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PubMed1997

Prediction of complete gene structures in human genomic DNA.

We introduce a general probabilistic model of the gene structure of human genomic sequences which incorporates descriptions of the basic transcriptional, translational and splicing signals, as well as length distributions and compositional features of exons, introns and intergenic regions. Distinct sets of model parameters are derived to account for the many substantial differences in gene density and structure observed in distinct C + G compositional regions of the human genome. In addition, new models of the donor and acceptor splice signals are described which capture potentially important dependencies between signal positions. The model is applied to the problem of gene identification in a computer program, GENSCAN, which identifies complete exon/intron structures of genes in genomic DNA. Novel features of the program include the capacity to predict multiple genes in a sequence, to deal with partial as well as complete genes, and to predict consistent sets of genes occurring on either or both DNA strands. GENSCAN is shown to have substantially higher accuracy than existing methods when tested on standardized sets of human and vertebrate genes, with 75 to 80% of exons identified exactly. The program is also capable of indicating fairly accurately the reliability of each predicted exon. Consistently high levels of accuracy are observed for sequences of differing C + G content and for distinct groups of vertebrates.

Animals↗
PubMed2026

Genetic Associations with Temporal Modeling of Alzheimer's Disease Progression Supports a Novel Paradigm for Disease Risk.

A major challenge in Alzheimer's disease (AD) research is predicting who will develop AD, how it progresses, and how to slow, prevent, or reverse progression. Here, we apply a data-driven timeline inference framework to sparse longitudinal blood metabolomics data to reconstruct AD timelines and derive individual-specific timeline progression rates. Inferred temporal locations for each metabolomics sample along the AD timeline closely track clinical severity, while timeline progression rates capture inter-individual differences in the speed of pathophysiological progression. Genome-wide association studies of timeline progression rate identify novel loci distinct from those in AD case-control studies, notably showing no effect of the major risk locus APOE. These findings support a multidimensional paradigm of AD risk in which disease potential and progression act as partially independent factors. By explicitly modeling disease dynamics, this work reveals genetic contributions not captured by traditional approaches and provides a framework for studying AD and other progressive disorders.

Journal Article↗
PubMed1992

Identification of a novel annexin in Hydra vulgaris. Characterization, cDNA cloning, and protein kinase C phosphorylation of annexin XII.

As a first step toward the elucidation of a simple animal model in which to investigate annexin function, we identified, isolated, and characterized a novel annexin from Hydra vulgaris, annexin XII. A hydra cDNA library was screened using a probe generated by polymerase chain reaction from primers based on the partial amino acid sequence of annexin XII. Annexin XII cDNA was cloned and the functional protein was expressed in high yields in Escherichia coli. The annexin XII cDNA sequence predicted a 316-amino acid protein that had between 44 and 54% sequence identity with the Ca2+-binding core domains of previously characterized vertebrate and Drosophila annexins. The amino-terminal domain of annexin XII did not have sequence similarity with other known annexins except at and around a site that resembled known protein kinase C (PKC) phosphorylation sites in other annexins. As anticipated from its sequence, annexin XII was a high affinity substrate for purified rat brain PKC; half-maximal phosphorylation occurred below 0.1 microM annexin XII, and incorporation of up to 0.8 mol of phosphate/mol of annexin XII was observed. A PKC-like activity in hydra extracts also phosphorylated annexin XII. In summary, hydra promises to be a valuable model system for investigating the biological function of annexins and for determining how this function is modulated by PKC phosphorylation.

Amino Acid Sequence↗
PubMed1997

Mechanisms of action of gabapentin.

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.

Acetates↗
PubMed2002

[Statistical analysis of maxillary sinus squamous cell carcinoma].

Cases of squamous cell carcinoma of the maxillary sinus initially treated at Keio University Hospital between January 1981 and December 1998 studied retrospectively involved 60 untreated cases--46 men and 14 women aged 36 to 86 years (mean: 59.8 years). Of these, 7 had T2, 41 T3 and 12 T4 tumors based on 1997 AJCC TNM classification. Seven (11.7%) had nodal involvement but none had distant metastasis at diagnosis. Of the 60, 53 (88.3%) were stage III or IV. Prognostic factors and survival were statistically analyzed for 59 cases, excluding the 60th who died of another cause. Follow-up was 4 to 227 months, with a median of 59 months and a mean of 38 months. Of the 59, 48 (81.4%) underwent neoadjuvant chemotherapy (NAC). Survival was estimated using the Kaplan-Meier method as univariate analysis. Cause-specific 5-year survival was 56.8% for all stages, 68.2% for T2, 60.0% for T3, and 41.7% for T4. T stage classification was thus a significant independent prognostic factor in multivariate analysis using Cox's proportional hazards model (p = 0.0240). It also identified T stage classification (p = 0.0486) and NAC (p = 0.0419) as significant independent factors affecting survival with organ preservation. We also statistically analyzed 48 cases treated with NAC, which showed complete response (CR) for 11, partial response (PR) for 25, no change (NC) for 11, and progressive disease (PD) for 1. Responders (CR + PR) showed significantly better survival and organ preservation than nonresponders (NC + PD). The NAC response enables us to predict prognosis. T4 cases without NAC response should be treated intensively.

Adult↗
PubMed1997

A surface on the G protein beta-subunit involved in interactions with adenylyl cyclases.

Receptor activation of heterotrimeric G proteins dissociates G alpha from the G betagamma complex, allowing both to regulate effectors. Little is known about the effector-interaction regions of G betagamma. We had used molecular modeling to dock a peptide encoding the region of residues 956-982 of adenylyl cyclase (AC) 2 onto Gbeta to identify residues on Gbeta that may interact with effectors. Based on predictions from the model, we synthesized peptides encoding sequences of residues 86-105 (Gbeta 86-105) and 115-135 (Gbeta 115-135) from Gbeta. The Gbeta 86-105 peptide inhibited G betagamma stimulation of AC2 and blocked G betagamma inhibition of AC1 and by itself inhibited calmodulin-stimulated AC1, thus displaying partial agonist activity. Substitution of Met-101 with Asn in this peptide resulted in the loss of both the inhibitory and partial agonist activities. Most activities of the Gbeta 115-135 peptide were similar to those of Gbeta 86-105 but Gbeta 115-135 was less efficacious in blocking G betagamma inhibition of AC1. Substitution of Tyr-124 with Val in the Gbeta 115-135 peptide diminished all of its activities. These results identify the region encoded by amino acids 84-143 of Gbeta as a surface that is involved in transmitting signals to effectors.

Adenylyl Cyclases↗
PubMed2000

Analysis of the roles of kinesin and dynein motors in microtubule-based transport in the Caenorhabditis elegans nervous system.

The heteromeric kinesins constitute a subfamily of kinesin-related motor complexes that function in several distinct intracellular transport events. The founding member of this subfamily, heterotrimeric kinesin II, has been purified and characterized from early sea urchin embryos, where it was shown using antibody perturbation to be required for the synthesis of motile cilia, presumably by driving the anterograde transport of raft complexes. To further characterize heteromeric kinesin transport pathways, and to attempt to identify cargo molecules, we are using the model organism Caenorhabditis elegans to exploit its well-characterized nervous system and simple genetics. Here we describe methods for large-scale nematode growth and partial purification of kinesin-related holoenzymes from C. elegans, and an in vivo transport assay that allows the direct labeling and visualization of motor complexes and putative cargo molecules moving in living C. elegans neurons. This transport assay is being used to characterize the in vivo transport properties of motor enzymes in living cells, and to exploit a number of existing mutations in C. elegans that may represent constituents of heteromeric kinesin-driven transport pathways, for example, the retrograde intraflagellar transport motor CHE-3 dynein, as well as cargo molecules and/or regulatory molecules.

Animals↗
PubMed2006

Denaturation of an extremely stable hyperthermophilic protein occurs via a dimeric intermediate.

To elucidate determinants of thermostability and folding pathways of the intrinsically stable proteins from extremophilic organisms, we are studying beta-glucosidase from Pyrococcus furiosus. Using fluorescence and circular dichroism spectroscopy, we have characterized the thermostability of beta-glucosidase at 90 degrees C, the lowest temperature where full unfolding is achieved with urea. The chemical denaturation profile reveals that this homotetrameric protein unfolds at 90 degrees C with an overall DeltaG degrees of approximately 20 kcal mol(-1). The high temperatures needed to chemically denature P. furiosus beta-glucosidase and the large DeltaG degrees of unfolding at high temperatures shows this to be one of the most stable proteins yet characterized. Unfolding proceeds via a three-state pathway that includes a stable intermediate species. Stability of the native and intermediate forms is concentration dependent, and we have identified a dimeric assembly intermediate using high temperature native gel electrophoresis. Based on this data, we have developed a model for the denaturation of beta-glucosidase in which the tetramer dissociates to partially folded dimers, followed by the coupled dissociation and denaturation of the dimers to unfolded monomers. The extremely high stability is thus derived from a combination of oligomeric interactions and subunit folding.

Archaeal Proteins↗
PubMed1996

The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization.

OBJECTIVE: Our purpose was to determine the risk of pregnancy after tubal sterilization for common methods of tubal occlusion. STUDY DESIGN: A multicenter, prospective cohort study was conducted in U.S. medical centers. A total of 10,685 women who underwent tubal sterilization was followed up for 8 to 14 years. The risk of pregnancy was assessed by cumulative life-table probabilities and proportional hazards models. RESULTS: A total of 143 sterilization failures was identified. Cumulative 10-year probabilities of pregnancy were highest after clip sterilization (36.5/1000 procedures) and lowest after unipolar coagulation (7.5/1000) and postpartum partial salpingectomy (7.5/1000). The cumulative risk of pregnancy was highest among women sterilized at a young age with bipolar coagulation (54.3/1000) and clip application (52.1/1000). CONCLUSIONS: Although tubal sterilization is highly effective, the risk of sterilization failure is higher than generally reported. The risk persists for years after the procedure and varies by method of tubal occlusion and age.

Age Factors↗
PubMed1983

Structure of partially denatured Escherichia coli 23 S ribosomal RNA determined by electron microscopy.

The secondary structure of 23 S ribosomal RNA was analyzed by electron microscopy after partial denaturation. A reproducible pattern of loops was seen when molecules were spread for electron microscopy in 50% formamide solutions containing various concentrations of Mg2+ and Na+. Some loops were stabilized more than others by Na+ or by Mg2+; but in general, small amounts of Mg2+ (0.5 to 1.0 mM) markedly stabilized all the major loops, as did much greater amounts of Na+ (100 mM). However, at all levels of Mg2+ examined, increasing levels of Na+ destabilized loop structures. These data are consistent with the known salt dependence of double-stranded DNA and transfer RNA structure. The four most frequently observed loops correspond, within the limits of measurement error, to the major loops in the secondary structure models of Noller et al. (1981) and Glotz et al. (1981). These four loops are, in length and position of their midpoints along the 23 S rRNA molecule: 490 +/- 50 at 250 +/- 40; 350 +/- 50 at 1860 +/- 80; 400 +/- 70 at 2330 +/- 150; and 570 +/- 100 at 2350 +/- 100. Three of the four have base-paired stems with delta G0 values among the lowest of all the loops in the two indirect models. At least two are also among the most stable loops found in computer searches of the 23 S rRNA sequence for dyad symmetry. These results demonstrate that partial denaturation mapping can both identify prominent features of secondary structure in rRNA and estimate their relative stability.

Escherichia coli↗
PubMed1995

Methylation of minimalist 23S rRNA sequences in vitro by ErmSF (TlrA) N-methyltransferase.

ermSF (synonym tlrA) from Streptomyces fradiae NRRL 2702 confers resistance to the macrolide-lincosamide- streptogramin type B (MLS) superfamily of antibiotics. ErmSF specifically methylates Bacillus subtilis 23S rRNA in vitro at A2085 (B. subtilis coordinate, which is equivalent to the Escherichia coli coordinate A2058). In the present studies, partial B. subtilis 23S rRNA sequences containing portions of the peptidyltransferase circle which include A2085 were constructed in order to identify structural requirements needed for RNA to function as substrate of ErmSF. A model methylase substrate based on the 41-nucleotide construct DK111, ggCCUAUCCGUCGCGGGUUCGCCCGCGACAGGACGGA*AAGA, had methyl-acceptor activity. This sequence contains 23S rRNA stem 73 [Stade, K., et al. (1994) Nucleic Acids Res. 22, 1394-1399] underlined, flanking a tetraloop-like (UUCG), and the impaired sequence AAAGA, at the 3' end containing A2085 (A*). A set of systematic alterations introduced into the sequence suggested that the four unpaired nucleotides in stem 73 are necessary for methyl-acceptor activity, whereas inversion of 11 out 13 paired bases in stem 73 conferred no significant reduction in methyl-acceptor activity.

Base Sequence↗
PubMed2003

Modeling hippocampal and neocortical contributions to recognition memory: a complementary-learning-systems approach.

The authors present a computational neural-network model of how the hippocampus and medial temporal lobe cortex (MTLC) contribute to recognition memory. The hippocampal component contributes by recalling studied details. The MTLC component cannot support recall, but one can extract a scalar familiarity signal from MTLC that tracks how well a test item matches studied items. The authors present simulations that establish key differences in the operating characteristics of the hippocampal-recall and MTLC-familiarity signals and identify several manipulations (e.g., target-lure similarity, interference) that differentially affect the 2 signals. They also use the model to address the stochastic relationship between recall and familiarity and the effects of partial versus complete hippocampal lesions on recognition.

Cerebral Cortex↗
PubMed2002

[Institutionalisation-index--a simple method to estimate direct treatment costs for institutionalised forms of community mental health care].

AIM: Investigations of treatment costs are of increasing importance in community mental health care. Yet, they are often difficult and expensive to conduct. This study explores whether and, if so, to what extent direct treatment costs as paid by insurance companies and social welfare in the German health care system can be estimated through a simple Institutionalisation-Index. METHOD: Based on the literature and clinical judgment, a simple Institutionalisation-Index was formed reflecting the degree of institutional protection in supported housing, long-term day care, partial hospitalisation and full hospitalisation programmes. As part of a comprehensive evaluation of a model institution for community mental health care in Berlin, actually paid treatment costs and Institutionalisation-Index (II) were identified for 1194 patients over a total period of 23 years and compared with each other. RESULTS: The Pearson correlation coefficient between II and paid costs was 0.97 (p < 0,001). In calculations for subgroups and different periods of time, II and costs were almost identical, too. CONCLUSIONS: The Institutionalisation-Index provides a sufficiently precise estimate of direct costs as paid by insurance companies and social welfare for different forms of care in community based institutions and hospitals. The II can be adjusted to incorporate further forms of community based care. In systems with similar funding arrangements, the simple method to establish a Institutionalisation-Index should facilitate cost analyses in community mental health care.

Berlin↗
PubMed1999

Differences in psychosocial experiences of employed, unemployed, and student samples of young adults.

The author conducted this cross-sectional study to assess the extent to which employed, unemployed, and student samples of young adults could be differentiated on the basis of psychosocial experiences. Forty-four employed, 41 unemployed, and 42 student volunteers completed measures of emotional distress, time structure, financial strain, skill use, task variety, social support, and demographic information. After the effects of educational and income differences were statistically controlled, results indicated that unemployed participants reported poorer functioning than employed and student respondents on most measures. In a discriminant function analysis, 66% of the sample was correctly identified from scores on psychosocial measures, with higher classification rates for employed and unemployed participants. The findings provide additional support for contextual models of mental health and suggest that full-time education partially buffers the negative psychological consequences of unemployment when opportunities for employment are absent.

Adaptation, Psychological↗
PubMed1995

Classification of contaminants by mode of action based on in vitro assays.

A concept for toxicity assessments based on in vitro assays of variant levels (i.e., from whole cells to isolated enzymes) is presented. Due to the complexity of organisms of different species, it is evident that no single in vitro test can represent the entire spectrum of toxic potency of chemicals, rather a carefully designed battery of tests has to be employed to account for the various targets attacked in organisms yielding the different modes of action. Cytotoxicity tests like the Neutral-Red Assay predominantly reflect non-specific toxicity, which can be modelled according to a log Pow dependent baseline QSAR. Specific toxicants (e.g., decouplers, acetylcholinesterase inhibitors or photosystem II inhibitors) may be identified based on according in vitro tests and eventually modelled by the respective mode of action related QSARs employing also, e.g., steric or polarizability descriptors to account for specific interactions. The complementation and partial replacement of in vivo (eco)toxicological testing by in vitro assays depends on two criteria: (a) the sensitivity of the tests to reliably detect environmentally relevant concentrations of toxicants and (b) the specificity of the assays to provide an unambiguous classification of toxicants by modes of action: the pattern of interaction with the various targets allows to recognize those compounds of specific effects that frequently occur as outliers in QSAR analyses.

Acetylcholine↗
PubMed1995

Influence of blood pressure on left atrial size. The Framingham Heart Study.

Increased left atrial size has been identified as a precursor of atrial fibrillation and of stroke once atrial fibrillation is manifest. Conflicting data exist regarding the effect of high blood pressure on left atrial size. Our objective was to evaluate the association of contemporary and long-term measures of blood pressure with echocardiographically determined left atrial size in a large, population-based cohort. The study sample consisted of 1849 male and 2152 female participants of the Framingham Heart Study and Framingham Offspring Study. All analyses were sex specific. In correlation analyses, systolic and pulse pressures were identified as statistically significant determinants of left atrial size after adjustment for age and body mass index, although the magnitudes of these relations were very modest (partial r < or = .10). Multivariable linear regression models showed the relative contributions of the pressure variables to the prediction of left atrial size to be substantially less than those of age and, in particular, body mass index. Furthermore, inclusion of left ventricular mass in these multivariable models eliminated or attenuated the associations of the pressure variables with left atrial size. In logistic analyses, increasing levels of the pressure variables were significantly predictive of left atrial enlargement. Subjects with 8-year average systolic pressure of 140 mm Hg or higher were twice as likely to have left atrial enlargement as those with values of 110 mm Hg or lower. Overall, in this population-based study sample, increased levels of systolic and pulse pressures (but not diastolic or mean arterial pressures) were significantly associated with increased left atrial size.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

The relationship between gas delivery patterns and the lower inflection point of the pressure-volume curve during partial liquid ventilation.

STUDY QUESTION: To determine whether a positive end-expiratory pressure (PEEP) level equivalent to the lower inflection point (LIP) could be identified by evaluation of the airway pressure, flow (f1. gif" BORDER="0">), and volume vs time waveforms during partial liquid ventilation (PLV). DESIGN: Prospective application of PEEP during PLV in a healthy animal model. SETTING: University hospital animal laboratory. PARTICIPANTS: Five healthy sheep weighing 30 kg each. INTERVENTIONS: The sequential application of 0 to 20 cm H(2)O PEEP in 2.5-cm H(2)O steps during PLV with both pressure and volume ventilation. MEASUREMENTS: Analysis of the pressure, volume, and f1. gif" BORDER="0"> waveforms as PEEP is sequentially increased. RESULTS: At 0 cm H(2)O PEEP, VT was markedly reduced compared with PEEP VT at > or = 7.5 cm H(2)O (p < 0.05) in pressure control ventilation (PCV), and peak inspiratory pressure minus PEEP was markedly increased compared with PEEP at > or = 5.0 cm H(2)O (p < 0.05) in volume control ventilation. At 10 cm H(2)O PEEP, all waveforms began to stabilize, and no significant differences in any variable assessed were measured at > 12.5 cm H(2)O PEEP. CONCLUSIONS: The application of PEEP during PLV markedly alters airway waveforms. Low PEEP decreases VT in PCV and increases airway pressure in VCV. The PEEP level equal to the LIP during PLV can be grossly estimated from airway waveforms. PEEP at > or = 10 cm H(2)O is needed to normalize gas delivery to functional residual capacity in the uninjured lung that is partially filled with perfluorocarbon.

Air Pressure↗