmHg (Fig. 2). For mean PCO2 values lesser than 100 mmHg, the bias and the 95% limits of agreement were 19 and 102 mmHg, respectively. As mean PCO2 increased, the scattering of differences widened (r 2 =0.71; P < 0.0001).
In an effort to prevent the bias related to multiple measurements per patient, we performed Bland-Altman analysis with the first measurement of each patient. After this the results remained similar (bias 55 mmHg, 95% limits of agreement 216 mmHg).
The AVL 945 blood gas analyzer showed a negative bias of 0.97 mmHg and a precision of 2.13 mmHg. This bias was considered negligible, so no further correction was made to saline tonometric values.
Discussion:
The results of the present study show that tonometric PCO2 and gastric juice PCO2 are not interchangeable. Gastric juice PCO2 is systematically higher. At high PCO2 values the differences widen, and data dispersion becomes even more marked.
There is no clear cause for these observations. A possible explanation might be that tonometric PCO2 is generated over a time interval, whereas gastric juice PCO2 might reflect rapid changes in mucosal metabolism. Different equilibrium time could also account for data dispersion, but not for the positive bias for gastric juice. Rapid changes should occur in both directions.
Another potential confounding factor is the ability of blood gas analyzers to measure PCO2 in gastric juice. Measurement of PCO2 in 0.9% saline is an important source of error in the estimation of pHi. Variation in PCO2 values may occur with different PCO2 equilibration solutions. For example, bias is -66.5% when the Nova Stat Profile 7 blood gas analyzer (Nova Biomedical, Waltham, MA, USA) measures concentration of 1.95% of CO2 equilibrated in normal saline. However, bias changes to +45.4% when 1.95% CO2 is equilibrated in human albumin solution 4.5%.
It would not be surprising if gastric juice components such as proteins, mucopolisaccharides and others interfere with CO2 solubility and its subsequent measurement by blood gas analyzers. In this way, intersubject and intrasubject variation in gastric juice composition could also account for data dispersion. Fiddian-Green et al [1] measured PCO2 in gastric contents of anaesthetized dogs. They isolated the stomach from the oesophagus and the duodenum with ligatures, and washed it through a catheter with saline. Then, they instilled 250 ml 0.9% saline and took samples to measure PCO2 and to estimate pHi. Simultaneously, mucosa pH was recorded with a microglass probe. They found a statistically significant correlation between both methods. However, data dispersion in the graph was considerable.
We were able to exclude analyzer underestimation of PCO2 in saline as the cause for the present results. In vitro performance of the AVL 945 in blood was good. It showed a negative bias less than 1 mmHg and a precision of about 2 mmHg.
We cannot infer from the present data the technique that should be the gold standard for measuring PCO2 in gastric mucosa. However, the studies that have established the normal values for pHi, prognostic changes and its uses as a therapeutic index have been performed with tonometry. Hence, more data are needed for the routine measurement of PCO2 in gastric juice.
Correlation between gastric juice and tonometric PCO2. We performed 112 pairs of measurements of gastric juice and tonometric PCO2 in 15 critical care patients under different haemodynamic and oxygen transport conditions. The linear regression coefficient is significant. However, the slope value indicates systematic overestimation of gastric juice PCO2 in relation to saline PCO2.
Bland-Altman analysis of the differences between gastric juice and tonometric PCO2. The bias calculated as the mean difference of gastric juice and tonometric PCO2 was 51 mmHg. The 95% limits of agreement were 315 mmHg. The bias and the scattering of differences widened as PCO2 increased.
Clinical characteristics and first value of arterial, tonometer and gastric juice PCO2
ARDS, acute respiratory distress syndrome.
PMCID: PMC29045  PMID: 11056754
gastric tonometry; intramucosal partial carbon dioxide tension; intramucosal pH
17.  Mutations in Intron 1 and Intron 22 Inversion Negative Haemophilia A Patients from Western India 
PLoS ONE  2014;9(5):e97337.
Despite increased awareness and diagnostic facilities, 70–80% of the haemophilia A (HA) patients still remain undiagnosed in India. Very little data is available on prevalent mutations in HA from this country. We report fifty mutations in seventy one Indian HA patients, of which twenty were novel. Ten novel missense mutations [p.Leu11Pro (p.Leu-8Pro), p.Tyr155Ser (p.Tyr136Ser), p.Ile405Thr (p.Ile386Thr), p.Gly582Val (p.Gly563Val) p.Thr696Ile (p.Thr677Ile), p.Tyr737Cys (p.Tyr718Cys), p.Pro1999Arg (p.Pro1980Arg), p.Ser2082Thr (p.Ser2063Thr), p.Leu2197Trp (p.Leu2178Trp), p.Asp2317Glu (p.Asp2298Glu)] two nonsense [p.Lys396* (p.Lys377*), p.Ser2205* (p.Ser2186*)], one insertion [p.Glu1268_Asp1269ins (p.Glu1249_Asp1250)] and seven deletions [p.Leu882del (p.Leu863del), p.Met701del (p.Met682del), p.Leu1223del (p.Leu1204del), p.Trp1961_Tyr1962del (p.Trp1942_Tyr1943del) p.Glu1988del (p.Glu1969del), p.His1841del (p.His1822del), p.Ser2205del (p.Ser2186del)] were identified. Double mutations (p.Asp2317Glu; p.Thr696Ile) were observed in a moderate HA case. Mutations [p. Arg612Cys (p.Arg593Cys), p.Arg2326Gln (p.Arg2307Gln)] known to be predisposing to inhibitors to factor VIII (FVIII) were identified in two patients. 4.6% of the cases were found to be cross reacting material positive (CRM+ve). A wide heterogeneity in the nature of mutations was seen in the present study which has been successfully used for carrier detection and antenatal diagnosis in 10 families affected with severe to moderate HA.
doi:10.1371/journal.pone.0097337
PMCID: PMC4028251  PMID: 24845853
18.  BION web server: predicting non-specifically bound surface ions 
Bioinformatics  2013;29(6):805-806.
Motivation: Ions are essential component of the cell and frequently are found bound to various macromolecules, in particular to proteins. A binding of an ion to a protein greatly affects protein’s biophysical characteristics and needs to be taken into account in any modeling approach. However, ion’s bounded positions cannot be easily revealed experimentally, especially if they are loosely bound to macromolecular surface.
Results: Here, we report a web server, the BION web server, which addresses the demand for tools of predicting surface bound ions, for which specific interactions are not crucial; thus, they are difficult to predict. The BION is easy to use web server that requires only coordinate file to be inputted, and the user is provided with various, but easy to navigate, options. The coordinate file with predicted bound ions is displayed on the output and is available for download.
Availability: http://compbio.clemson.edu/bion_server/
Supplementary information: Supplementary data are available at Bioinformatics online.
Contact: ealexov@clemson.edu
doi:10.1093/bioinformatics/btt032
PMCID: PMC3597141  PMID: 23380591
19.  PHI-base update: additions to the pathogen–host interaction database 
Nucleic Acids Research  2007;36(Database issue):D572-D576.
The pathogen–host interaction database (PHI-base) is a web-accessible database that catalogues experimentally verified pathogenicity, virulence and effector genes from bacterial, fungal and Oomycete pathogens, which infect human, animal, plant, insect, fish and fungal hosts. Plant endophytes are also included. PHI-base is therefore an invaluable resource for the discovery of genes in medically and agronomically important pathogens, which may be potential targets for chemical intervention. The database is freely accessible to both academic and non-academic users. This publication describes recent additions to the database and both current and future applications. The number of fields that characterize PHI-base entries has almost doubled. Important additional fields deal with new experimental methods, strain information, pathogenicity islands and external references that link the database to external resources, for example, gene ontology terms and Locus IDs. Another important addition is the inclusion of anti-infectives and their target genes that makes it possible to predict the compounds, that may interact with newly identified virulence factors. In parallel, the curation process has been improved and now involves several external experts. On the technical side, several new search tools have been provided and the database is also now distributed in XML format. PHI-base is available at: http://www.phi-base.org/.
doi:10.1093/nar/gkm858
PMCID: PMC2238852  PMID: 17942425
20.  Community Attitudes to the Appropriation of Mobile Phones for Monitoring and Managing Depression, Anxiety, and Stress 
Background
The benefits of self-monitoring on symptom severity, coping, and quality of life have been amply demonstrated. However, paper and pencil self-monitoring can be cumbersome and subject to biases associated with retrospective recall, while computer-based monitoring can be inconvenient in that it relies on users being at their computer at scheduled monitoring times. As a result, nonadherence in self-monitoring is common. Mobile phones offer an alternative. Their take-up has reached saturation point in most developed countries and is increasing in developing countries; they are carried on the person, they are usually turned on, and functionality is continually improving. Currently, however, public conceptions of mobile phones focus on their use as tools for communication and social identity. Community attitudes toward using mobile phones for mental health monitoring and self-management are not known.
Objective
The objective was to explore community attitudes toward the appropriation of mobile phones for mental health monitoring and management.
Methods
We held community consultations in Australia consisting of an online survey (n = 525), focus group discussions (n = 47), and interviews (n = 20).
Results
Respondents used their mobile phones daily and predominantly for communication purposes. Of those who completed the online survey, the majority (399/525 or 76%) reported that they would be interested in using their mobile phone for mental health monitoring and self-management if the service were free. Of the 455 participants who owned a mobile phone or PDA, there were no significant differences between those who expressed interest in the use of mobile phones for this purpose and those who did not by gender (χ21, = 0.98, P = .32, phi = .05), age group (χ24, = 1.95, P = .75, phi = .06), employment status (χ22, = 2.74, P = .25, phi = .08) or marital status (χ24, = 4.62, P = .33, phi = .10). However, the presence of current symptoms of depression, anxiety, or stress affected interest in such a program in that those with symptoms were more interested (χ2 1, = 16.67, P < .001, phi = .19). Reasons given for interest in using a mobile phone program were that it would be convenient, counteract isolation, and help identify triggers to mood states. Reasons given for lack of interest included not liking to use a mobile phone or technology, concerns that it would be too intrusive or that privacy would be lacking, and not seeing the need. Design features considered to be key by participants were enhanced privacy and security functions including user name and password, ease of use, the provision of reminders, and the availability of clear feedback.
Conclusions
Community attitudes toward the appropriation of mobile phones for the monitoring and self-management of depression, anxiety, and stress appear to be positive as long as privacy and security provisions are assured, the program is intuitive and easy to use, and the feedback is clear.
doi:10.2196/jmir.1475
PMCID: PMC3057321  PMID: 21169174
Mobile phones; monitoring; self-help; depression; anxiety; stress; Internet intervention
21.  Electrostatic Selectivity in Protein–nanoparticle Interactions 
Biomacromolecules  2011;12(7):2552-2561.
The binding of bovine serum albumin (BSA) and β-lactoglobulin (BLG) to TTMA (a cationic gold nanoparticle coupled to 3, 6, 9, 12-Tetraoxatricosan-1-Aminium, 23-mercapto-N, N, N-TriMethyl)- was studied by high-resolution turbidimetry (to observe a critical pH for binding), dynamic light scattering (to monitor particle growth), and isothermal titration calorimetry (to measure binding energetics), all as a function of pH and ionic strength. Distinctively higher affinities observed for BLG vs. BSA, despite the lower pI of the latter, were explained in terms of their different charge anisotropies, namely the negative charge patch of BLG. To confirm this effect, we studied two isoforms of BLG that differ in only two amino acids. Significantly stronger binding to BLGA could be attributed to the presence of the additional aspartates in that negative charge domain for dimer, best portrayed in DelPhi. This selectivity decreases with ionic strength, for which both isoforms bind well below pI, but increases with ionic strength for BLG vs. BSA which binds above pI. This result points to the diminished role of long-range repulsions for binding above pI. Dynamic light scattering reveals a tendency for higher-order aggregation for TTMA–BSA at pH above the pI of BSA, due to its ability to bridge nanoparticles, whereas soluble BLG–TTMA complexes were stable over a range of pH because the charge anisotropy of this protein at pH < pI makes it unable to bridge nanoparticles. Finally, isothermal titration calorimetry shows endoenthalpic binding for all proteins; the higher affinity of TTMA for BLGA vs. BLGB comes from a difference in the dominant entropy term.
doi:10.1021/bm200374e
PMCID: PMC3134168  PMID: 21574652
bovine serum albumin; β-lactoglobulin; electrostatic selectivity; gold nanoparticle; complexation
22.  Internet-Based Delphi Research: Case Based Discussion 
Environmental management  2013;51(3):511-523.
The interactive capacity of the Internet offers benefits that are intimately linked with contemporary research innovation in the natural resource and environmental studies domains. However, e-research methodologies, such as the e-Delphi technique, have yet to undergo critical review. This study advances methodological discourse on the e-Delphi technique by critically assessing an e-Delphi case study. The analysis suggests that the benefits of using e-Delphi are noteworthy but the authors acknowledge that researchers are likely to face challenges that could potentially compromise research validity and reliability. To ensure that these issues are sufficiently considered when planning and designing an e-Delphi, important facets of the technique are discussed and recommendations are offered to help the environmental researcher avoid potential pitfalls associated with coordinating e-Delphi research.
doi:10.1007/s00267-012-0005-5
PMCID: PMC3581739  PMID: 23288149
Delphi technique; e-research; Internet; Natural resources; Environmental management; Social values; Coastal zone
23.  Automated collection of imaging and phenotypic data to centralized and distributed data repositories 
Accurate data collection at the ground level is vital to the integrity of neuroimaging research. Similarly important is the ability to connect and curate data in order to make it meaningful and sharable with other investigators. Collecting data, especially with several different modalities, can be time consuming and expensive. These issues have driven the development of automated collection of neuroimaging and clinical assessment data within COINS (Collaborative Informatics and Neuroimaging Suite). COINS is an end-to-end data management system. It provides a comprehensive platform for data collection, management, secure storage, and flexible data retrieval (Bockholt et al., 2010; Scott et al., 2011). It was initially developed for the investigators at the Mind Research Network (MRN), but is now available to neuroimaging institutions worldwide. Self Assessment (SA) is an application embedded in the Assessment Manager (ASMT) tool in COINS. It is an innovative tool that allows participants to fill out assessments via the web-based Participant Portal. It eliminates the need for paper collection and data entry by allowing participants to submit their assessments directly to COINS. Instruments (surveys) are created through ASMT and include many unique question types and associated SA features that can be implemented to help the flow of assessment administration. SA provides an instrument queuing system with an easy-to-use drag and drop interface for research staff to set up participants' queues. After a queue has been created for the participant, they can access the Participant Portal via the internet to fill out their assessments. This allows them the flexibility to participate from home, a library, on site, etc. The collected data is stored in a PostgresSQL database at MRN. This data is only accessible by users that have explicit permission to access the data through their COINS user accounts and access to MRN network. This allows for high volume data collection and with minimal user access to PHI (protected health information). An added benefit to using COINS is the ability to collect, store and share imaging data and assessment data with no interaction with outside tools or programs. All study data collected (imaging and assessment) is stored and exported with a participant's unique subject identifier so there is no need to keep extra spreadsheets or databases to link and keep track of the data. Data is easily exported from COINS via the Query Builder and study portal tools, which allow fine grained selection of data to be exported into comma separated value file format for easy import into statistical programs. There is a great need for data collection tools that limit human intervention and error while at the same time providing users with intuitive design. COINS aims to be a leader in database solutions for research studies collecting data from several different modalities.
doi:10.3389/fninf.2014.00060
PMCID: PMC4046572  PMID: 24926252
assessment data collection; neuroinformatics; tool suite; database; intuitive; COINS
24.  Excision and duplication of su3+-transducing fragments carried by bacteriophage phi 80. I. Novel structure of phi 80sus2psu3+ DNA molecule. 
Journal of Virology  1976;18(3):1016-1023.
DNA molecules of phi 80sus2psu3+ and phi 80dsu3+ isolated by Andoh and Ozeki (1968) were studied by the electron microscope heteroduplex method. The phi 80sus2psu3+ and phi 80dsu3+ DNA lengths were found to be 108.7 and 103.3% of the phi 80 DNA, respectively. The phi 80sus2psu3+/phi 80 heteroduplex shows an insertion loop of 8.7% of the phi 80 DNA which migrates from 7.7 to 9.7%, as measured relative to the left (0%) and right (100%) termini of the mature phi 80 DNA molecule. The region of loop migration occupies the central region of the phi 80 head gene cluster. The presence of su3+-containing Escherichia coli DNA of 6.7% phi 80 unit flanked by two homologous regions of phage DNA of 2.0% of phi 80 unit gives rise to a movable insertion loop. In phi 80dsu3+, from which phi 80sus2psu3+ was derived, 50.5% of the phi 80 DNA at the left arm was replaced by E. coli DNA containing the su3+ gene, equivalent to about 53.8% phi 80 unit in length. The phi 80sus2psu3+/phi 80dsu3+ heteroduplex appears as a double-stranded molecule that bifurcates into two clearly visible single-stranded regions, rejoins, bifurcates, and rejoins again. The middle double-stranded stretches of 6.7% phi 80 unit correspond to the E. coli DNA inserted in phi 80sus2psu3+. Therefore the transducing fragment carried by phi 80sus2psu3+ originates from the inside region of the transducing fragment of defective phage phi 80dsu3+ by at least two illegitimate recombination events.
Images
PMCID: PMC354801  PMID: 1271527
25.  Predicting folding free energy changes upon single point mutations 
Bioinformatics  2012;28(5):664-671.
Motivation: The folding free energy is an important characteristic of proteins stability and is directly related to protein's wild-type function. The changes of protein's stability due to naturally occurring mutations, missense mutations, are typically causing diseases. Single point mutations made in vitro are frequently used to assess the contribution of given amino acid to the stability of the protein. In both cases, it is desirable to predict the change of the folding free energy upon single point mutations in order to either provide insights of the molecular mechanism of the change or to design new experimental studies.
Results: We report an approach that predicts the free energy change upon single point mutation by utilizing the 3D structure of the wild-type protein. It is based on variation of the molecular mechanics Generalized Born (MMGB) method, scaled with optimized parameters (sMMGB) and utilizing specific model of unfolded state. The corresponding mutations are built in silico and the predictions are tested against large dataset of 1109 mutations with experimentally measured changes of the folding free energy. Benchmarking resulted in root mean square deviation = 1.78 kcal/mol and slope of the linear regression fit between the experimental data and the calculations was 1.04. The sMMGB is compared with other leading methods of predicting folding free energy changes upon single mutations and results discussed with respect to various parameters.
Availability: All the pdb files we used in this article can be downloaded from http://compbio.clemson.edu/downloadDir/mentaldisorders/sMMGB_pdb.rar
Contact: ealexov@clemson.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts005
PMCID: PMC3289912  PMID: 22238268

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