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PubMed1998

CEP-1347/KT7515 prevents motor neuronal programmed cell death and injury-induced dedifferentiation in vivo.

CEP-1347, also known as KT7515, a derivative of a natural product indolocarbazole, inhibited motor neuronal death in vitro, inhibited activation of the stress-activated kinase JNK1 (c-jun NH terminal kinase) in cultured spinal motor neurons, but had no effect on the mitogen-activated protein kinase ERK1 in these cells. Results reported here profile the functional activity of CEP-1347/KT7515 in vivo in models of motor neuronal death or dedifferentiation. Application of CEP-1347/KT7515 to the chorioallantoic membrane of embryonic chicks rescued 40% of the lumbar motor neurons that normally die during the developmental period assessed. Peripheral administration of low doses (0.5 and 1 mg/kg daily) of CEP-1347/KT7515 reduced death of motor neurons of the spinal nucleus of the bulbocavernosus in postnatal female rats, with efficacy comparable to testosterone. Strikingly, daily administration of CEP-1347/KT7515 during the 4-day postnatal window of motor neuronal death resulted in persistent long-term motor neuronal survival in adult animals that received no additional CEP-1347/KT7515. In a model of adult motor neuronal dedifferentiation following axotomy, local application of CEP-1347/KT7515 to the transected hypoglossal nerve substantially reduced the loss of choline acetyl transferase immunoreactivity observed 7 days postaxotomy compared to untreated animals. Results from these experiments demonstrate that a small organic molecule that inhibits a signaling pathway associated with stress and injury also reduces neuronal death and degeneration in vivo.

Animals↗
PubMedDate not supplied

Pure multiple RNA secondary structure alignments: a progressive profile approach.

In functional, noncoding RNA, structure is often essential to function. While the full 3D structure is very difficult to determine, the 2D structure of an RNA molecule gives good clues to its 3D structure, and for molecules of moderate length, it can be predicted with good reliability. Structure comparison is, in analogy to sequence comparison, the essential technique to infer related function. We provide a method for computing multiple alignments of RNA secondary structures under the tree alignment model, which is suitable to cluster RNA molecules purely on the structural level, i.e., sequence similarity is not required. We give a systematic generalization of the profile alignment method from strings to trees and forests. We introduce a tree profile representation of RNA secondary structure alignments which allows reasonable scoring in structure comparison. Besides the technical aspects, an RNA profile is a useful data structure to represent multiple structures of RNA sequences. Moreover, we propose a visualization of RNA consensus structures that is enriched by the full sequence information.

5' Untranslated Regions↗
PubMed2002

Cardiovascular effects of successful renal transplantation: a 1-year sequential study of left ventricular morphology and function, and 24-hour blood pressure profile.

BACKGROUND: Cardiovascular disease is the leading cause of death in renal transplant recipients. The purpose of this study was to determine the effects of a successful renal transplantation on left ventricular morphology and function and on the 24-hr blood pressure profile. METHODS: Twenty-four patients with end-stage renal disease were prospectively studied by ambulatory blood pressure monitoring and echocardiography before and at 3, 6, and 12 months after renal transplantation. Patients were also analyzed according to their renal function after transplantation. RESULTS: We observed a significant drop in the mean values of daytime and nocturnal systolic blood pressure and in the 24-hr systolic pressure load at 12 months after transplantation. The most frequent echocardiographic finding was left ventricular hypertrophy (LVH), for which the incidence decreased from 75% before transplantation to 52.1% at 12 months after transplantation (P = 0.125). There was a significant decrease in left ventricular dilatation, and systolic dysfunction normalized in all patients after 12 months. The variables that best independently predicted the decrease in LVH were serum creatinine levels and the 24-hr systolic pressure load as registered by ambulatory blood pressure monitoring at 12 months after transplantation. We observed significant decreases in left ventricular mass and left ventricular mass index in the group of patients who had adequate renal function, as compared with no changes in patients who did not. CONCLUSIONS: Correction of the uremic state by renal transplantation leads to complete resolution of systolic dysfunction, regression of LVH, and improvement of left ventricular dilatation. In fact the reduction of LVH was dependent on adequate renal function and on a decrease in the systolic pressure levels.

Adult↗
PubMed2003

Recognizing complex, asymmetric functional sites in protein structures using a Bayesian scoring function.

The increase in known three-dimensional protein structures enables us to build statistical profiles of important functional sites in protein molecules. These profiles can then be used to recognize sites in large-scale automated annotations of new protein structures. We report an improved FEATURE system which recognizes functional sites in protein structures. FEATURE defines multi-level physico-chemical properties and recognizes sites based on the spatial distribution of these properties in the sites' microenvironments. It uses a Bayesian scoring function to compare a query region with the statistical profile built from known examples of sites and control nonsites. We have previously shown that FEATURE can accurately recognize calcium-binding sites and have reported interesting results scanning for calcium-binding sites in the entire Protein Data Bank. Here we report the ability of the improved FEATURE to characterize and recognize geometrically complex and asymmetric sites such as ATP-binding sites and disulfide bond-forming sites. FEATURE does not rely on conserved residues or conserved residue geometry of the sites. We also demonstrate that, in the absence of a statistical profile of the sites, FEATURE can use an artificially constructed profile based on a priori knowledge to recognize the sites in new structures, using redoxin active sites as an example.

Adenosine Triphosphate↗
PubMed2006

Chemical proteomics profiling of proteasome activity.

Proteolysis is a key mechanism for protein homeostasis in living cells. This process is effected by different classes of proteases. The proteasome is one of the most abundant and versatile proteases, bearing three different proteolytic active sites. The proteasome plays an important role in essential biological pathways such as antigen presentation, signal transduction, and cell-cycle control feedback loops. The aim of this work is to design novel chemical strategies for capturing, detection, identification, and quantification--in one word, profiling--the active protease fractions of interest, in cells of different phenotypes. Here, a set of chemistry-based functional proteomics techniques is demonstrated by profiling the multi-catalytic protease activities of the proteasome. Importantly, functional profiling is complementary to expression level profiling and is an indispensable parameter for better understanding of mechanisms underlying biological processes.

Blotting, Western↗
PubMed1992

Schizotypal personality disorder in individuals with and without schizophrenic relatives: similarities and contrasts in neurocognitive and clinical functioning.

Schizophrenia-spectrum disorders may reflect the genotype for schizophrenia. One such disorder, Schizotypal Personality Disorder (SPD), was examined as a function of family history of schizophrenia. Clinical profiles and neurocognitive functioning were evaluated in 25 schizotypal subjects (10 SPD with schizophrenic relatives and 15 SPD without schizophrenic relatives), and in 24 normal controls. The primary finding is that vigilance performance was similarly impaired in both SPD groups. An additional neurocognitive impairment, comprehension of grammatical constructions, was observed only in the SPD group with schizophrenic relatives. Of interest, the clinical profiles of the two SPD groups did not differ significantly. These results suggest that schizotypal personality disorder is associated with a continuum of neurocognitive vulnerability that increases as a function of family history of schizophrenia.

Adult↗
PubMed2004

[The efficacy of a combination herbal medicine in the treatment of functional dyspepsia. Meta-analysis of randomized double-blind studies on the basis of a valid gastrointestinal symptom profile].

BACKGROUND AND AIM: Functional dyspepsia is a heterogeneous clinical entity of incompletely known etiology. Overall, four randomized double-blind studies from the nineteen-nineties investigating acute treatment of this condition with the combination herbal medicine Iberogast, are available. A meta-analysis of the studieswas carried out to evaluate the overall therapeutic effect. PATIENTS AND METHODS: In all four, triple-arm, controlled multicentre studies, the efficacy of 4 weeks of treatment with 3 x 20 drops daily, applied after a washout phase, was investigated, the primary efficacy parameter being a specific gastrointestinal symptom score. Of the 592 participants in the studies, 196 were treated with Iberogast, 131 with placebo, and 61 with cisapride as positive control. The remaining 204 patients, who were treated with an experimental herbal preparation of similar composition, were not admitted to the final analysis. RESULTS: While overall appreciable improvement of the clinically relevant symptoms of moderate severity was seen under treatment with the combination herbal preparation, the individual studies differed in terms of the statistical significance of the results obtained. The meta-analysis of studies revealed a clear therapeutic effect for the herbal medicine (p < 0.0001). CONCLUSION: The clinical experience with the combination preparation for the treatment of functional dyspepsia was confirmed by the meta-analysis of the modern double-blind studies.

Adult↗
PubMed2004

Automated prediction of protein function and detection of functional sites from structure.

Current structural genomics projects are yielding structures for proteins whose functions are unknown. Accordingly, there is a pressing requirement for computational methods for function prediction. Here we present PHUNCTIONER, an automatic method for structure-based function prediction using automatically extracted functional sites (residues associated to functions). The method relates proteins with the same function through structural alignments and extracts 3D profiles of conserved residues. Functional features to train the method are extracted from the Gene Ontology (GO) database. The method extracts these features from the entire GO hierarchy and hence is applicable across the whole range of function specificity. 3D profiles associated with 121 GO annotations were extracted. We tested the power of the method both for the prediction of function and for the extraction of functional sites. The success of function prediction by our method was compared with the standard homology-based method. In the zone of low sequence similarity (approximately 15%), our method assigns the correct GO annotation in 90% of the protein structures considered, approximately 20% higher than inheritance of function from the closest homologue.

Amino Acid Sequence↗
PubMed2005

Insights into TOR function and rapamycin response: chemical genomic profiling by using a high-density cell array method.

With the advent of complete genome sequences, large-scale functional analyses are generating new excitement in biology and medicine. To facilitate genomewide functional analyses, we developed a high-density cell array with quantitative and automated readout of cell fitness. Able to print at > x 10 higher density on a standard microtiter plate area than currently possible, our cell array allows single-plate screening of the complete set of Saccharomyces cerevisiae gene-deletion library and significantly reduces the amount of small molecules and other materials needed for the study. We used this method to map the relation between genes and cell fitness in response to rapamycin, a medically important natural product that targets the eukaryotic kinase Tor. We discuss the implications for pharmacogenomics and the uncharted complexity in genotype-dependent drug response in molecularly targeted therapies. Our analysis leads to several basic findings, including a class of gene deletions that confer better fitness in the presence of rapamycin. This result provides insights into possible therapeutic uses of rapamycin/CCI-779 in the treatment of neurodegenerative diseases (including Alzheimer's, Parkinson's, and Huntington's diseases), and cautions the possible existence of similar rapamycin-enhanceable mutations in cancer. It is well established in yeast that although TOR2 has a unique rapamycin-insensitive function, TOR1 and TOR2 are interchangeable in the rapamycin-sensitive functions. We show that even the rapamycin-sensitive functions are distinct between TOR1 and TOR2 and map the functional difference to a approximately 120-aa region at the N termini of the proteins. Finally, we discuss using cell-based genomic pattern recognition in designing electronic or optical biosensors.

Cell Cycle Proteins↗
PubMed1993

A qualitative analysis of some models of tissue growth.

Using maximum principles for parabolic and elliptic operators, we examine, in a general way, some models of tissue growth. These typically consist of a model mechanism for the diffusion of a mitotic inhibitor (growth inhibitory factor, GIF) throughout the tissue. Central to the modeling is the inclusion of a source function that models the production of GIF throughout the tissue. We examine the effect this term has on the resulting distribution of GIF in the tissue and comment on the appropriateness of different source functions, in particular a uniform production rate or a nonuniform production rate of inhibitor. Given that it is more appropriate to infer from the patterns of mitosis that are observed experimentally in various tissues the GIF concentration profile rather than the source function profile, it may be more appropriate to use these types of models to determine the qualitative form of the source term rather than proposing this function a priori.

Animals↗
PubMed1996

Comparative studies on urethral function.

Urethral pressure profiles (in vivo), opening pressures, and flow rates at opening pressure (in vitro) were determined for female, male, pregnant, ovariectomized (OVX), OVX and then estrogen-treated, and OVX and then progesterone-treated rabbits. Using the isolated whole-urethra preparation, we determined the opening pressures and flow rates as well as the effects of 250 microM phenylephrine, 250 microM bethanechol, and 120 mM KCl on the urethral opening pressure and flow rate. The results demonstrated that (1) the urethral pressure profiles were similar for male and female rabbits, (2) ovariectomy and pregnancy decreased the urethral pressure profiles, (3) estrogen therapy partially reversed the effect of ovariectomy on the urethra, and (4) progesterone therapy had little effect on the urethral pressure profile. With regard to opening pressure and flow, (1) flow at opening pressure was lower in the male than in the female; (2) the opening pressure was increased by ovariectomy; (3) phenylephrine and KCl stimulated a greater response in the male than in the female, whereas the response to bethanechol was significantly lower in the male than in the female; (4) the male had the greatest resistance to flow among all the groups; and (5) ovariectomy increased the resistance to flow and estrogen treatment reversed the effect of ovariectomy. In conclusion, ovariectomy had significant effects on urethral function that were reversed by estrogen therapy but not by progesterone therapy.

Adrenergic alpha-Agonists↗
PubMed1995

The Sickness Impact Profile as a tool to evaluate functional outcome in trauma patients.

Because the ultimate goal of trauma care is to restore injured patients to their former functional status, reliable evaluation of functional status is needed to assess fully the effectiveness of trauma care. We hypothesized that the Sickness Impact Profile (SIP), a widely used measure of general health status, would be a useful tool to evaluate the long-term functional outcome of trauma patients and that the SIP would identify unexpected problems in the recovery process and groups of patients at high risk for long-term disability. A prospective cohort of 329 patients with lower extremity fractures admitted to three level I trauma centers were interviewed using SIP at 6 and 12 months postinjury. Patients with major neurologic injuries were excluded. Overall SIP scores and each of the component subscores may range from 0 (no disability) to 100. In this series, the mean overall SIP was 9.5 at 6 months and 6.8 at 12 months, compared with a preinjury baseline of 2.5. At 12 months, 52% of patients had no disability (SIP 0 to 3), 23% mild disability (4 to 9), 16% moderate disability (10 to 19), and 9% severe disability ( > or = 20). Disability was widely distributed across the spectrum of activities of daily living, including physical functioning (mean score of 5.5), psychosocial health (mean score of 5.5), sleeping (mean score of 10.0), and work (mean score of 21.0). The SIP scores did not correlate with Injury Severity Score.(ABSTRACT TRUNCATED AT 250 WORDS)

Activities of Daily Living↗
PubMed1981

The development of fetal adrenal function.

The response profiles of fetal sheep adrenals to tropic stimulation have been examined ih vivo and in vitro. Isolated adrenal cells from sheep fetuses in early pregnancy (Day 50) reduced cortisol in response to ACTH, dibutyryl cyclic AMP and GTP. The response was minimal on Day 100, but reappeared near term. 17 alpha-Hydroxyprogesterone was converted to cortisol by adrenals of all ages, but pregnenolone and progesterone were converted to cortisol only in early and late, but not mid-pregnancy. These studies suggested that the mid-gestation loss of fetal adrenal responsiveness was associated with post-receptor/adenylate cyclase events and involved loss of 17 alpha-hydroxylase activity. Fetal adrenal function was activated by exogenous ACTH in vivo, and was reflected in an increase in the ratio of cortisol to corticosterone in fetal plasma and in augmented cortisol output in vitro from dispersed fetal adrenal cells. The results were consistent with an effect of ACTH administration on 17 alpha-hydroxylation. Fetal pituitary cells, prostaglandin E2, alpha-MSH and term placental extract are other potential (sources of) corticotropins, although further studies are required to delineate the nature and origin of the active substances, and/or their primary sites of action.

Adrenal Glands↗
PubMed1987

Effects of ethanol on gastric epithelial cell phospholipid dynamics and cellular function.

The lipid profile of isolated gastric superficial epithelial cells (SEC) was evaluated by proton nuclear magnetic resonance spectroscopy (1H-NMR). The most conspicuous resonance band in SEC spectra was due to the protons of +N(CH3)3 groups of phosphatidylcholine and, to a lesser degree, other phospholipid derivatives, on the basis of their chemical shift and addition of purified phospholipids. NMR of cell lysates and phospholipid extracts of SEC in deutero-chloroform provided further spectral resolution of these components. Phospholipase or ethanol treatments of SEC produced membrane disorganization reflected as increased peak intensity of the phospholipid signals. In addition, ethanol, in a dose-dependent manner, attenuated paranitrophenyl phosphatase activity, which correlated with inhibition of total and ouabain-sensitive 86Rubidium chloride uptake by SEC. This study suggests that NMR used in conjunction with other biochemical techniques can monitor SEC membrane structure-function relationships. NMR is a potentially powerful noninvasive probe to show changes in lipid membrane organization induced by low concentrations of ethanol (1%) and may indicate an early sign of "cytotoxicity" in intact SEC.

4-Nitrophenylphosphatase↗
PubMed1997

FP prostaglandin receptors mediating inositol phosphates generation and calcium mobilization in Swiss 3T3 cells: a pharmacological study.

A detailed pharmacological characterization of the prostaglandin (PG) receptor coupled to phosphoinositide (PI) turnover and intracellular calcium mobilization in Swiss 3T3 mouse fibroblast cells was undertaken. The pharmacological profile of this functional receptor was compared with the pharmacological profile of specific [3H]PGF2 alpha binding to bovine corpus luteum membranes, which are known to contain a bona fide FP receptor. PGs that were potent stimulators and full agonists in the PI turnover assay in the 3T3 cells were the following (for all, n = 3-45): 16-phenoxy-PGF2 alpha (EC50 = 0.61 +/- 0.1 nM), cloprostenol (EC50 = 0.73 +/- 0.04 nM), 17-phenyl-PGF2 alpha (EC50 = 2.71 +/- 0.35 nM), fluprostenol (EC50 = 3.67 +/- 0.61 nM), PhXA85 (EC50 = 27.3 +/- 5.63 nM) and PGF2 alpha (EC50 = 28.5 +/- 5.26 nM). However, PGD2 (EC50 = 155 +/- 29.9 nM; Emax = 49% of cloprostenol), PGE2 (EC50 = 2570 +/- 566 nM; Emax = 59%) and U46619 (EC50 = 1060 +/- 310 nM; Emax = 63%) were less potent and were partial agonists, and iloprost and BW245C were inactive. Although the PGs tested exhibited lower affinities in the 3[H]PGF2 alpha binding assay than their functional potencies in the PI turnover assay, the rank orders of potencies and affinities were well correlated (r = 0.94; n = 15 compounds). However, the PI turnover assay was more sensitive than the calcium mobilization assay for rank ordering PG agonists. In conclusion, the Swiss 3T3 cells express an FP receptor coupled to PI turnover and intracellular Ca+2 mobilization signal transduction pathways. The pharmacological profile of this receptor was similar to that of the FP receptor found in the bovine corpus luteum, a tissue previously used to clone the first pharmacologically defined FP receptor.

3T3 Cells↗
PubMed1997

In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug.

BACKGROUND: Classical (typical) antipsychotic drugs are in wide use clinically, but some patients do not respond at all to treatment, while in others, negative symptoms and cognitive deficits fail to respond. Also, these drugs often cause serious motor disturbances. Clozapine, an atypical antipsychotic, appears to correct many of these deficiencies, but has a significant incidence of potentially fatal agranulocytosis. Accordingly, we attempted to develop a prototype of a new generation of antipsychotics that is both more efficacious and safe. Our strategy was to create a compound that is not only active in behavioral tests that predict antipsychotic action but also shares the rich, multifaceted receptor pharmacology of clozapine without its side effects. To this end, Eli Lilly and Co. developed olanzapine. In this article we characterize the in vitro and in vivo receptor pharmacology of olanzapine. METHOD: We evaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor binding in vitro and well-established in vivo (functional) assays. RESULTS: Binding studies showed that olanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors. In vivo olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at alpha-adrenergic and muscarinic receptors. Olanzapine has little or no effect at other receptors, enzymes, or key proteins in neuronal function. Olanzapine has a receptor profile that is similar to that of clozapine: it is relatively nonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophysiology; Fos). CONCLUSION: The binding and functional profile of olanzapine (1) is similar to that of clozapine, (2) indicates that olanzapine is an atypical antipsychotic drug, and (3) is consistent with clinical efficacy. If olanzapine also proves to be safe, then it will have high potential to become a more ideal antipsychotic drug.

Animals↗
PubMed2006

Functional pharmacology in human brain.

Most neurological and psychiatric disorders involve selective or preferential impairments of neurotransmitter systems. Therefore, studies of functional transmitter pathophysiology in human brain are of unique importance in view of the development of effective, mechanism-based, therapeutic modalities. It is well known that central nervous system functional proteins, including receptors, transporters, ion channels, and enzymes, can exhibit high heterogeneity in terms of structure, function, and pharmacological profile. If the existence of types and subtypes of functional proteins amplifies the possibility of developing selective drugs, such heterogeneity certainly increases the likelihood of interspecies differences. It is therefore essential, before choosing animal models to be used in preclinical pharmacology experimentation, to establish whether functionally corresponding proteins in men and animals also display identical pharmacological profiles. Because of evidence that scaffolding proteins, trafficking between plasma membrane and intracellular pools, phosphorylation and allosteric modulators can affect the function of receptors and transporters, experiments with human clones expressed in host cells where the environment of native receptors is rarely reproduced should be interpreted with caution. Thus, the use of neurosurgically removed fresh human brain tissue samples in which receptors, transporters, ion channels, and enzymes essentially retain their natural environment represents a unique experimental approach to enlarge our understanding of human brain processes and to help in the choice of appropriate animal models. Using this experimental approach, many human brain functional proteins, in particular transmitter receptors, have been characterized in terms of localization, function, and pharmacological properties.

Acetylcholine↗
PubMed1993

Isotretinoin therapy for acne vulgaris: a re-evaluation of the need for measurements of plasma lipids and liver function tests.

A retrospective analysis of patients receiving isotretinoin for acne was performed, in order to determine the necessity for routine testing of lipid profiles and liver function tests during therapy. Data were analysed from 209 individuals, 113 (69 males, 44 females) of whom had been treated with 1 mg/kg/day, and 96 (67 males, 29 females) with 0.5 mg/kg/day. There were no significant changes in any of the tests of liver function. There were significant elevations in both plasma cholesterol and triglycerides at 8 and 16 weeks (P < 0.01) for both dose schedules, which were significant in both male and female subjects (P < 0.001). All the individuals with elevated cholesterol (> 6.5 mmol/l) at 16 weeks had elevated cholesterol at the onset of therapy. Triglyceride concentrations were elevated at 8 weeks, but there was no further increase thereafter. It was not possible to predict which subjects would become hypertriglyceridaemic from pretreatment lipid estimations. In conclusion, there appears to be little evidence to support the previously recommended regular biochemical monitoring of liver function and lipid profiles in patients who are treated with isotretinoin for 16 weeks. It would appear prudent to ensure that there is neither liver disease nor hyperlipidaemia prior to the onset of therapy, and to determine the triglyceride response to therapy on one occasion after 4 weeks' treatment. This change in patient management should result in considerable savings both in patient time and in blood collection and analysis.

Acne Vulgaris↗