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PubMed2000

Pathological gambling.

With increasing access to gambling facilities through casinos, the Internet, and other venues, PG is a rapidly emerging mental health concern. This impulse-control disorder tends to be comorbid with a wide range of other disorders and is reportedly associated with a high rate of suicide. For most gamblers, gambling is a form of entertainment, but for many individuals, the activity leads to far-reaching disruption of family and work. The personal and societal financial ramifications are severe, and many individuals with PG end up in the criminal justice system. An understanding of the neurobiology of PG is beginning to surface. 5-HT is linked to behavioral initiation and disinhibition, which are important in the onset of the gambling cycle and the difficulty in ceasing the behavior. Norepinephrine is associated with the arousal and risk taking in patients with PG. Dopamine is linked to positive and negative reward, the addictive component of this disorder. Effective treatment strategies for pathological gamblers are emerging. Potentially useful pharmacologic agents include SRIs (clomipramine and fluvoxamine), mood stabilizers for pathological gamblers with comorbid bipolar disorders (lithium), and naltrexone. Cognitive-behavioral psychotherapies offer promising results in the treatment of patients with this disorder. To devise prevention and early-intervention programs, research is needed to identify specific features of the individuals at risk for gambling problems. Education targeting vulnerable youth that show early signs of gambling behavior may be worthwhile and should be investigated further. Funding is necessary to support these endeavors, so perhaps a portion of tax revenues generated from the gambling industry should go toward specialized treatment facilities, educational efforts, and research into the neurobiology and treatment of PG.

Cognitive Behavioral Therapy↗

PubMedDate not supplied

[Thermosensitivity of naphthalene biodegradation plasmids].

The object of the work was to study the functional expression of naphthalene and salicylic acid catabolism systems and the stability of naphthalene biodegradation plasmids NAH, pBS2, pBS3 and NPL-41 in Pseudomonas aeruginosa PAO. The catabolic systems of the plasmids were shown to be thermosensitive, with a slight variation between one another. The plasmids became unstable at a high temperature; the temperature of effective elimination was 41 degrees C for plasmids NPL-41 and pBS3, and 42 degrees C for plasmids NAH and pBS2. NAH and pBS2 produced a weak inhibiting effect while NPL-41 and pBS3 caused a strong inhibition of the PAO strain growth at 42 degrees C. As a result, many anomalous filamentous cells (partly in the state of lysis) appeared in the cultural broth. Only PAO cells that had lost their plasmid were capable of normal growth in a medium with MPA at an elevated temperature; this creates a convenient system for selection of clones that have lost the plasmids of naphthalene biodegradation. Some of these plasmids can inhibit growth of Pseudomonas strains at an elevated temperature; this fact should be taken into account when the capability of Pseudomonas to grow at a high temperature is used as a taxonomic feature.

Adaptation, Physiological↗

PubMed1993

Divergence pattern and selective mode in protein evolution: the example of vertebrate myoglobins and hemoglobin chains.

The evolutionary relation of vertebrate myoglobin and the hemoglobin chains including the agnathan hemoglobin chain is investigated on the basis of a new view of amino acid changes that is developed by canonical discriminant analysis of amino acid residues at individual sites. In contrast to the clear discrimination of amino acid residues between myoglobin, hemoglobin alpha chain, and hemoglobin beta chain in warm-blood vertebrates, the three types of globins in the lower class of vertebrates show so much variation that they are not well discriminated. This is seen particularly at the sites that are ascertained in mammals to carry the amino acid residues participating in stabilizing the monomeric structure in myoglobin and the residues forming the subunit contacts in hemoglobin. At these sites, agnathan hemoglobin chains are evaluated to be intermediate between the myoglobin and hemoglobin chains of gnathostomes. The variation in the phylogenetically lower class of globins is also seen in the internal region; there the amino acid residues of myoglobin and hemoglobin chains in the phylogenetically higher class exhibit an example of parallel evolution at the molecular level. New quantities, the distance of sequence property between discriminated groups and the variation within each group, are derived from the values of discriminant functions along the peptide chain, and this set of quantities simply describes an overall feature of globins such that the distinction between the three types of globins has been clearer as the vertebrates have evolved to become jawed, landed, and warm-blooded. This result strongly suggests that the functional constraint on the amino acid sequence of a protein is changed by living conditions and that severe conditions constitute a driving force that creates a distinctive protein from a less-constrained protein.

Amino Acid Sequence↗

PubMed1997

Conformational analysis of glutamic acid analogues as probes of glutamate receptors using molecular modelling and NMR methods. Comparison with specific agonists.

The activity of five glutamic acid analogues substituted in position 3 or 4 by a methyl (3T, 3E, 4T, and 4E) or a methylene group (4M) has been examined at one cloned Glu receptor subtype, mGluR1. These analogues interact with glutamate receptors of the central nervous system, especially the ligand 4T [(2S,4S)-4-methylglutamic acid] at the metabotropic glutamate receptor mGluR1. It was observed that only the 4T isomer is as potent an agonist as glutamic acid, whereas other isomers are less active. Furthermore, 4E [(2S,4R)-4-methylglutamic acid] exhibited an exceptional selectivity for the KA ionotropic receptor subtype while 4M [(2S)-4-methyleneglutamic acid] was active at the NMDA receptors. These molecules represent suitable tools among a population of similar glutamate analogues for a classical structure-function relationship study. We have undertaken a conformational analysis by 1H and 13C NMR spectroscopy and molecular modelling of these molecules. Hetero- and homonuclear coupling constants were measured in order to assign the diastereotopic methylene protons at C(3) or C(4), and used for comparison in molecular dynamics (MD) simulations. The hydrogen-bonding possibility, steric effects or electrostatic interactions may be a considerable influence in stabilizing a conformational population in D2O solution. The conformations may be grouped by the two backbone torsion angles, chi 1 [alpha-CO2(-)-C(2)-C(3)-C(4)] and chi 2 [+NC(2)-C(3)-C(4)-gamma CO2-] and by the two characteristic distances between the potentially active functional groups, alpha N(+)-gamma CO2- (d1) and alpha CO2(-)-gamma CO2- (d2). The conformational preferences in solution of 4T, 4E and (3T, 3E, 4M) are discussed in the light of the physical features known for a specific metabotropic agonist (ACPD) and specific ionotropic agonists (KA) and (NMDA), respectively.

Animals↗

PubMed2005

Novel CdCl2 and HgCl2 complexes with 3-monosubstituted and 3,3-disubstituted 1-furoylthioureas: IR and Raman spectra.

Two series of coordination complexes of CdCl(2) and HgCl(2) with 3-monosubstituted and 3,3-disubstituted 1-furoylthioureas were prepared and characterized. These complexes were obtained with a medium to high yield from ethanolic solutions of both ligand and salt. The formed complex results from the salt-ligand interaction with participation of both the salt anion and cation. Information on the coordination chemistry of these complexes was derived from thermal stability data, and IR, Raman and (13)C CPMAS NMR spectra. On coordination the electronic structure of these ligands changes as a whole, affecting practically all their vibrational pattern, however, within that complex pattern some vibrations provide valuable information on the nature of the studied complexes. These thiourea derivatives behave as neutral ligands, which coordinate the metal ion through the sulfur atom of the thiocarbonyl group. This fact is supported by the observed frequency shift, to lower values, in the nu(CS) vibration on the coordination and the appearance of a low frequency Raman line which was assigned to the metal-sulfur stretching, nu(M-S), in the formed complex. The frequency of the nu(CO) vibration always increases on complex formation, which discards the participation of the carbonyl group in the coordination process. The complexation takes place preserving the free ligand conformation, established from intra-molecular interactions, particularly in 3-monosubstituted ligands. Such features of the studied ligands and their complexes are also supported by (13)C CPMAS NMR spectra. This spectroscopic information correlates with the reported behavior of the ligands in ion selective electrodes.

Cadmium Chloride↗

PubMed2004

Application of locked nucleic acids to improve aptamer in vivo stability and targeting function.

Aptamers are powerful candidates for molecular imaging applications due to a number of attractive features, including rapid blood clearance and tumor penetration. We carried out structure-activity relationship (SAR) studies with the Tenascin-C binding aptamer TTA1, which is a promising candidate for application in tumor imaging with radioisotopes. The aim was to improve its in vivo stability and target binding. We investigated the effect of thermal stabilization of the presumed non-binding double-stranded stem region on binding affinity and resistance against nucleolytic degradation. To achieve maximal thermal stem stabilization melting experiments with model hexanucleotide duplexes consisting of unmodified RNA, 2'-O-methyl RNA (2'-OMe), 2'-Fluoro RNA (2'-F) or Locked Nucleic Acids (LNAs) were initially carried out. Extremely high melting temperatures have been found for an LNA/LNA duplex. TTA1 derivatives with LNA and 2'-OMe modifications within the non-binding stem have subsequently been synthesized. Especially, the LNA-modified TTA1 derivative exhibited significant stem stabilization and markedly improved plasma stability while maintaining its binding affinity to the target. In addition, higher tumor uptake and longer blood retention was found in tumor-bearing nude mice. Thus, our strategy to introduce LNA modifications after the selection procedure is likely to be generally applicable to improve the in vivo stability of aptamers without compromising their binding properties.

Animals↗

PubMed2026

Discovery and validation of a multi-protein panel for predicting non-fatal major adverse cardiovascular events in diabetic kidney disease.

OBJECTIVE: To identify plasma protein biomarkers associated with incident non-fatal major adverse cardiovascular events (MACE) in diabetic kidney disease (DKD) patients. RESEARCH DESIGN AND METHODS: We analyzed 317 DKD patients from the UK Biobank. Plasma proteomics and clinical data (demographics, metabolism, renal function) were integrated. In an exploratory discovery phase, three sequential Cox regression models (crude, socio-demographic-adjusted, socio-demographic-metabolic adjusted) screened non-fatal MACE-associated proteins. To prevent information leakage, the cohort was then randomly split into training (70%) and testing (30%) sets; machine-learning feature selection, hyperparameter optimization, and final model development were performed exclusively within the training set. The associated proteins were input into the four-step machine-learning pipeline (LASSO-Cox, random survival forest, Boruta, XGBoost-Cox). Predictive performance was validated using Kaplan-Meier survival analyses, longitudinal trajectory modeling, and ROC benchmarking. An interactive web application was deployed for clinical implementation. RESULTS: Of 1,463 plasma proteins, 561 were associated with non-fatal MACE across Cox models, with 14 overlapping proteins. Nine core proteins (ANG, IL1R1, CXCL14, ESAM, PTGDS, HAVCR1, FGFR2, IGSF8, CCL3) were validated: ANG showed the strongest non-fatal MACE association (HR = 3.88, 95%CI 2.33-6.48, p<0.001), and all high-expression groups had elevated non-fatal MACE risk. GO/KEGG enrichment highlighted inflammatory-immune pathways like positive regulation of MAPK cascade, Cytokine-cytokine receptor interaction and PI3K-Akt signaling pathway as key mechanisms. The model integrating proteins, demographic factors, and clinical variables achieved the highest predictive performance across non-fatal MACE (AUC = 0.768), myocardial infarction (MI) (0.808), and stroke (0.816) outcomes, with superior stability in cross-validation. CoxBoost + Elastic Net framework was selected as the optimal framework via benchmarking of 101 algorithms. The model demonstrated favorable calibration in high-risk patients and yielded positive net clinical benefit across decision thresholds of 5% to 45%. The web tool (https://jiangli2941.github.io/MACE-prediction-v2/) enables input of 28 variables, outputs non-fatal MACE risk status, risk probability, and highlights abnormal indicators. CONCLUSION: Plasma proteomics combined with machine learning identifies robust non-fatal MACE predictors in DKD.

Humans↗

PubMed1998

A strain-dependent ratchet model for [phosphate]- and [ATP]-dependent muscle contraction.

A minimal strain-dependent ratchet model of muscle cross-bridge action is proposed which is broadly compatible with structural and kinetic constraints. Its essential features are: (1) dynamic binding of the S1-products complex to actin through a disorder-order transition coupled to the release of inorganic phosphate; (2) the absence of a force-generating rotation of the myosin head between the two force-holding states A.M.ADP and A.M; (3) strain-control of ADP release and ATP binding, giving net isometric tension and directed motility by the selective dissociation of negatively strained bound states. With a disordered pre-force state, the binding rate to state A.M.ADP need not be symmetric in x, the actin site displacement. With faster binding at positive x, the model predicts many steady-state and transient properties of striated muscle observed experimentally, including phases 2-4 of tension recovery from length changes and their dependence on excess phosphate (which enhances and accelerates phase 3) and reduced ATP (which gives a bimodal phase 2 and slows one mode). The response to large perturbations is often sensitive to the number of actin sites used, and to the inclusion of a 1 nm displacement of the neck region on release of ADP. The latter stabilizes the periodic tension behaviour produced by repeated releases.

Adenosine Triphosphate↗

PubMedDate not supplied

Analysis of the pH-dependencies of the association and dissociation kinetics of HIV-1 protease inhibitors.

The kinetic constants for the interactions between HIV-1 protease and a selection of inhibitors were determined at different pH-values using a biosensor based interaction assay. Since this technique does not involve a substrate, it was possible to determine the pH-dependencies of the association and dissociation rates of an inhibitor, without the complication of a pH-dependent enzyme-substrate/product equilibrium. The importance of these interactions was evaluated by correlating the free energy changes upon association and dissociation of inhibitors with the predicted change in electrostatic properties of the interacting groups as a result of altered pH. It was found that the kinetic parameters varied with pH in a unique manner for all inhibitors, demonstrating that the kinetic features were associated with the specific structure of each inhibitor. Association and dissociation had different pH-profiles, indicating that the two processes proceeded by different pathways/mechanisms. The energy barrier for dissociation of the enzyme-indinavir complex increased with pH from 4.1 to 7.4, while it was generally reduced for the other inhibitors as the pH was increased from 5.1 to 7.4. The pH-dependent interactions involved in the recognition/binding of inhibitors and in the stabilization of the complex were identified by analysing three-dimensional structures of enzyme-inhibitor complexes. The interaction between the pyridine nitrogen of indinavir with Arg-8 was hypothesized to be responsible for the unique pH-dependency of indinavir. The analysis revealed features of interactions that are significant for understanding enzyme function and for optimization of new drug leads. It also highlighted the importance of environmental conditions on interactions.

HIV Protease↗

PubMed2000

Gene-expression profile of the ageing brain in mice.

Ageing of the brain leads to impairments in cognitive and motor skills, and is the major risk factor for several common neurological disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Recent studies suggest that normal brain ageing is associated with subtle morphological and functional alterations in specific neuronal circuits, as opposed to large-scale neuronal loss. In fact, ageing of the central nervous system in diverse mammalian species shares many features, such as atrophy of pyramidal neurons, synaptic atrophy, decrease of striatal dopamine receptors, accumulation of fluorescent pigments, cytoskeletal abnormalities, and reactive astrocytes and microglia. To provide the first global analysis of brain ageing at the molecular level, we used oligonucleotide arrays representing 6,347 genes to determine the gene-expression profile of the ageing neocortex and cerebellum in mice. Ageing resulted in a gene-expression profile indicative of an inflammatory response, oxidative stress and reduced neurotrophic support in both brain regions. At the transcriptional level, brain ageing in mice displays parallels with human neurodegenerative disorders. Caloric restriction, which retards the ageing process in mammals, selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses.

Aging↗

PubMedDate not supplied

Prognostic factors in metastatic breast cancer patients obtaining objective response or disease stabilization after first-line chemotherapy with epirubicin. Evidence for a positive effect of maintenance hormonal therapy on overall survival.

Randomized trials suggest that the outcome of metastatic breast cancer (BC) patients is not affected by the currently available therapies. Although response rates per se may be associated with survival prolongation, patients experiencing objective response may be those patients fated to have the longest natural disease history. The separation of responders from progressing patients after first-line chemotherapy could allow the selection of a more homogeneous subgroup in which further treatment strategies might achieve a better control of the disease. This study investigated the influence of some patient characteristics, disease characteristics, and previous treatments on the outcome of non progressing patients after first-line chemotherapy with epirubicin administration. We also evaluated the effect of the maintenance endocrine therapy in improving response rate and overall survival (OS). From May 91 to May 93, 207 patients were enrolled in a randomized trial aiming to compare the activity of epirubicin (120 mg/sqm) +/- lonidamine (600 mg/daily). Among the 169 patients attaining complete (CR), partial response (PR) or disease stabilization (SD), 65 were not randomly submitted to maintenance endocrine therapy (MET). Liver involvement, previous adjuvant chemotherapy and previous hormonal therapy (administered in adjuvant setting or for advanced disease) were found to negatively influence OS both in univariate and multivariate analysis. Differences in OS stratifying patients according to DFI, estrogen receptor status and PS did not attain statistical significance. Patients receiving MET survived significantly longer than those submitted to observation and this difference maintained the statistical significance also within patient subsets homogeneous for specific prognostic features. In conclusion, most prognostic factors for advanced BC have been confirmed in our series of patients obtaining CR, PR or SD to full dose epirubicin. The positive prognostic impact of MET is impressive and deserves confirmation in randomized studies.

Adult↗

PubMed2006

Enrichment of carbonylated peptides using Girard P reagent and strong cation exchange chromatography.

It has been shown that oxidatively modified forms of proteins accumulate during oxidative stress, aging, and in some age-related diseases. One of the unique features of protein oxidation by a wide variety of routes is the generation of carbonyl groups. Of major interest in the study of oxidative stress diseases is which proteins in a proteome are being oxidized and the site(s) of oxidation. Based on the fact that proteins are generally characterized through tryptic peptide fragments, this paper reports a method for the isolation of oxidized peptides, which involves (1) derivatization of oxidized proteins with Girard P reagent (GRP; 1-(2-hydrazino-2-oxoethyl)pyridinium chloride), (2) following proteolysis enrichment of the derivatized peptide using strong cation exchange (SCX) chromatography, and (3) identification of oxidation sites using tandem mass spectrometry. Derivatization of aldehydes and ketones in oxidized proteins was accomplished by reacting protein carbonyls with the hydrazide of GRP. The resulting hydrazone bond was reduced by sodium cyanoborohydride to further stabilize the labeling. Derivatization time and concentrations of the derivatizing agent were optimized with model peptides. Oxidized transferrin was used as model protein to study derivatization efficiency at the protein level. Following metal-catalyzed oxidation of transferrin, the protein was derivatized with GRP and trypsin digested. Positively charged peptides were then selected from the digest with SCX chromatography at pH 6.0. Seven GRP-derivatized peptides were found to be selected from transferrin by MALDI-TOF-TOF analysis. Fourteen underivatized native peptides were also captured by the SCX column at pH 6.0. Mapping of the derivatized peptides onto the primary structure of transferrin indicated that the oxidation sites were all on solvent-accessible regions at the protein surface. Efficiency of the method was further demonstrated in the identification of oxidized proteins from yeast.

Binding Sites↗

PubMed2002

A conserved cis peptide bond is necessary for the activity of Bowman-Birk inhibitor protein.

The Bowman-Birk inhibitor (BBI) family of protease inhibitors has an inhibitory region comprising a disulfide-linked nine-residue loop that adopts the characteristic canonical motif found in many serine protease inhibitors. A unique feature of the BBI loop is the presence of a cis peptide bond at the edge of the inhibitory loop. BBI-related protein fragments that encapsulate this loop retain the structure and inhibitory activity of the parent protein. The most common BBI loop sequence has a proline-proline element with a cis-trans geometry at P3'-P4'. We have examined this element by analysis of the inhibitory activity and structure for a series of synthetic fragments where each of these proline residues has been systematically replaced with alanine. The results show that only when a proline is present at P3' are potent inhibition and a cis peptide bond at that position in the solution structure observed, suggesting that this conformation is required for biological activity. Though a P4' proline is not essential for activity, it effectively stabilizes the cis conformation at P3' by suppressing alternative conformations. This is most evident from the Pro-Ala variant, which comprises a 1:1 mixture of slowly exchanging and structurally different cis and trans isomers. Monitoring the action of trypsin on this mixture by NMR shows that this protease interacts selectively with the cis P3' structure, providing direct evidence for the link between activity and the nativelike structure of the cis isomer. This is, to the best of our knowledge, the first example where cis isomer selectivity can be demonstrated for a proteinase.

Alanine↗

PubMedDate not supplied

The simulation approach to bacterial outer membrane proteins.

The outer membrane of Gram-negative bacteria serves as a protective barrier against the external environment but is rendered selectively permeable to nutrients and waste by proteins called porins. Other outer membrane proteins (OMPs) provide the membrane with a variety of other functions including active transport, catalysis, pathogenesis and signal transduction. A relatively small number of crystal or NMR structures of these proteins are known, and it is therefore essential that the maximum possible information be extracted. In this respect, computational techniques enable extrapolation from time- and space-averaged static structures to dynamic, physiological events. Electrostatics approaches have been used to investigate the structures of porins. The stochastic simulation of ion trajectories through these channels has been possible with Brownian dynamics, which treats the membrane and solvent approximately, enabling the prediction of conduction properties. Molecular dynamics has also been applied, enabling fully atomistic descriptions of 'virtual outer membranes'. This has provided atomic resolution descriptions of solute permeation through porins. It has also yielded insights into the dynamics of gating in active transporters and ion channels, as well as providing clues to catalytic mechanisms in outer membrane enzymes. Additionally, simulations are beginning to reveal the common features of interactions between membrane proteins and lipids, with biological implications for OMP folding, stability and mechanism. Future prospects include the simulation of longer, larger and more complex outer membrane systems, with more accurate descriptions of inter-atomic forces.

Bacterial Outer Membrane Proteins↗

PubMed1986

Arrhythmia control by selective lengthening of cardiac repolarization: role of N-acetylprocainamide, active metabolite of procainamide.

In recent years, data has become available to support the concept that a selective lengthening of the cardiac action potential (a Class III antiarrhythmic action) by whatever mechanism with an attendant increase in the effective refractory period constitutes a distinct antiarrhythmic mechanism. Such an action is exemplified clinically by hypocalemia and hypothyroidism and pharmacologically by amiodarone, sotalol and bretylium, all of which have other associated features. The N-acetylation of procainamide leads to the pharmacologically active compound, N-acetylprocainamide (NAPA). The loss of propensity to block depolarization with the preservation of the effect on repolarization in the case of NAPA makes the compound a class III antiarrhythmic agent. The process of N-acetylation has also led to longer elimination half-life and predominantly renal excretion with linear kinetics but with the preservation of the antiarrhythmic properties of the parent compound. The electrophysiologic data are consistent with the results of studies which have demonstrated that NAPA has the potential to suppress premature ventricular contractions and prevent spontaneously occurring as well inducible ventricular tachycardia in patients with heart disease. The effects on atria indicate that the drug has the potential to electively reverse atrial flutter and fibrillation to normal rhythm and maintain stability of sinus rhythm. The overall experimental and clinical data warrant further evaluation of NAPA as an antiarrhythmic agent.

Acecainide↗

PubMed1996

The vowel-sequence illusion: intrasubject stability and intersubject agreement of syllabic forms.

Earlier studies have found that listeners presented with a loud and clear repeating sequence of brief steady-state vowels typically report hearing two voices with distinctly different timbres repeating different syllables that either are English words or occur in English words. One of the simultaneous voices is generally based upon frequencies below, and the other above, the "crossover frequency" at approximately 1500 Hz that divides normal speech into regions contributing equally to intelligibility. It has been hypothesized that the lack of linguistic content halts the processing of vowel sequences at the syllabic level, and that the spectral splitting corresponding to the concurrent voices reflects a mechanism for independent processing of different frequency regions that can lead to increased intelligibility under difficult listening conditions. The present study employed twelve randomly selected arrangements of the same six 70-ms vowels, and it was determined that: (1) individuals reported the same perceptual organizations the following week; (2) insertion of a brief silent gap between restatements of a sequence resulted in reports of similar (and occasionally identical) syllables by different listeners hearing the same sequence; and (3) when two listeners' responses differed, they could nevertheless identify the particular vowel sequences corresponding to each other's verbal forms. Spectrograms of vowel sequences were compared with time-aligned spectrograms of a speaker's synchronous production of the forms as they were being heard, and some common features of the acoustic patterns were noted. It is suggested that vowel sequences provide a reliable and useful tool for probing aspects of the perceptual organization of speech sounds that are normally obscured by additional linguistic processing.

Humans↗

PubMed2005

Human pol II promoter prediction: time series descriptors and machine learning.

Although several in silico promoter prediction methods have been developed to date, they are still limited in predictive performance. The limitations are due to the challenge of selecting appropriate features of promoters that distinguish them from non-promoters and the generalization or predictive ability of the machine-learning algorithms. In this paper we attempt to define a novel approach by using unique descriptors and machine-learning methods for the recognition of eukaryotic polymerase II promoters. In this study, non-linear time series descriptors along with non-linear machine-learning algorithms, such as support vector machine (SVM), are used to discriminate between promoter and non-promoter regions. The basic idea here is to use descriptors that do not depend on the primary DNA sequence and provide a clear distinction between promoter and non-promoter regions. The classification model built on a set of 1000 promoter and 1500 non-promoter sequences, showed a 10-fold cross-validation accuracy of 87% and an independent test set had an accuracy >85% in both promoter and non-promoter identification. This approach correctly identified all 20 experimentally verified promoters of human chromosome 22. The high sensitivity and selectivity indicates that n-mer frequencies along with non-linear time series descriptors, such as Lyapunov component stability and Tsallis entropy, and supervised machine-learning methods, such as SVMs, can be useful in the identification of pol II promoters.

Algorithms↗

PubMed2005

Annual report to the nation on the status of cancer, 1975-2002, featuring population-based trends in cancer treatment.

BACKGROUND: The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide information on cancer rates and trends in the United States. This year's report updates statistics on the 15 most common cancers in the five major racial/ethnic populations in the United States for 1992-2002 and features population-based trends in cancer treatment. METHODS: The NCI, the CDC, and the NAACCR provided information on cancer cases, and the CDC provided information on cancer deaths. Reported incidence and death rates were age-adjusted to the 2000 U.S. standard population, annual percent change in rates for fixed intervals was estimated by linear regression, and annual percent change in trends was estimated with joinpoint regression analysis. Population-based treatment data were derived from the Surveillance, Epidemiology, and End Results (SEER) Program registries, SEER-Medicare linked databases, and NCI Patterns of Care/Quality of Care studies. RESULTS: Among men, the incidence rates for all cancer sites combined were stable from 1995 through 2002. Among women, the incidence rates increased by 0.3% annually from 1987 through 2002. Death rates in men and women combined decreased by 1.1% annually from 1993 through 2002 for all cancer sites combined and also for many of the 15 most common cancers. Among women, lung cancer death rates increased from 1995 through 2002, but lung cancer incidence rates stabilized from 1998 through 2002. Although results of cancer treatment studies suggest that much of contemporary cancer treatment for selected cancers is consistent with evidence-based guidelines, they also point to geographic, racial, economic, and age-related disparities in cancer treatment. CONCLUSIONS: Cancer death rates for all cancer sites combined and for many common cancers have declined at the same time as the dissemination of guideline-based treatment into the community has increased, although this progress is not shared equally across all racial and ethnic populations. Data from population-based cancer registries, supplemented by linkage with administrative databases, are an important resource for monitoring the quality of cancer treatment. Use of this cancer surveillance system, along with new developments in medical informatics and electronic medical records, may facilitate monitoring of the translation of basic science and clinical advances to cancer prevention, detection, and uniformly high quality of care in all areas and populations of the United States.

Age Distribution↗