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PubMed2002

Distinguishing native conformations of proteins from decoys with an effective free energy estimator based on the OPLS all-atom force field and the Surface Generalized Born solvent model.

Protein decoy data sets provide a benchmark for testing scoring functions designed for fold recognition and protein homology modeling problems. It is commonly believed that statistical potentials based on reduced atomic models are better able to discriminate native-like from misfolded decoys than scoring functions based on more detailed molecular mechanics models. Recent benchmark tests on small data sets, however, suggest otherwise. In this work, we report the results of extensive decoy detection tests using an effective free energy function based on the OPLS all-atom (OPLS-AA) force field and the Surface Generalized Born (SGB) model for the solvent electrostatic effects. The OPLS-AA/SGB effective free energy is used as a scoring function to detect native protein folds among a total of 48,832 decoys for 32 different proteins from Park and Levitt's 4-state-reduced, Levitt's local-minima, Baker's ROSETTA all-atom, and Skolnick's decoy sets. Solvent electrostatic effects are included through the Surface Generalized Born (SGB) model. All structures are locally minimized without restraints. From an analysis of the individual energy components of the OPLS-AA/SGB energy function for the native and the best-ranked decoy, it is determined that a balance of the terms of the potential is responsible for the minimized energies that most successfully distinguish the native from the misfolded conformations. Different combinations of individual energy terms provide less discrimination than the total energy. The results are consistent with observations that all-atom molecular potentials coupled with intermediate level solvent dielectric models are competitive with knowledge-based potentials for decoy detection and protein modeling problems such as fold recognition and homology modeling.

Animals↗
PubMed2003

ZDOCK: an initial-stage protein-docking algorithm.

The development of scoring functions is of great importance to protein docking. Here we present a new scoring function for the initial stage of unbound docking. It combines our recently developed pairwise shape complementarity with desolvation and electrostatics. We compare this scoring function with three other functions on a large benchmark of 49 nonredundant test cases and show its superior performance, especially for the antibody-antigen category of test cases. For 44 test cases (90% of the benchmark), we can retain at least one near-native structure within the top 2000 predictions at the 6 degrees rotational sampling density, with an average of 52 near-native structures per test case. The remaining five difficult test cases can be explained by a combination of poor binding affinity, large backbone conformational changes, and our algorithm's strong tendency for identifying large concave binding pockets. All four scoring functions have been integrated into our Fast Fourier Transform based docking algorithm ZDOCK, which is freely available to academic users at http://zlab.bu.edu/~ rong/dock.

Algorithms↗
PubMed2004

Single-body residue-level knowledge-based energy score combined with sequence-profile and secondary structure information for fold recognition.

An elaborate knowledge-based energy function is designed for fold recognition. It is a residue-level single-body potential so that highly efficient dynamic programming method can be used for alignment optimization. It contains a backbone torsion term, a buried surface term, and a contact-energy term. The energy score combined with sequence profile and secondary structure information leads to an algorithm called SPARKS (Sequence, secondary structure Profiles and Residue-level Knowledge-based energy Score) for fold recognition. Compared with the popular PSI-BLAST, SPARKS is 21% more accurate in sequence-sequence alignment in ProSup benchmark and 10%, 25%, and 20% more sensitive in detecting the family, superfamily, fold similarities in the Lindahl benchmark, respectively. Moreover, it is one of the best methods for sensitivity (the number of correctly recognized proteins), alignment accuracy (based on the MaxSub score), and specificity (the average number of correctly recognized proteins whose scores are higher than the first false positives) in LiveBench 7 among more than twenty servers of non-consensus methods. The simple algorithm used in SPARKS has the potential for further improvement. This highly efficient method can be used for fold recognition on genomic scales. A web server is established for academic users on http://theory.med.buffalo.edu.

Algorithms↗
PubMed2006

SSALN: an alignment algorithm using structure-dependent substitution matrices and gap penalties learned from structurally aligned protein pairs.

In template-based modeling of protein structures, the generation of the alignment between the target and the template is a critical step that significantly affects the accuracy of the final model. This paper proposes an alignment algorithm SSALN that learns substitution matrices and position-specific gap penalties from a database of structurally aligned protein pairs. In addition to the amino acid sequence information, secondary structure and solvent accessibility information of a position are used to derive substitution scores and position-specific gap penalties. In a test set of CASP5 targets, SSALN outperforms sequence alignment methods such as a Smith-Waterman algorithm with BLOSUM50 and PSI_BLAST. SSALN also generates better alignments than PSI_BLAST in the CASP6 test set. LOOPP server prediction based on an SSALN alignment is ranked the best for target T0280_1 in CASP6. SSALN is also compared with several threading methods and sequence alignment methods on the ProSup benchmark. SSALN has the highest alignment accuracy among the methods compared. On the Fischer's benchmark, SSALN performs better than CLUSTALW and GenTHREADER, and generates more alignments with accuracy >50%, >60% or >70% than FUGUE, but fewer alignments with accuracy >80% than FUGUE. All the supplemental materials can be found at http://www.cs.cornell.edu/ approximately jianq/research.htm.

Algorithms↗
PubMed2006

Detection of operons.

Operons are clusters of genes that are transcribed as a single message, and regulated by the same gene expression machinery. They are found primarily in prokaryotic genomes. Because genes in the same operon are likely to have related functions, identification of the operon structure is potentially useful for assigning gene function. We report the development and benchmarking of two different methods for detecting operons, based on an analysis of 42 fully sequenced prokaryotic organisms. The Gene Neighbor method (GNM) utilizes the relatively high conservation of gene order in operons, compared with genes in general. The Gene Gap Method (GGM) makes use of the relatively short gap between genes in operons compared with that otherwise found between adjacent genes. The methods have been benchmarked using KEGG pathway data and RegulonDB Escherichia coli operon data. With optimum parameters, the specificity of the GNM is 93% and the sensitivity is 70%. For the GGM, the specificity is 95% and the sensitivity is 68%. Together, the two methods have a sensitivity of 87.2%, while joint predictions have a sensitivity of 50% and a specificity of 98%. The methods are used to infer possible functions for some hypothetical genes in prokaryotic genomes. The methods have proven a useful addition to structure information in deriving protein function in a structural genomics project.

Computational Biology↗
PubMed2002

Cloned and expressed fungal phyA gene in alfalfa produces a stable phytase.

The phyA gene from Aspergillus ficuum that codes for a 441-amino-acid full-length phosphomonoesterase (phytase) was cloned and expressed in Medicago sativa (alfalfa) leaves. The expressed enzyme from alfalfa leaves was purified to homogeneity and biochemically characterized, and its catalytic properties were elucidated. The expressed phytase in alfalfa leaves retained all the biochemical properties of the benchmark A. ficuum phytase. Although the characteristic bi-hump pH optima were retained in the cloned phytase, the optimal pH shifted downward from 5.5 to 5.0. Also, the recombinant phytase was inhibited by the pseudo-substrate myo-inositol hexasulfate and also by antibody raised against a 20-mer peptide belonging to fungal phytase. The expressed phytase in alfalfa could also be modified by phenylglyoxal. Taken together, the results indicate that fungal phytase when cloned and expressed in alfalfa leaves produces stable and catalytically active phytase while retaining all the properties of the benchmark phytase. This affirms our view that "molecular biofarming" could be an alternative means of producing stable hydrolytic enzymes such as phytase.

6-Phytase↗
PubMed2000

Combination of threading potentials and sequence profiles improves fold recognition.

Using a benchmark set of structurally similar proteins, we conduct a series of threading experiments intended to identify a scoring function with an optimal combination of contact-potential and sequence-profile terms. The benchmark set is selected to include many medium-difficulty fold recognition targets, where sequence similarity is undetectable by BLAST but structural similarity is extensive. The contact potential is based on the log-odds of non-local contacts involving different amino acid pairs, in native as opposed to randomly compacted structures. The sequence profile term is that used in PSI-BLAST. We find that combination of these terms significantly improves the success rate of fold recognition over use of either term alone, with respect to both recognition sensitivity and the accuracy of threading models. Improvement is greatest for targets between 10 % and 20 % sequence identity and 60 % to 80 % superimposable residues, where the number of models crossing critical accuracy and significance thresholds more than doubles. We suggest that these improvements account for the successful performance of the combined scoring function at CASP3. We discuss possible explanations as to why sequence-profile and contact-potential terms appear complementary.

Algorithms↗
PubMed1997

Evaluation of alternative methods for establishing safe levels of occupational exposure to vinyl halides.

The facts that reduction of occupational vinyl chloride exposures to levels within or below the 0.5-5 ppm range has so far been successful in eliminating vinyl chloride-induced liver angiosarcoma and that humans appear to be less sensitive to the carcinogenic effect of vinyl chloride than rats offered an opportunity to verify or dispute risk assessment extrapolation models used, and proposed, by the U.S. EPA. Safe occupational vinyl chloride exposures were defined as levels associated with an incidence of one angiosarcoma in 100,000 exposed workers, determined from rat bioassay data using default no-threshold (linearized multistage model and benchmark dose approach with linear extrapolation) and threshold (NOEL/LOEL and benchmark dose uncertainty factor approaches) models, and then compared against the likely protective range of 0.5-5 ppm. Safe levels derived using either no-threshold model are equivalent and are two to three orders of magnitude below the 0.5-5 ppm range. Safe levels derived using either threshold model, when applying uncertainty factors which reflect equal or less sensitivity in humans compared to rats, fall within the 0.5-5 ppm range. Similar results were obtained for vinyl bromide and vinyl fluoride. These results undermine the U.S. EPA default assumption of no-threshold for vinyl halides as well as for other DNA-reactive carcinogens while simultaneously supporting the notion that a practical threshold exists. They further suggest that when threshold models are appropriate, the default assumption of greater sensitivity in humans compared to rats should be carefully evaluated.

Animals↗
PubMed1998

Dose-response characteristics of uterine responses in rats exposed to estrogen agonists.

Assays for uterine response have played major roles in developing an understanding of estrogen-mediated processes and for identifying compounds with hormonal activity. Data from assays measuring increases in uterine wet weight in rats were evaluated in terms of their dose-response characteristics. Analysis using a Hill equation found inconsistent estimates for the ED50 (concentration giving half-maximal response) and n (steepness of response) among the assays. This variability reflects disparate assay protocols and limitations of the dose-response data collected in the experiments. Although uterine wet weight is easily measured, it arises from several physiological processes (e.g., water retention, cell proliferation). This contributes to the assay variability with different protocols. The potential use of the Hill equation for dose-response analysis to estimate a benchmark dose was also considered using these data sets as surrogates for receptor-mediated toxicological effects. Strengths and weaknesses were identified, but overall the Hill equation should likely become a favored option for determining a benchmark dose, particularly when a data set demonstrates a maximal response. For screening purposes, empirical analysis using the Hill equation provides adequate information for classifying and prioritizing compounds. To develop an understanding of how incremental exposures to compounds with estrogen agonist activities would affect intact adult females, quantitative analyses are required that account for the pharmacokinetics of estradiol and subsequent interactions of the receptor complexes in regulating the responses.

Animals↗
PubMed1999

Evaluation of functional nerve recovery shows that allogeneic nerve graft treated with ICAM-1 and LFA-1 mAbs can be good alternative to syngeneic graft.

The objective of the study is to establish recovery results of tibial nerve defects reconstructed using allogeneic and xenogeneic graft, in host immunosuppressed with Intercellular Adhesion Molecule-1 (ICAM-1) and Lymphocyte Function Antigen-1 (LFA-1) monoclonal antibodies (mAbs). A pilot study was conducted in fifteen Fischer rats by forming a 1 cm right tibial nerve gap, then reconstructing it with 1.2 cm long grafts, namely, Wistar allogeneic, Black mouse xenogeneic, and syngeneic (n = 5/group). The main study included forty-eight rats allocated to the following groups (n = 12/group): 1) Allograft without treatment as control group. 2) Allograft with intraperitoneal ICAM-1 and LFA-1 mAbs treatment. 3) Allograft preserved in Belzers' solution including ICAM-1 mAbs plus standard intraperitoneal treatment. 4) Syngraft as benchmark. At 3, 6 and 9 weeks postengraftment walking track analysis was performed and expressed as Tibial Functional Index (TFI). Motor and compound nerve action potential across the graft conduction velocities were measured at week 10. Xenograft did not show any functional recovery and was therefore excluded from main study. However, pilot and main study results showed recovery results in both treated allogeneic groups and were comparable to benchmark syngraft. Therefore, allogeneic nerve graft could be an alternative in peripheral nerve reconstruction and spinal cord grafting.

Action Potentials↗
PubMed2004

[Assessing the quality of structures, concepts, and processes in prevention, health promotion, and education. Requirements and solutions].

The effectiveness of health promotion is determined by the foundation of evidence, the targeting of health problems, and the adaptation of interventions to specific social and organizational contexts. Methods for the implementation of these objectives must be able to balance interacting intervention goals, to account for the suitability of interventions for specific target groups and settings, and to integrate complex and divergent data. The core methodology underlying these conditions is peer review assessment. A quality assurance system based on this approach is presented: Two inventories elicit detailed self-descriptions characterizing either actors or activities within health promotion and education. Two assessment instruments instruct experts in reviewing these data according to primary and partial dimensions of quality. Thus, systematically structured and quantifiable quality profiles of organizational units or specific activities are produced. On this basis, comparative indicators for benchmarking purposes can be calculated. Quality profiles containing the strengths and weaknesses of organizations or activities, including indicators, benchmarks, and reviewers' recommendations, are communicated to participating organizations in order to stimulate continuous quality improvement by feedback. Moreover, the system offers a database of comparative indicators for monitoring and optimizing health promotion and education.

Germany↗
PubMed2005

[Quality control in imaging standards for stroke diagnosis].

Hospitals in "Rhineland-Palatinate" and "Saarland" as well as in other German states are using benchmarking in quality control and to improve diagnostic procedures and treatment in stroke. The goal is a continuous learning process in which participants improve their performance by comparing themselves to the highest quality care. CCT/MRI procedures are an important tool in stroke therapy and prophylaxis. Structural quality was good in all 39 participating hospitals. The best evidence-based indicator in quality control of CCT/MRI procedures is the process quality in performing these procedures within 3 h after stroke onset. Process quality was better in hospitals that cared for many stroke patients than in those with fewer cases. The latter hospitals also had less clinical and diagnostic competence. Benchmarking in quality control was successful because over the years improvement in stroke management was obvious in the participating hospitals.

Appointments and Schedules↗
PubMed2003

Evaluation of health-related quality of life using the MOS 36-Item Short-Form Health Status Survey in patients receiving noninvasive positive pressure ventilation.

OBJECTIVE: To collect benchmark data on the MOS 36-Item Short-Form Health Status Survey (SF-36) in patients receiving noninvasive positive pressure ventilation and to examine whether health-related quality of life is influenced by the underlying disease or by physical parameters. DESIGN AND SETTING: Multicentric clinical cross-sectional trial in four general wards specialized in noninvasive positive pressure ventilation. PATIENTS AND PARTICIPANTS: 226 patients (78 chronic obstructive pulmonary disease, 57 kyphoscoliosis, 20 posttuberculosis sequelae, 17 Duchenne muscular dystrophy, 13 polyneuropathy, 13 myopathy, 6 amyotrophic lateral sclerosis, 12 obesity-hypoventilation syndrome, 4 poliomyelitis sequelae, 3 phrenic nerve lesion, 3 central hypoventilation syndrome) who used noninvasive positive pressure ventilation for home mechanical ventilation. MEASUREMENTS AND RESULTS: Health-related quality of life as assessed by the SF-36 was lower than in the general population. Overall the Physical Component Summary (PCS) was significantly lower than the general population norm; the Mental Component Summary (MCS) was also reduced but less markedly. Patients with chronic obstructive pulmonary disease were more impaired in MCS than those with kyphoscoliosis. PCS was significantly associated with age. Gender, lung function, and arterial blood gas values were not significant predictors of health-related quality of life. CONCLUSIONS: Benchmark SF-36 data in patients receiving noninvasive positive pressure ventilation are given. Although physical health is significantly impaired in these patients, this does not necessarily lead to mental limitation, and mental health is influenced by the underlying disease, but not by physical parameters.

Analysis of Variance↗
PubMed2004

Surveillance of antimicrobial use and antimicrobial resistance in intensive care units (SARI): 1. Antimicrobial use in German intensive care units.

OBJECTIVE: To study antimicrobial use for benchmarking and ensuring quality of antimicrobial treatment and to identify risk factors associated with the high use of antimicrobials in German intensive care units (ICUs) through implementation of the SARI (Surveillance of Antimicrobial Use and Antimicrobial Resistance in ICUs) system. DESIGN: Prospective, unit-based surveillance on antimicrobial use from February, 2000, until June, 2002. The data are standardised by use of the defined daily dose (DDD) for each antimicrobial defined by the WHO and by calculating use per 1000 patient days. SETTING: The data were obtained from 35 German ICUs and stratified by type of ICU (medical, surgical, interdisciplinary). RESULTS: To date, the project covers a total of 266,013 patient days in 744 reported ICU months and 354,356 DDDs. Mean antimicrobial use density (AD) was 1,332 DDD/1000 patient days and was correlated with length of stay. Penicillins with beta-lactamase inhibitor (AD 338.3) and quinolones (155.5) were the antimicrobial group with the highest ADs. Comparison with US ICARE (Intensive Care Antimicrobial Resistance Epidemiology)/AUR (Antimicrobial Use and Resistance) data revealed a higher AD for glycopeptides and 3rd generation cephalosporins in ICARE/AUR ICUs, but a higher AD for carbapenems in German SARI ICUs regardless of the type of ICU. In the multivariate analysis, length of stay was an independent risk factor for an AD above the 75% percentile of the total amount of antimicrobials used (OR 1.96 per day); likewise, for the AD above the 75% percentile of carbapenems (OR 1.90 per day) and penicillins with extended spectrum (OR 2.01 per day). High use of glycopeptides and quinolones (AD >75% percentile) correlated with central venous catheter (CVC) rate (OR 1.14 per CVC day per 100 patient days and 1.16, respectively). CONCLUSION: The SARI data on antimicrobials serve ICUs as a benchmark by which to improve the quality of antimicrobial drug administration and for international comparison.

Anti-Bacterial Agents↗
PubMed2000

Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers.

RATIONALE: The psychopharmacological profile of hydromorphone, an opioid that has been used extensively for many years for post-operative pain management, has not been adequately characterized in non-drug abusers. OBJECTIVES: To characterize the subjective, psychomotor, and physiological effects of a range of single doses of hydromorphone in non-drug-abusing volunteers and to compare the effects of hydromorphone with that of morphine, a benchmark mu opioid agonist. METHODS: Subjects in a six-session study were injected in an upper extremity vein with 0, 0.33, 0.65, 1.3 mg/70 kg hydromorphone, and 5 and 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. RESULTS: Hydromorphone increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of ("dry mouth", "flushing", and "nodding", and increased visual analog scale ratings indicative of both pleasant (e.g., drug liking) and unpleasant (e.g., "feel bad") effects. The subjective effects of morphine at putatively equianalgesic doses to those of hydromorphone were similar to those of hydromorphone, but in some cases of lesser magnitude. Psychomotor impairment was modest with hydromorphone and absent with morphine. Both opioids produced dose-dependent decreases in pupil size. A relative potency analysis indicated that hydromorphone was 10 times as potent as morphine (1 mg hydromorphone=10 mg morphine). CONCLUSIONS: The results of this study demonstrate that 0.33-1.3 mg hydromorphone had orderly, dose-related effects on subjective, psychomotor, and physiological variables, and similar effects to those of a benchmark mu opioid agonist, morphine.

Adult↗
PubMed2007

Computerized performance monitoring systems: learning and living with its limitations.

Computer technology now allows clinical administrators to collect and analyze large data sets for performance monitoring. Despite the obvious usefulness of this technology, there are limitations. The indices that we can measure are at best proxies that might correlate with good clinical care but can also become dissociated from it in a variety of ways. First, there may not be a relationship throughout the entire continuum between the indicator and what we really value. Second, change in an indicator may not be associated with comparable change in the underlying value. Thirdly, the valence of an indicator can change depending on the context. Fourth, the very act of measuring an indicator can change its valence. Although, from a research perspective there may be technical solutions to these problems, in the real world where clinical care and politics meet, this may not be possible. Indices become reified. Measures become benchmarks and benchmarks quotas. Average is not a statistical phrase but a judgment and below average a term of approbation. To maximize the benefits of computerized monitoring, administrators need to be sensitive to this political dimension.

Community Mental Health Centers↗
PubMed2006

Quantitative analysis of the conservation of the tertiary structure of protein segments.

The publication of the crystallographic structure of calmodulin protein has offered an example leading us to believe that it is possible for many protein sequence segments to exhibit multiple 3D structures referred to as multi-structural segments. To this end, this paper presents statistical analysis of uniqueness of the 3D-structure of all possible protein sequence segments stored in the Protein Data Bank (PDB, Jan. of 2003, release 103) that occur at least twice and whose lengths are greater than 10 amino acids (AAs). We refined the set of segments by choosing only those that are not parts of longer segments, which resulted in 9297 segments called a sponge set. By adding 8197 signature segments, which occur uniquely in the PDB, into the sponge set we have generated a benchmark set. Statistical analysis of the sponge set demonstrates that rotating, missing and disarranging operations described in the text, result in the segments becoming multi-structural. It turns out that missing segments do not exhibit a change of shape in the 3D-structure of a multi-structural segment. We use the root mean square distance for unit vector sequence (URMSD) as an improved measure to describe the characteristics of hinge rotations, missing, and disarranging segments. We estimated the rate of occurrence for rotating and disarranging segments in the sponge set and divided it by the number of sequences in the benchmark set which is found to be less than 0.85%. Since two of the structure changing operations concern negligible number of segment and the third one is found not to have impact on the structure, we conclude that the 3D-structure of proteins is conserved statistically for more than 98% of the segments. At the same time, the remaining 2% of the sequences may pose problems for the sequence alignment based structure prediction methods.

Amino Acid Sequence↗
PubMed2006

Poor outcomes after fibrinolytic therapy for ST-segment elevation myocardial infarction: impact of age (a meta-analysis of a decade of trials).

BACKGROUND: Fibrinolysis for ST-segment elevation myocardial infarction (STEMI) reduces mortality, but its relative efficacy and risks are age-dependent. We aimed to quantify the outcomes of fibrinolysis and adjunctive antithrombin therapy for STEMI stratified by age. METHODS: We performed a meta-analysis of 11 published (1992-2001) randomized clinical trials of fibrinolysis in STEMI (sample size >or=3,000, no age limit, no placebo-controlled arms) identified by MEDLINE through June 2005. Event rates and odds ratios (OR) in elderly vs. younger patients were calculated for mortality, intracranial hemorrhage (ICH) and total stroke (CVA). Elderly patients were defined as >or=75 years (GUSTO I, TIMI 9B, GUSTO III, COBALT, ASSENT-2, InTIME-II TIMI-17, ASSENT-3, GUSTO V, and HERO-2), except when defined as >65 or >or=70 years by the study (INJECT and ISIS-3). RESULTS: Elderly (n = 24,531) vs. younger (n = 123,568) patients had increased rates of mortality (19.7% vs. 5.5%), ICH (1.4% vs. 0.5%) and CVA (3.5 vs. 1.2%) by 30-35 days; the excess risk for these events was substantial (OR mortality 4.37, 95% CI 4.16-4.58; ICH 2.83, 2.47-3.24; CVA 2.92, 2.62-3.25; p < 0.001 for all). CONCLUSIONS: Despite established mortality reductions with fibrinolysis for STEMI, elderly compared with younger patients, still have a three to four fold increased risk of mortality and adverse events when treated with fibrinolysis and antithrombin therapy in the modern era. These robust estimates of the anticipated rates for mortality, ICH, and CVA can be used as benchmarks to monitor the efficacy and safety of therapies in ongoing and newly completed clinical trials. We aimed to quantify the outcomes of death, intracranial hemorrhage (ICH), and total cerebrovascular accidents (CVA) in elderly compared with younger patients treated with fibrinolysis for STEMI based on a meta-analysis of 11 randomized clinical trials (1992-2001) of more than 3,000 patients. Elderly (n = 24,531) vs. younger (n = 123 568) patients had increased rates of mortality, ICH and CVA by 30-35 days; the excess risk was substantial (OR 4.37, 2.83, and 2.92 respectively, p < 0.001 for all). These robust estimates can be used as benchmarks to monitor the efficacy and safety of therapies in ongoing and newly completed clinical trials.

Age Factors↗