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At least 613 records · Page 34Linked to original sources
PubMed1993

Sigma s-dependent promoters in Escherichia coli are located in DNA regions with intrinsic curvature.

Expression of a number of genes during stationary phase in Escherichia coli is controlled by the alternative sigma factor sigma s (KatF). Promoters recognized by sigma s do not present a well-defined consensus sequence in their -10 and -35 regions. By polyacrylamide gel electrophoresis of DNA fragments performed at different temperatures, and by computer prediction analyses, we have found that sigma s-regulated promoters are located in regions where DNA shows intrinsic curvatures. This feature does not appear in a stationary-phase-induced promoter which is not controlled by sigma s. We propose that DNA bending may help in recognition and/or binding of sigma s to stationary-phase-induced promoters.

Bacterial Proteins↗
PubMed1998

Assessing life expectancies of older nursing home residents.

OBJECTIVE: Care of nursing home (NH) residents is often based on the usual survival of the home's residents. In order to improve our understanding of this population, and, thus, ultimately facilitate individualization of their care, we developed a mathematical model that predicts their survival. SETTING: The Jewish Home and Hospital (JHH), a nursing home. PARTICIPANTS: 1145 older residents who were at the JHH from January 1, 1986, through July 1, 1986. MEASUREMENTS: Information abstracted from medical records and JHH computerized data: clinical, demographic, and dependencies in activities of daily living (ADLs). MAIN OUTCOME MEASURE: survival from July 1, 1986. DESIGN: Retrospective cohort study via medical chart review. The study period covered admission to JHH through January 17, 1996. Accelerated failure time (AFT) models generated the life expectancy model derived from 50% of the study group and were validated on the remaining sample. We computed predicted AFT and proportional hazards (PH) life expectancies. RESULTS: Significant, independent predictors of decreased survival were male gender, increased age, increase in summary ADL index, and impairment of cardiac, respiratory, neurological, and endocrine/metabolic systems. The interaction between gender and respiratory system impairment was significant. The Spearman correlation coefficients between the observed survivals and those predicted by the Phase I model are 0.49 for Phase I residents and 0.42 for Phase II residents. Our sample life table includes NH residents with different risk profiles and their associated survival estimates as well as interquartile ranges. AFT and PH survivals were similar. CONCLUSION: This first comprehensive model that predicts survival of NH residents can help formulate public health policies and identify appropriate NH residents for clinical trials. The model is a promising step toward improving the health care of NH residents.

Actuarial Analysis↗
PubMed1980

The computer calculation of intraocular lens power. A clinical study.

A series of forty eyes received intraocular lenses (IOLs) of power +17, +19, or +21 D after consideration of computer calculation based upon data of corneal curvature, axial length, and anterior chamber depth using the formula of R. D. Binkhorst. Results were compared with those of a control group of ninety eyes which were given IOLs of standard +19 D power. No difference was found between the resulting visual acuities or range of postoperative refractions. The preoperative refraction was found to offer no guide to the selection of IOL power. The results were analysed in detail and it was found that the computer prediction of postoperative refraction for the IOLs implanted was of a high level of accuracy. This suggests that improved clinical results are to be expected from a close adherence to the IOL power calculated by a system which has been tested for accuracy and reliability. The cautious minor adjustment of IOL power as in the protocol of this study does not influence the outcome.

Aged↗
PubMed2003

On the sensitivity of wall stresses in diseased arteries to variable material properties.

Accurate estimates of stress in an atherosclerotic lesion require knowledge of the material properties of its components (e.g., normal wall, fibrous plaque, calcified regions, lipid pools) that can only be approximated. This leads to considerable uncertainty in these computational predictions. A study was conducted to test the sensitivity of predicted levels of stress and strain to the parameter values of plaque used in finite element analysis. Results show that the stresses within the arterial wall, fibrous plaque, calcified plaque, and lipid pool have low sensitivities for variation in the elastic modulus. Even a +/- 50% variation in elastic modulus leads to less than a 10% change in stress at the site of rupture. Sensitivity to variations in elastic modulus is comparable between isotropic nonlinear, isotropic nonlinear with residual strains, and transversely isotropic linear models. Therefore, stress analysis may be used with confidence that uncertainty in the material properties generates relatively small errors in the prediction of wall stresses. Either isotropic nonlinear or anisotropic linear models provide useful estimates, however the predictions in regions of stress concentration (e.g., the site of rupture) are somewhat more sensitive to the specific model used, increasing by up to 30% from the isotropic nonlinear to orthotropic model in the present example. Changes resulting from the introduction of residual stresses are much smaller.

Anisotropy↗
PubMed2007

Characterization and predictive discovery of evolutionarily conserved mammalian alternative promoters.

Recent studies suggest that surprisingly many mammalian genes have alternative promoters (APs); however, their biological roles, and the characteristics that distinguish them from single promoters (SPs), remain poorly understood. We constructed a large data set of evolutionarily conserved promoters, and used it to identify sequence features, functional associations, and expression patterns that differ by promoter type. The four promoter categories CpG-rich APs, CpG-poor APs, CpG-rich SPs, and CpG-poor SPs each show characteristic strengths and patterns of sequence conservation, frequencies of putative transcription-related motifs, and tissue and developmental stage expression preferences. APs display substantially higher sequence conservation than SPs and CpG-poor promoters than CpG-rich promoters. Among CpG-poor promoters, APs and SPs show sharply contrasting developmental stage preferences and TATA box frequencies. We developed a discriminator to computationally predict promoter type, verified its accuracy through experimental tests that incorporate a novel method for deconvolving mixed sequence traces, and used it to find several new APs. The discriminator predicts that almost half of all mammalian genes have evolutionarily conserved APs. This high frequency of APs, together with the strong purifying selection maintaining them, implies a crucial role in expanding the expression diversity of the mammalian genome.

Alternative Splicing↗
PubMed2004

MitoP2, an integrated database on mitochondrial proteins in yeast and man.

The aim of the MitoP2 database (http://ihg.gsf.de/mitop2) is to provide a comprehensive list of mitochondrial proteins of yeast and man. Based on the current literature we created an annotated reference set of yeast and human proteins. In addition, data sets relevant to the study of the mitochondrial proteome are integrated and accessible via search tools and links. They include computational predictions of signalling sequences, and summarize results from proteome mapping, mutant screening, expression profiling, protein-protein interaction and cellular sublocalization studies. For each individual approach, specificity and sensitivity for allocating mitochondrial proteins was calculated. By providing the evidence for mitochondrial candidate proteins the MitoP2 database lends itself to the genetic characterization of human mitochondriopathies.

Computational Biology↗
PubMed2005

A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference.

The PERIOD2 (PER2) gene is a key component of the molecular mechanism that generates circadian rhythms in mammals. A missense mutation in the human PER2 gene has previously been linked to advanced sleep phase syndrome (ASPS). We have investigated three other single-nucleotide polymorphisms in the hPER2 gene, one downstream of the transcription start site (C-1228T), one in exon 2 in the 5'-untranslated region (5'-UTR) (C111G), and one missense mutation (G3853A) causing a glycine to glutamine substitution in the predicted protein. Subjects selected from a group of 484 volunteers for extreme morning or evening preference, or intermediate diurnal preference were genotyped with regard to the three polymorphisms (n=35 for each group). Whereas allele frequencies for the other two polymorphisms did not differ significantly between any of the groups, the 111G allele frequency was significantly higher in subjects with extreme morning preference (0.14) than in subjects with extreme evening preference (0.03) (Fisher's exact test, two-sided P value=0.031, odds ratio=5.67). No significant difference in 111G allele frequency was observed between either of these groups and subjects with intermediate diurnal preference. Computer prediction indicated that the C111G polymorphism, which occurs 12 bases upstream from the translation start codon, might alter the secondary structure of the transcript. The PER2 111G allele associates with morning preference and is a potential candidate allele for ASPS.

5' Untranslated Regions↗
PubMed2003

Kinematics, kinetics, and finite element analysis of commonplace maneuvers at risk for total hip dislocation.

Dislocation remains a disturbingly frequent complication of total hip arthroplasty (THA). Over the past several years, increasingly rigorous biomechanical approaches have been developed for studying dislocation, both experimentally and computationally. Realism of the input motion challenge data has lagged behind most other aspects of this body of work, and anterior dislocation maneuvers remain unstudied. To enhance realism of biomechanical studies of dislocation, motion data are here reported for ten THA-aged subjects, each repeatedly performing seven maneuvers known to be dislocation-prone. An optoelectronic motion tracking system and a recessed force plate captured the kinematics and ground reaction forces of these maneuvers. Using an established inverse dynamics model to estimate hip joint loading, 354 motion trials were evaluated using an existing finite element model of THA dislocation. Worst-case-scenario THA constructs were simulated (22 mm femoral head, acetabular cup orientations at the limit of the accepted safe zone), in order to deliberately induce impingement and dislocation. The results showed a high incidence of computationally predicted dislocation for all movements studied, but also that risk was very maneuver-dependent, with patients being six times more likely to dislocate from a low-sit-to-stand maneuver than from stooping. These new motion data hopefully will help facilitate systematic efforts to reduce the incidence of dislocation.

Activities of Daily Living↗
PubMed2004

Decompression sickness risk model: development and validation by 150 prospective hypobaric exposures.

INTRODUCTION: High altitude exposure has an inherent risk of altitude decompression sickness (DCS). A predictive DCS model was needed to reduce operational risk. To be operationally acceptable, such a theoretical model would need to be validated in the laboratory using human subjects. METHODS: The Air Force Research Laboratory (AFRL) has conducted numerous studies on human subjects exposed to simulated altitudes in hypobaric chambers. The database from those studies was used to develop a statistical altitude DCS model. In addition, a bubble growth model was developed using a finite difference method to solve for bubble radius as a function of time. The bubble growth model, integrated with the statistical model, constitutes the AFRL DCS Risk Assessment Model. Validation of the model was accomplished by comparing computer predictions of DCS risk with results from subsequent prospective human subject exposures. There were five exposure profiles, not previously found in the database, covering a wide parameter of ranges of altitude (18,000-35,000 ft), exposure time (180-360 min), prebreathe time (0-90 min), and activity level (rest-strenuous) that were used. The subjects were monitored for DCS symptoms and venous gas emboli. RESULTS: There were 30 subjects who were exposed to each of the 5 altitude profiles. The DCS incidence onset curves predicted by the model were not significantly different from the experimental values for all scenarios tested and were generally within +/- 5% of the actual values. CONCLUSION: A predictive altitude DCS model was successfully developed and validated.

Altitude Sickness↗
PubMed2002

Rational cytokine design for increased lifetime and enhanced potency using pH-activated "histidine switching".

We describe a method for the rational design of more effective therapeutic proteins using amino acid substitutions that reduce receptor binding affinity in intracellular endosomal compartments, thereby leading to increased recycling in the ligand-sorting process and consequently resulting in longer half-life in extracellular medium. We demonstrate this approach for granulocyte colony-stimulating factor by using computationally predicted histidine substitutions that switch protonation states between cell-surface and endosomal pH. Molecular modeling of binding electrostatics indicates two different single-histidine mutants that fulfill our design requirements; experimental assays demonstrate that each mutant indeed exhibits an order-of-magnitude increase in medium half-life along with enhanced potency due to increased endocytic recycling.

Computer Simulation↗
PubMed2001

A draft annotation and overview of the human genome.

BACKGROUND: The recent draft assembly of the human genome provides a unified basis for describing genomic structure and function. The draft is sufficiently accurate to provide useful annotation, enabling direct observations of previously inferred biological phenomena. RESULTS: We report here a functionally annotated human gene index placed directly on the genome. The index is based on the integration of public transcript, protein, and mapping information, supplemented with computational prediction. We describe numerous global features of the genome and examine the relationship of various genetic maps with the assembly. In addition, initial sequence analysis reveals highly ordered chromosomal landscapes associated with paralogous gene clusters and distinct functional compartments. Finally, these annotation data were synthesized to produce observations of gene density and number that accord well with historical estimates. Such a global approach had previously been described only for chromosomes 21 and 22, which together account for 2.2% of the genome. CONCLUSIONS: We estimate that the genome contains 65,000-75,000 transcriptional units, with exon sequences comprising 4%. The creation of a comprehensive gene index requires the synthesis of all available computational and experimental evidence.

Chromosome Mapping↗
PubMed2002

The role of aromaticity in the planarity of lumiflavin.

Ab initio MP2/6-31G(d,p) and density functional theory B3LYP/6-31G(d,p) calculations were performed to investigate the molecular structure of the active part of flavins in the oxidized and reduced forms, using lumiflavin as a model compound. The possible aromatic character of these systems was explored by using the following aromaticity indexes: nucleus-independent chemical shifts, the anisotropy of the magnetic susceptibility, the Bird index, and natural bond orbital analysis. To provide further insight, calculations on the 2+ charged species were also carried out. Both the MP2 and B3LYP computations predict a planar conformation for the oxidized form and a bent structure for the reduced form, in agreement with previous experience. For both the oxidized and reduced states, ring A is found to be the most aromatic, as expected. The calculations suggest that the folding in the reduced form is mainly a result of electronic preferences rather than steric hindrance.

Computational Biology↗
PubMed2006

Structures of tetrafluorocyclopropene, hexafluorocyclobutene, octafluorocyclopentene and related perfluoroalkene radical anions revealed by electron spin resonance spectroscopic and computational studies.

Isotropic and anisotropic ESR spectra were observed for the radical anions of hexafluorocyclobutene (c-C(4)F(6)(-)), octafluorocyclopentene (c-C(5)F(8)(-)) and perfluoro-2-butene (CF(3)CF=CFCF(3)(-)) in gamma-irradiated plastically crystalline neopentane, tetramethylsilane (TMS) and TMS-d(12) matrices, or the rigid 2-methyltetrahydrofuran (MTHF) matrix. The isotropic spectra of c-C(4)F(6)(-) and c-C(5)F(8)(-) are characterized by three different sets of pairs of (19)F nuclei with the isotropic hyperfine (hf) splittings of 15.2 (2F), 6.5 (2F), 1.1 (2F) mT for c-C(4)F(6)(-) and 14.7 (2F), 7.4 (2F), 1.0 (2F) mT for c-C(5)F(8)(-). By comparison with the results of ab initio quantum chemical computations, the large triplet (19)F hf splittings of ca. 15 mT are assigned to the two fluorines attached to the C=C bond. The UHF, B3LYP and MP2 computations predict that the geometrical structures of the perfluoroalkenes are strongly distorted by one-electron reduction to form their radical anions; c-C(3)F(4)(-): C(2) symmetry ((2)A state) <-- C(2)(v) ((1)A(1)), c-C(4)F(6)(-): C(1) ((2)A) <-- C(2)(v) ((1)A(1)) and c-C(5)F(8)(-): C(1) ((2)A) <-- C(s) ((1)A'). The structural distortion arises from a mixing of the pi* and higher-lying sigma* orbitals at the C=C carbons similar to that previously found for CF(2)=CF(2)(-) with a C(2)(h) distortion. The isotropic (19)F hf splittings computed with the B3LYP method with 6-311+G(2df,p) basis set for the geometry optimized by the UHF and/or MP2 methods are within 6% error of the experimental values. The experimental anisotropic spectra of c-C(4)F(6)(-), c-C(5)F(8)(-) and CF(2)=CF(2)(-) were satisfactorily reproduced by the ESR spectral simulation method using the computed hf principal values and orientation of (19)F nuclei. In addition, the electronic excitation energies and oscillator strengths for the CF(2)=CF(2)(-), c-C(3)F(4)(-), c-C(4)F(6)(-) and c-C(5)F(8)(-) radical anions were computed for the first time by TD-DFT methods.

Journal Article↗
PubMed2006

RegulonDB (version 5.0): Escherichia coli K-12 transcriptional regulatory network, operon organization, and growth conditions.

RegulonDB is the internationally recognized reference database of Escherichia coli K-12 offering curated knowledge of the regulatory network and operon organization. It is currently the largest electronically-encoded database of the regulatory network of any free-living organism. We present here the recently launched RegulonDB version 5.0 radically different in content, interface design and capabilities. Continuous curation of original scientific literature provides the evidence behind every single object and feature. This knowledge is complemented with comprehensive computational predictions across the complete genome. Literature-based and predicted data are clearly distinguished in the database. Starting with this version, RegulonDB public releases are synchronized with those of EcoCyc since our curation supports both databases. The complex biology of regulation is simplified in a navigation scheme based on three major streams: genes, operons and regulons. Regulatory knowledge is directly available in every navigation step. Displays combine graphic and textual information and are organized allowing different levels of detail and biological context. This knowledge is the backbone of an integrated system for the graphic display of the network, graphic and tabular microarray comparisons with curated and predicted objects, as well as predictions across bacterial genomes, and predicted networks of functionally related gene products. Access RegulonDB at http://regulondb.ccg.unam.mx.

Databases, Genetic↗
PubMed1989

Adapting best linear unbiased prediction (BLUP) for timely genetic evaluation: II. Progeny traits in multiple contemporary groups within a herd.

The second step of a procedure to partially circumvent the voluminous calculations for some BLUP (Best Linear Unbiased Prediction) computing algorithms for genetic evaluation is presented. In addition, the procedure allows timely evaluations of each contemporary group. This procedure is pertinent especially for polytocous species such as swine and poultry, for which the occurrence of full-sib families makes the inclusion of dam effects in the model necessary and tests are completed throughout the year. Formulas are developed for a model including sires, dams, individuals within full-sib families and records within individuals. This model has a fundamentally hierarchical structure but includes some cross-classification. The formulas for predictors combine information across contemporary groups within a herd and incorporate relationships between sires and(or) dams in that herd. Formulas to approximate prediction error variances also are developed.

Algorithms↗
PubMed1999

Predicting binding energetics from structure: looking beyond DeltaG degrees.

Structure-based design of pharmaceuticals requires the ability to predict ligand affinity based on knowledge of structure. The primary term of interest is the binding affinity constant, K, or the free energy of binding, DeltaG degrees. It is common to attempt to predict DeltaG degrees based on empirically derived terms which represent common contributions such as the hydrophobic effect, hydrogen bonding, and conformational entropy. Although these approaches have met with some success, when they fail it is difficult to know which parameter(s) need refinement. Confidence in these approaches is also limited by the fact that DeltaG degrees typically is made up of compensating enthalpic and entropic terms, DeltaH degrees and DeltaS degrees, so that accurate prediction of a DeltaG degrees value may be fortuitous and may not indicate a reasonable understanding of the underlying relationship between structure and affinity. This is further complicated by the fact that both DeltaH degrees and DeltaS degrees are strongly temperature dependent through the heat capacity change, DeltaCp. In order to avoid these difficulties, we attempt to use structural data to predict DeltaH degrees, DeltaS degrees, and DeltaCp from which DeltaG degrees can be calculated as a function of temperature. The predictions are then compared to experimentally determined values. These calculations have been applied to several systems by ourselves and others. Systems include the binding of angiotensin II to an antibody, the dimerization of interleukin-8, and the binding of inhibitors to aspartic and serine proteases. Overall the calculations are very successful, and suggest that our understanding of the contributions of the hydrophobic effect, hydrogen bonding, and conformational entropy are quite good. Several of these systems show a strong dependence of the binding energetics on pH, indicative of changes in proton affinity of ionizable groups upon binding. It is critical to account for these protonation contributions to the binding energetics in order to assess the reliability of any computational prediction of energetics from structure. Methods have been developed for determining the energetics of proton binding using isothermal titration calorimetry. The availability of these methods provides a means of understanding how protein structure can modify the pKa's of ionizable groups. This information will further add to our understanding of structural energetic relationships and our ability accurately to predict binding affinities.

Energy Metabolism↗
PubMed2004

Binding of calcium ions to an avian flight muscle troponin T.

Numerous troponin T (TnT) isoforms are generated by alternative RNA splicing primarily in its N-terminal hypervariable region, but the functions of these isoforms are not completely understood. Here for the first time, we discovered that a chicken fast TnT isoform with a unique Tx motif (HEEAH)(n) binds calcium. The metal binding behavior of this TnT isoform was first investigated using terbium as a calcium analogue due to its more readily detectable fluorescence variation upon TnT binding. Both intact TnT and TnT N-terminal fragment (TnT N47) bound terbium with high affinity indicating that the N-terminal sequence was the site of binding. Since terbium often substitutes at calcium-binding sites, radioactive calcium was tested and found to bind both intact TnT and TnT N47. Fluorescence measurements using the calcium-sensitive fluorescent dye, calcium green 5N, confirmed that calcium bound to the tertiary complex of TnT and the tropomyosin dimer with a fast on-rate (10(6)-10(7) M(-1) s(-1)) as detected in stopped-flow analysis. Consistent with these observations, computational predictions suggest that TnT N47 might fold into an elongated structure with at least one high-affinity metal ion binding pocket comprised primarily of the Tx motif sequence and several lower affinity binding sites. These results suggest that TnT may play a role in modulating the calcium-mediated regulatory process of striated muscle contraction.

Amino Acid Sequence↗
PubMed1991

Proposed secondary structure of eukaryotic U14 snRNA.

U14 snRNA is a small nuclear RNA that plays a role in the processing of eukaryotic ribosomal RNA. We have investigated the folded structure of this snRNA species using comparative analysis of evolutionarily diverse U14 snRNA primary sequences coupled with nuclease digestion analysis of mouse U14 snRNA. Covariant nucleotide analysis of aligned mouse, rat, human, and yeast U14 snRNA primary sequences suggested a basic folding pattern in which the 5' and 3' termini of all U14 snRNAs were base-paired. Subsequent digestion of mouse U14 snRNA with mung bean (single-strand-specific), T2 (single-strand-preferential), and V1 (double-strand-specific) nucleases defined the major and minor cleavage sites for each nuclease. This digestion data was then utilized in concert with the comparative sequence analysis of aligned U14 snRNA primary sequences to refine the secondary structure model suggested by computer-predicted folding. The proposed secondary structure of U14 snRNA is comprised of three major hairpin/helical regions which includes the helix of base-paired 5' and 3' termini. Strict and semiconservative covariation of specific base-pairs within two of the three major helices, as well as nucleotide changes that strengthen or extend base-paired regions, support this folded conformation as the evolutionary conserved secondary structure for U14 snRNA.

Animals↗