bluuebunny/crossref_metadata_2025 huggingface dataset:
MESON EXCHANGE THEORY FOR HIGH ENERGY PROTON-PROTON SCATTERING
Authors: PUMSA-ARD K. , UCHAI W. , YAN Y.
Published: January 2006

We study high energy proton-proton (pp) elastic reactions in a meson-exchange model. The observed differential cross sections at small momentum exchanges (|t|<0.8 GeV 2) are well reproduced for a large energy range (s~100 to 1000 GeV 2) in the model. Our study reveals that the meson-exchange model developed in the low and medium energy sector is applicable to the high-energy pp elastic reactions. It might be argued that high-energy reactions at small momentum transfers might be as soft as low and medium energy processes.
ON THE SURVIVAL OF THE SD-PAIR SHELL MODEL UNDER PSEUDO-SPIN TRANSFORMATION
Authors: BAHRI C. , LUO YAN-AN , DRAAYER J. P. , PAN FENG
Published: January 2006

The pseudo-spin concept and the SD-pair shell model provide for tractable truncations of large model spaces. We tested the compatibility of these concepts, and hence the applicability of the SD-pair shell model to its pseudo SD-pair analog, for the (1h9/2 2f7/2 2f5/2 3p3/2 3p1/2)8 system. The validity of the SD-pair concept is found to survive under pseudo-spin transformation.
EXTENDED LINEAR SIGMA MODEL IN HIGHER ORDER MESONIC INTERACTIONS
Authors: RASHDAN M. , ABU-SHADY M. , ALI T. S. T.
Published: January 2006

The Gell-Mann and Levy model, as well as the Birse and Banerjee model, describe quark interactions via the exchange of σ- and π-mesons. We extend these models to include higher order mesonic interactions. The field equations were solved in the mean-field approximation and good agreement with the data for nucleon properties was obtained. Our agreement is better than that obtained by the original model of Birse and Banerjee and by other models. This indicates the importance of including higher order meson correlations.
PRIMORDIAL NUCLEOSYNTHESIS: SUCCESSES AND CHALLENGES
Authors: STEIGMAN GARY
Published: January 2006

Primordial nucleosynthesis provides a probe of the Universe during its early evolution. Given the progress exploring the constituents, structure, and recent evolution of the Universe, it is timely to review the status of Big Bang Nucleosynthesis (BBN) and to confront its predictions, and the constraints which emerge from them, with those derived from independent observations of the Universe at much later epochs in its evolution. Following an overview of the key physics controlling element synthesis in the early Universe, the predictions of the standard models of cosmology and particle physics (SBBN) are presented, along with those from some non-standard models. The observational data used to infer the primordial abundances are described, with an emphasis on the distinction between precision and accuracy. These relic abundances are compared with predictions, testing the internal consistency of BBN and enabling a comparison of the BBN constraints with those derived from the WMAP Cosmic Background Radiation data. Emerging from these comparisons is a successful standard model along with constraints on (or hints of) physics beyond the standard models of particle physics and of cosmology.
Testing of CpG-Optimized Protein and DNA Vaccines against the Hepatitis B Virus in Chimpanzees for Immunogenicity and Protection from Challenge
Authors: Payette Paul J. , Ma Xiaoying , Weeratna Risini D. , McCluskie Michael J. , Shapiro Max , Engle Ron E. , Davis Heather L. , Purcell Robert H.
Published: January 2006

Despite the existence for some time of effective prophylactic vaccines, hepatitis B virus (HBV) infection remains an important global concern. Improvements on existing vaccines could be beneficial, especially in situations where it is desirable or necessary to induce protective immunity more rapidly or with fewer doses. We have compared, in chimpanzees, a current HBV vaccine that contains recombinant hepatitis B surface antigen HBsAg) adsorbed to alum, with two novel vaccine strategies that have proven superior to the current vaccine in mice. The first approach was the use of oligodeoxynucleotides containing CpG motifs (CpG ODN) as an adjuvant to Engerix-B®, a commercial HBV vaccine. The addition of CpG ODN to Engerix-B greatly improved the kinetics and magnitude of the humoral response, suggesting that CpG ODN might allow induction of protective immunity in humans more quickly and with fewer vaccine doses. All animals receiving either control or CpG-containing subunit vaccines at 0 and 4 weeks attained titers of HBsAg-specific antibody (anti-HBs) considered protective (≧10 mIU/ml) and were indeed protected from challenge at 8 weeks with 103.5 50% chimp infectious doses (CID50) of intravenous HBV. The second approach was a DNA vaccine with a plasmid vector optimized for content of immunostimulatory CpG motifs. Despite the fact that earlier studies had shown four doses of a similar DNA vaccine (except not optimized for CpG content) to induce strong humoral responses in 1 of 2 chimpanzees, in this study two doses of DNA vaccine (at 0 and 4 weeks) did not generate any detectable anti-HBs in either of 2 chimpanzees, although it did protect 1 that rapidly developed anti-HBs during the incubation period, suggesting priming of an antibody response. The poor results may be due to an inadequate number of doses or amount of plasmid DNA in these larger animals, but nevertheless point to the need to improve delivery methods for DNA vaccines for use in larger animals such as primates.
Statins Decrease Serotonin-Induced Contractions in Coronary Arteries of Swine in vitro
Authors: Crespo Maria J. , Quidgley José A.
Published: January 2006

Recent evidence suggests that statins improve the status of patients with coronary artery disease not only by reducing cholesterol levels, but also by acting at the level of the endothelium-smooth muscle unit. Previous results from our laboratory showed that these drugs interact with the vascular wall by partially inhibiting calcium-dependent, agonist-induced contractions in rat aortas. To evaluate whether this effect is also extended to the coronary vasculature, we assessed the effect of statins on serotonin (5-HT) induced contractions of left and right coronary arteries of swine. Concentration-response curves for the 5-HT-induced contractions (from 0.1 nmol/l to 100 µmol/l) were calculated on rings from both coronaries in the presence and absence of either (5 µmol/l) pravastatin, mevastatin, simvastatin, lovastatin, or atorvastatin. After a 45-min incubation period, all statins significantly reduced the Emax for the 5-HT-induced contractions, ranging from 51.9 ± 1.9% (simvastatin) to 15.9 ± 2.0% (pravastatin) in the left coronary artery and from 48.8 ± 2.0% (simvastatin) to 17.8 ± 2.5% (pravastatin) in the right coronary artery. The EC50 values for the 5-HT-induced contractions were 0.150 ± 0.005 µmol/l for the left coronary artery and 0.171 ± 0.010 µmol/l for the right coronary artery. These values significantly changed after incubation with statins, ranging from 1.240 ± 0.101 µmol/l (for simvastatin) to 0.081± 0.008 µmol/l (for pravastatin) in the left coronary artery and from 1.410 ± 0.075 µmol/l (for simvastatin) to 0.084 ± 0.008 µmol/l (for pravastatin) in the right coronary artery. This evidence supports the possibility that, beyond their lipid-lowering properties, statins may provide a beneficial effect in atherosclerotic patients by reducing the tone in the coronary vasculature, facilitating blood flow to the myocardium.
An Overview of Hereditary Hearing Loss
Authors: Bayazit Yildirim A. , Yılmaz Metin
Published: January 2006

Understanding the genetic basis of hearing loss is important because almost 50% of profound hearing loss are caused by genetic factors and more than 120 independent genes have been identified. In this review, after a brief explanation of some genetic terms (allele, heterozygosis, homozygosis, polymorphism, genotype and phenotype), classification of genetic hearing loss (syndromic versus nonsyndromic, and recessive dominant, X-linked and mitochondrial) was performed. Some of the most common syndromes (Usher, Pendred, Jervell and Lange-Nielsen, Waardenburg, branchio-oto-renal, Stickler, Treacher Collins and Alport syndromes, biotinidase deficiency and Norrie disease) causing genetic hearing loss were also explained briefly. The genes involved in hearing loss and genetic heterogeneity were presented.
Matrix Metalloproteinase-8 and -9 Are Increased at the Site of Abdominal Aortic Aneurysm Rupture
Authors: Wilson W. Richard W. , Anderton Marcus , Schwalbe Edward C. , Jones J. Louise , Furness Peter N. , Bell Peter R.F. , Thompson Matthew M.
Published: January 2006

Background—Abdominal aortic aneurysm (AAA) expansion is characterized by extracellular matrix degradation and widespread inflammation. In contrast, the processes that characterize AAA rupture are not well understood. The aim of this study was to investigate the proteolytic and cellular activity of ruptured AAA, focusing on matrix metalloproteinases (MMPs) and their inhibitors (TIMPs).

Methods and Results—Anterior aneurysm wall biopsies were taken from 55 nonruptured and 21 ruptured AAAs. A further biopsy from the site of rupture was taken from 12 of the ruptured AAAs. MMP-1, -2, -3, -8, -9, and -13, as well as TIMP-1 and -2, were quantified in each biopsy with ELISA. A comparison of anterior aneurysm biopsies showed no difference in MMP or TIMP concentrations between nonruptured and ruptured AAA. In a comparison of ruptured AAA biopsies, MMP-8 and -9 levels were significantly elevated in the 12 rupture site biopsies compared with their 12 paired anterior wall biopsies, whereas other MMPs and TIMPs showed no difference (MMP-8,P<0.001; MMP-9,P=0.01). MMP-8 and -9 expression was mediated by native mesenchymal cells and was independent of the inflammatory infiltrate.

Conclusions—A localized increase in MMP-8 and –9, mediated by native mesenchymal cells, presents a potential pathway for collagen breakdown and AAA rupture.
Late Stent Malapposition After Drug-Eluting Stent Implantation
Authors: Hong Myeong-Ki , Mintz Gary S. , Lee Cheol Whan , Park Duk-Woo , Park Kyoung-Min , Lee Bong-Ki , Kim Young-Hak , Song Jong-Min , Han Ki-Hoon , Kang Duk-Hyun , Cheong Sang-Sig , Song Jae-Kwan , Kim Jae-Joong , Park Seong-Wook , Park Seung-Jung
Published: January 2006

Background—

Late stent malapposition (LSM) after drug-eluting stent (DES) implantation has not been evaluated sufficiently in real-world practice.

Methods and Results—

We evaluated the incidence, mechanisms, predictors, and long-term prognosis of LSM after DES implantation in 557 patients (705 native lesions; sirolimus-eluting stent in 538 lesions and paclitaxel-eluting stent in 167 lesions) in whom intravascular ultrasound was performed at index and 6-month follow-up. LSM occurred in 82 patients with 85 lesions (12.1% overall, 95% CI 9.7% to 14.5%, 71 lesions (13.2%) in sirolimus-eluting stents and 14 lesions [8.4%] in paclitaxel-eluting stents,
P
=0.12]; the incidence was 25.0% (4/16) after directional coronary atherectomy before stenting, 27.5% (14/51) in chronic total occlusion lesions, and 31.8% (7/22) after primary stenting in acute myocardial infarction (
P
=0.13,
P
<0.001, and
P
=0.001, respectively, versus elective stenting with conventional balloon predilation, 9.7% [60/616]). There was an increase of external elastic membrane area (from 17.1±3.6 to 21.4±4.8 mm
2
,
P
<0.001) that was greater than the increase in plaque area (from 9.3±2.5 to 10.5±2.7 mm
2
,
P
<0.001). Independent predictors of LSM were total stent length, primary stenting in acute myocardial infarction, and chronic total occlusion lesions. Except for 1 death in the non-LSM group, there were no major adverse cardiac events in either LSM or non-LSM patients during a mean 10-month follow-up after detection of LSM.

Conclusions—

LSM occurs in 12% of cases after DES implantation. The predictors of LSM are total stent length, primary stenting in acute myocardial infarction, and chronic total occlusion lesions. LSM after DES implantation was not associated with any major adverse cardiac events during a subsequent 10-month (mean) follow-up.
Most LQT2 Mutations Reduce Kv11.1 (hERG) Current by a Class 2 (Trafficking-Deficient) Mechanism
Authors: Anderson Corey L. , Delisle Brian P. , Anson Blake D. , Kilby Jennifer A. , Will Melissa L. , Tester David J. , Gong Qiuming , Zhou Zhengfeng , Ackerman Michael J. , January Craig T.
Published: January 2006

Background—

The
KCNH2
or
human ether-a-go-go related gene
(
hERG
) encodes the Kv11.1 α-subunit of the rapidly activating delayed rectifier K
+
current (
I
Kr
) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from
KCNH2
mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (
I
Kv11.1
). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected.

Methods and Results—

Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27°C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type–like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants.

Conclusions—

This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.
Practical Perspectives on the Use of Tipranavir in Combination With Other Medications: Lessons Learned From Pharmacokinetic Studies
Authors: Boffito Marta , Maitland Desmond , Pozniak Anton
Published: January 2006

Drug‐drug interactions are a major practical concern for physicians treating human immunodeficiency virus (HIV) because of the many medications that HIV‐positive patients must take. Pharmacokinetic drug interactions can occur at different levels (absorption, distribution, metabolism, excretion) and are difficult to predict. Of all the processes that give rise to drug interactions, metabolism by cytochrome P450 (CYP3A) is the most frequent. Moreover, medications prescribed to HIV‐positive patients may also be CYP3A inhibitors and inducers: Tipranavir, in the absence of ritonavir, is a CYP3A inducer, and ritonavir is a CYP3A inhibitor. Fortunately, the drug interactions between tipranavir coadministered with ritonavir and other antiretroviral medications or with other medications commonly used in HIV therapy are well characterized. This review summarizes the pharmacokinetic interactions between tipranavir/ritonavir and 11 other antiretroviral medications and between tipranavir/ritonavir and drugs used to treat opportunistic infections such as fungal infections, antiretroviral‐treatment‐related conditions such as hyperlipidemia, and side effects such as diarrhea.
Disposition Kinetics and Tolerance of Escalating Single Doses of Ramelteon, a High‐Affinity MT1 and MT2 Melatonin Receptor Agonist Indicated for Treatment of Insomnia
Authors: Karim Aziz , Tolbert Dwain , Cao Charlie
Published: January 2006

Ramelteon is a selective MT1/MT2 receptor agonist, indicated for insomnia treatment. Safety, tolerance, pharmacokinetics, and cognitive performance were evaluated following increasing ramelteon doses. Healthy adults (35–65 years) were randomly assigned to receive 1 of 5 oral ramelteon doses (4, 8, 16, 32, or 64 mg; n = 8 per group) or placebo (n = 20). Cmax and AUC∞ (mean [%CV]) increased with each dose: Cmax = 1.15 (109), 5.73 (97), 6.92 (77), 17.4 (76), and 25.9 (77) ng/mL, respectively, and AUC∞ = 1.71 (114), 6.95 (108), 9.88 (78), 22.5 (80), and 36.1 (71 ng•h/mL), respectively. Mean Tmax values of 0.75 to 0.94 hours and mean elimination half‐life of 0.83 to 1.90 hours remained relatively constant. Ramelteon was extensively metabolized. Besides ramelteon, 4 metabolites, M‐I, M‐II, M‐III, and M‐IV, were measured in serum. Metabolite M‐II, which has shown weak ramelteon‐like activity in vitro, was the major metabolite in serum. Digit Symbol Substitution Test and visual analog scale alertness scores were similar across all dose groups and did not differ from placebo. All adverse events were mild or moderate and resolved before study completion.
Investigation of the Potential Relationships Between Plasma Voriconazole Concentrations and Visual Adverse Events or Liver Function Test Abnormalities
Authors: Tan Keith , Brayshaw Nigel , Tomaszewski Konrad , Troke Peter , Wood Nolan
Published: January 2006

This study investigated the relationship between plasma voriconazole concentrations (pVC) and risk of visual adverse events (VAEs) or liver function test (LFT) abnormalities using longitudinal logistic regression. Seven‐day mean pVC were calculated from 2925 plasma samples (1053 patients); in each 7‐day period, the presence or absence of VAEs/abnormal LFTs was analyzed as a binary outcome variable. There was a relationship between pVC and risk of VAE (P = .011) and a weaker, but statistically significant, association with risk of aspartate transaminase (AST), alkaline phosphatase (ALP), or bilirubin but not alanine transaminase (ALT) abnormalities. The odds ratios of LFT abnormalities per 1 μg/mL pVC increase ranged from 1.07 to 1.17. Maximum weekly occurrences were 10%, 8%, 5%, and 14% for AST, ALT, ALP, and bilirubin abnormalities, respectively. Receiver‐operating characteristic curve analysis indicates that individual pVC cannot be used to predict subsequent LFT abnormalities.
Pharmacokinetics of Olanzapine After Single‐Dose Oral Administration of Standard Tablet Versus Normal and Sublingual Administration of an Orally Disintegrating Tablet in Normal Volunteers
Authors: Markowitz John S. , DeVane C. Lindsay , Malcolm Robert J. , Gefroh Holly A. , Wang Jun‐Sheng , Zhu Hao‐Jie , Donovan Jennifer L.
Published: January 2006

Olanzapine (OLZ) is a second‐generation antipsychotic agent available in 2 solid oral dosage forms, a standard oral tablet (SOT) and an orally disintegrating tablet (ODT). This study assessed the absorption of each by different routes of administration. Secondarily, the influence of P‐glycoprotein (P‐gp) genotype was assessed. It was hypothesized that more rapid absorption of the OLZ ODT would occur when administered sublingually versus standard oral administration. A randomized, 3‐way crossover study assessed the 5‐mg OLZ formulations in healthy volunteers (n = 10). Blood was collected (0–8 hours) to assess OLZ pharmacokinetics using liquid chromatography/mass spectrometry. Both routes of ODT administration resulted in more measurable early concentraions relative to SOT. However, there were no statistically significant differences observed between any of the OLZ exposures for observed pharmacokinetic parameters (Cmax, Tmax, AUC0–8h). The homozygous TT genotype for P‐gp resulted in an increased AUC of OLZ for SOT administration but not for either condition where sublingual absorption could occur.
Pharmacokinetics and Pharmacodynamics of Multiple Sublingual Buprenorphine Tablets in Dose‐Escalation Trials
Authors: Ciraulo Domenic A. , Hitzemann Robert J. , Somoza Eugene , Knapp Clifford M. , Rotrosen John , Sarid‐Segal Ofra , Ciraulo Ann Marie , Greenblatt David J. , Chiang C. Nora
Published: January 2006

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4–24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration‐time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose‐adjusted Cmax for both tablet formulations and for the dose‐adjusted AUCs for the buprenorphine‐naloxone tablets. For both formulations, the maximal buprenorphine‐induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.
Assessing the Clinical Significance of Botanical Supplementation on Human Cytochrome P450 3A Activity: Comparison of a Milk Thistle and Black Cohosh Product to Rifampin and Clarithromycin
Authors: Gurley Bill , Hubbard Martha A. , Williams D. Keith , Thaden John , Tong Yudong , Gentry W. Brooks , Breen Philip , Carrier Danielle J. , Cheboyina Shreekar
Published: January 2006

Phytochemical‐mediated modulation of cytochrome P450 enzymes (CYPs) may underlie many herb‐drug interactions. This study's purpose was to assess the effects of milk thistle and black cohosh supplementation on CYP3A activity and compare them to a clinically recognized inducer, rifampin, and inhibitor, clarithromycin. Healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg) or black cohosh (80 mg) supplement for 14 days. Subjects also received rifampin (600 mg) and clarithromycin (1000 mg) for 7 days as positive controls for CYP3A induction and inhibition, respectively. Midazolam was administered orally before and after each supplementation and control period. The effects of milk thistle, black cohosh, rifampin, and clarithromycin on midazolam pharmacokinetics were determined using noncompartmental techniques. Unlike those observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected by milk thistle or black cohosh. Milk thistle and black cohosh appear to have no clinically relevant effect on CYP3A activity in vivo.
Mild cognitive impairment
Authors: Whitehouse Peter J. , Moody Harry R.
Published: January 2006

Mild cognitive impairment (MCI) is a controversial label for forms of age-related, intellectual difficulties unassociated with impairments in activities of daily living. The principal issue is whether this arbitrary, heterogeneous and unreliable term is appropriate to use clinically. Persons with the label MCI may progress to different types of dementia, stay stable, or even improve. In this article we offer a philosophical analysis of MCI from epistemological, ethical and semantic perspectives. We believe that the term should currently not be used clinically.
The role of advocacy in our adventure with Alzheimer's
Authors: Knauss Jenny , Moyer Don
Published: January 2006

We show how our natural reaction to Jenny's diagnosis of Alzheimer's was advocacy, explain how this gives positive meaning to our lives and how it revealed flaws in the Alzheimer's establishment. We give some examples of projects this has led us to initiate and show why it is best for our ilk to initiate, inform and act as jury for activities affecting us.
Inhaled nitric oxide alleviates hyperoxia suppressed phosphatidylcholine synthesis in endotoxin-induced injury in mature rat lungs
Authors: Gong Xiaohui , Guo Chunbao , Huang Shibing , Sun Bo
Published: January 2006

Background

We investigated efficacy of inhaled nitric oxide (NO) in modulation of metabolism of phosphatidylcholine (PC) of pulmonary surfactant and in anti-inflammatory mechanism of mature lungs with inflammatory injury.

Methods

Healthy adult rats were divided into a group of lung inflammation induced by i.v. lipopolysaccharides (LPS) or a normal control (C) for 24 h, and then exposed to: room air (Air), 95% oxygen (O), NO (20 parts per million, NO), both O and NO (ONO) as subgroups, whereas [3H]-choline was injected i.v. for incorporation into PC of the lungs which were processed subsequently at 10 min, 4, 8, 12 and 24 h, respectively, for measurement of PC synthesis and proinflammatory cytokine production.

Results

LPS-NO subgroup had the lowest level of labeled PC in total phospholipids and disaturated PC in bronchoalveolar lavage fluid and lung tissue (decreased by 46–59%), along with the lowest activity of cytidine triphosphate: phosphocholine cytidylyltransferase (-14–18%) in the lungs, compared to all other subgroups at 4 h (p < 0.01), but not at 8 and 12 h. After 24-h, all LPS-subgroups had lower labeled PC than the corresponding C-subgroups (p < 0.05). LPS-ONO had higher labeled PC in total phospholipids and disaturated PC, activity of cytidylyltransferase, and lower activity of nuclear transcription factor-κB and expression of proinflammatory cytokine mRNA, than that in the LPS-O subgroup (p < 0.05).

Conclusion

In LPS-induced lung inflammation in association with hyperoxia, depressed PC synthesis and enhanced proinflammatory cytokine production may be alleviated by iNO. NO alone only transiently suppressed the PC synthesis as a result of lower activity of cytidylyltransferase.
Biochemical and morphological changes in endothelial cells in response to hypoxic interstitial edema
Authors: Botto Laura , Beretta Egidio , Daffara Rossella , Miserocchi Giuseppe , Palestini Paola
Published: January 2006

Background

A correlation between interstial pulmonary matrix disorganization and lung cellular response was recently documented in cardiogenic interstitial edema as changes in the signal-cellular transduction platforms (lipid microdomains: caveoale and lipid rafts). These findings led to hypothesize a specific "sensing" function by lung cells resulting from a perturbation in cell-matrix interaction. We reason that the cell-matrix interaction may differ between the cardiogenic and the hypoxic type of lung edema due to the observed difference in the sequential degradation of matrix proteoglycans (PGs) family. In cardiogenic edema a major fragmentation of high molecular weight PGs of the interfibrillar matrix was found, while in hypoxia the fragmentation process mostly involved the PGs of the basement membrane controlling microvascular permeability. Based on these considerations, we aim to describe potential differences in the lung cellular response to the two types of edema.

Methods

We analysed the composition of plasma membrane and of lipid microdomains in lung tissue samples from anesthetized rabbits exposed to mild hypoxia (12 % O2 for 3–5 h) causing interstitial lung edema. Lipid analysis was performed by chromatographic techniques, while protein analysis by electrophoresis and Western blotting. Lipid peroxidation was assessed on total plasma membranes by a colorimetric assay (Bioxytech LPO-586, OxisResearch). Plasma membrane fluidity was also assessed by fluorescence. Lipid microdomains were isolated by discontinuous sucrose gradient. We also performed a morphometric analysis on lung cell shape on TEM images from lung tissue specimen.

Results

After hypoxia, phospholipids content in plasma membranes remained unchanged while the cholesterol/phospholipids ratio increased significantly by about 9% causing a decrease in membrane fluidity. No significant increase in lipid peroxidation was detected. Analysis of lipid microdomains showed a decrease of caveolin-1 and AQP1 (markers of caveolae), and an increase in CD55 (marker of lipid rafts). Morphometry showed a significant decrease in endothelial cell volume, a marked increase in the cell surface/volume ratio and a decrease in caveolar density; epithelial cells did not show morphological changes.

Conclusion

The biochemical, signaling and morphological changes observed in lung endothelial cell exposed to hypoxia are opposite to those previously described in cardiogenic edema, suggesting a differential cellular response to either type of edema.
SuperMimic – Fitting peptide mimetics into protein structures
Authors: Goede Andrean , Michalsky Elke , Schmidt Ulrike , Preissner Robert
Published: January 2006

Background

Various experimental techniques yield peptides that are biologically active but have unfavourable pharmacological properties. The design of structurally similar organic compounds, i.e. peptide mimetics, is a challenging field in medicinal chemistry.

Results

SuperMimic identifies compounds that mimic parts of a protein, or positions in proteins that are suitable for inserting mimetics. The application provides libraries that contain peptidomimetic building blocks on the one hand and protein structures on the other. The search for promising peptidomimetic linkers for a given peptide is based on the superposition of the peptide with several conformers of the mimetic. New synthetic elements or proteins can be imported and used for searching.

Conclusion

We present a graphical user interface for finding peptide mimetics that can be inserted into a protein or for fitting small molecules into a protein. Using SuperMimic, promising locations in proteins for the insertion of mimetics can be found quickly and conveniently.
Utilization of two sample t-test statistics from redundant probe sets to evaluate different probe set algorithms in GeneChip studies
Authors: Hu Zihua , Willsky Gail R
Published: January 2006

Background

The choice of probe set algorithms for expression summary in a GeneChip study has a great impact on subsequent gene expression data analysis. Spiked-in cRNAs with known concentration are often used to assess the relative performance of probe set algorithms. Given the fact that the spiked-in cRNAs do not represent endogenously expressed genes in experiments, it becomes increasingly important to have methods to study whether a particular probe set algorithm is more appropriate for a specific dataset, without using such external reference data.

Results

We propose the use of the probe set redundancy feature for evaluating the performance of probe set algorithms, and have presented three approaches for analyzing data variance and result bias using two samplet-test statistics from redundant probe sets. These approaches are as follows: 1) analyzing redundant probe set variance based ont-statistic rank order, 2) computing correlation oft-statistics between redundant probe sets, and 3) analyzing the co-occurrence of replicate redundant probe sets representing differentially expressed genes. We applied these approaches to expression summary data generated from three datasets utilizing individual probe set algorithms ofMAS5.0,dChip, orRMA. We also utilized combinations of options from the three probe set algorithms. We found that results from the three approaches were similar within each individual expression summary dataset, and were also in good agreement with previously reported findings by others. We also demonstrate the validity of our findings by independent experimental methods.

Conclusion

All three proposed approaches allowed us to assess the performance of probe set algorithms using the probe set redundancy feature. The analyses of redundant probe set variance based ont-statistic rank order and correlation oft-statistics between redundant probe sets provide useful tools for data variance analysis, and the co-occurrence of replicate redundant probe sets representing differentially expressed genes allows estimation of result bias. The results also suggest that individual probe set algorithms have dataset-specific performance.
Construction of a nasopharyngeal carcinoma 2D/MS repository with Open Source XML Database – Xindice
Authors: Li Feng , Li Maoyu , Xiao Zhiqiang , Zhang Pengfei , Li Jianling , Chen Zhuchu
Published: January 2006

Background

Many proteomics initiatives require integration of all information with uniformcriteria from collection of samples and data display to publication of experimental results. The integration and exchanging of these data of different formats and structure imposes a great challenge to us. The XML technology presents a promise in handling this task due to its simplicity and flexibility. Nasopharyngeal carcinoma (NPC) is one of the most common cancers in southern China and Southeast Asia, which has marked geographic and racial differences in incidence. Although there are some cancer proteome databases now, there is still no NPC proteome database.

Results

The raw NPC proteome experiment data were captured into one XML document with Human Proteome Markup Language (HUP-ML) editor and imported into native XML database Xindice. The 2D/MS repository of NPC proteome was constructed with Apache, PHP and Xindice to provide access to the database via Internet. On our website, two methods, keyword query and click query, were provided at the same time to access the entries of the NPC proteome database.

Conclusion

Our 2D/MS repository can be used to share the raw NPC proteomics data that are generated from gel-based proteomics experiments. The database, as well as the PHP source codes for constructing users' own proteome repository, can be accessed at http://www.xyproteomics.org/.
preAssemble: a tool for automatic sequencer trace data processing
Authors: Adzhubei Alexei A , Laerdahl Jon K , Vlasova Anna V
Published: January 2006

Background

Trace or chromatogram files (raw data) are produced by automatic nucleic acid sequencing equipment or sequencers. Each file contains information which can be interpreted by specialised software to reveal the sequence (base calling). This is done by the sequencer proprietary software or publicly available programs. Depending on the size of a sequencing project the number of trace files can vary from just a few to thousands of files. Sequencing quality assessment on various criteria is important at the stage preceding clustering and contig assembly. Two major publicly available packages – Phred and Staden are used by preAssemble to perform sequence quality processing.

Results

The preAssemble pre-assembly sequence processing pipeline has been developed for small to large scale automatic processing of DNA sequencer chromatogram (trace) data. The Staden Package Pregap4 module and base-calling program Phred are utilized in the pipeline, which produces detailed and self-explanatory output that can be displayed with a web browser. preAssemble can be used successfully with very little previous experience, however options for parameter tuning are provided for advanced users. preAssemble runs under UNIX and LINUX operating systems. It is available for downloading and will run as stand-alone software. It can also be accessed on the Norwegian Salmon Genome Project web site where preAssemble jobs can be run on the project server.

Conclusion

preAssemble is a tool allowing to perform quality assessment of sequences generated by automatic sequencing equipment. preAssemble is flexible since both interactive jobs on the preAssemble server and the stand alone downloadable version are available.

Virtually no previous experience is necessary to run a default preAssemble job, on the other hand options for parameter tuning are provided. Consequently preAssemble can be used as efficiently for just several trace files as for large scale sequence processing.
Evaluation of methods for oligonucleotide array data via quantitative real-time PCR
Authors: Qin Li-Xuan , Beyer Richard P , Hudson Francesca N , Linford Nancy J , Morris Daryl E , Kerr Kathleen F
Published: January 2006

Background

There are currently many different methods for processing and summarizing probe-level data from Affymetrix oligonucleotide arrays. It is of great interest to validate these methods and identify those that are most effective. There is no single best way to do this validation, and a variety of approaches is needed. Moreover, gene expression data are collected to answer a variety of scientific questions, and the same method may not be best for all questions. Only a handful of validation studies have been done so far, most of which rely on spike-in datasets and focus on the question of detecting differential expression. Here we seek methods that excel at estimating relative expression. We evaluate methods by identifying those that give the strongest linear association between expression measurements by array and the "gold-standard" assay.

Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) is generally considered the "gold-standard" assay for measuring gene expression by biologists and is often used to confirm findings from microarray data. Here we use qRT-PCR measurements to validate methods for the components of processing oligo array data: background adjustment, normalization, mismatch adjustment, and probeset summary. An advantage of our approach over spike-in studies is that methods are validated on a real dataset that was collected to address a scientific question.

Results

We initially identify three of six popular methods that consistently produced the best agreement between oligo array and RT-PCR data for medium- and high-intensity genes. The three methods are generally known as MAS5, gcRMA, and the dChip mismatch mode. For medium- and high-intensity genes, we identified use of data from mismatch probes (as in MAS5 and dChip mismatch) and a sequence-based method of background adjustment (as in gcRMA) as the most important factors in methods' performances. However, we found poor reliability for methods using mismatch probes for low-intensity genes, which is in agreement with previous studies.

Conclusion

We advocate use of sequence-based background adjustment in lieu of mismatch adjustment to achieve the best results across the intensity spectrum. No method of normalization or probeset summary showed any consistent advantages.
Analysis and visualization of chromosomal abnormalities in SNP data with SNPscan
Authors: Ting Jason C , Ye Ying , Thomas George H , Ruczinski Ingo , Pevsner Jonathan
Published: January 2006

Background

A variety of diseases are caused by chromosomal abnormalities such as aneuploidies (having an abnormal number of chromosomes), microdeletions, microduplications, and uniparental disomy. High density single nucleotide polymorphism (SNP) microarrays provide information on chromosomal copy number changes, as well as genotype (heterozygosity and homozygosity). SNP array studies generate multiple types of data for each SNP site, some with more than 100,000 SNPs represented on each array. The identification of different classes of anomalies within SNP data has been challenging.

Results

We have developed SNPscan, a web-accessible tool to analyze and visualize high density SNP data. It enables researchers (1) to visually and quantitatively assess the quality of user-generated SNP data relative to a benchmark data set derived from a control population, (2) to display SNP intensity and allelic call data in order to detect chromosomal copy number anomalies (duplications and deletions), (3) to display uniparental isodisomy based on loss of heterozygosity (LOH) across genomic regions, (4) to compare paired samples (e.g. tumor and normal), and (5) to generate a file type for viewing SNP data in the University of California, Santa Cruz (UCSC) Human Genome Browser. SNPscan accepts data exported from Affymetrix Copy Number Analysis Tool as its input. We validated SNPscan using data generated from patients with known deletions, duplications, and uniparental disomy. We also inspected previously generated SNP data from 90 apparently normal individuals from the Centre d'Étude du Polymorphisme Humain (CEPH) collection, and identified three cases of uniparental isodisomy, four females having an apparently mosaic X chromosome, two mislabelled SNP data sets, and one microdeletion on chromosome 2 with mosaicism from an apparently normal female. These previously unrecognized abnormalities were all detected using SNPscan. The microdeletion was independently confirmed by fluorescence in situ hybridization, and a region of homozygosity in a UPD case was confirmed by sequencing of genomic DNA.

Conclusion

SNPscan is useful to identify chromosomal abnormalities based on SNP intensity (such as chromosomal copy number changes) and heterozygosity data (including regions of LOH and some cases of UPD). The program and source code are available at the SNPscan website http://pevsnerlab.kennedykrieger.org/snpscan.htm.
WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data
Authors: Yi Ming , Horton Jay D , Cohen Jonathan C , Hobbs Helen H , Stephens Robert M
Published: January 2006

Background

Analysis of High Throughput (HTP) Data such as microarray and proteomics data has provided a powerful methodology to study patterns of gene regulation at genome scale. A major unresolved problem in the post-genomic era is to assemble the large amounts of data generated into a meaningful biological context. We have developed a comprehensive software tool, WholePathwayScope (WPS), for deriving biological insights from analysis of HTP data.

Result

WPS extracts gene lists with shared biological themes through color cue templates. WPS statistically evaluates global functional category enrichment of gene lists and pathway-level pattern enrichment of data. WPS incorporates well-known biological pathways from KEGG (Kyoto Encyclopedia of Genes and Genomes) and Biocarta, GO (Gene Ontology) terms as well as user-defined pathways or relevant gene clusters or groups, and explores gene-term relationships within the derived gene-term association networks (GTANs). WPS simultaneously compares multiple datasets within biological contexts either as pathways or as association networks. WPS also integrates Genetic Association Database and Partial MedGene Database for disease-association information. We have used this program to analyze and compare microarray and proteomics datasets derived from a variety of biological systems. Application examples demonstrated the capacity of WPS to significantly facilitate the analysis of HTP data for integrative discovery.

Conclusion

This tool represents a pathway-based platform for discovery integration to maximize analysis power. The tool is freely available at http://www.abcc.ncifcrf.gov/wps/wps_index.php.
Similarity-based gene detection: using COGs to find evolutionarily-conserved ORFs
Authors: Powell Bradford C , Hutchison Clyde A
Published: January 2006

Background

Experimental verification of gene products has not kept pace with the rapid growth of microbial sequence information. However, existing annotations of gene locations contain sufficient information to screen for probable errors. Furthermore, comparisons among genomes become more informative as more genomes are examined. We studied all open reading frames (ORFs) of at least 30 codons from the genomes of 27 sequenced bacterial strains. We grouped the potential peptide sequences encoded from the ORFs by forming Clusters of Orthologous Groups (COGs). We used this grouping in order to find homologous relationships that would not be distinguishable from noise when using simple BLAST searches. Although COG analysis was initially developed to group annotated genes, we applied it to the task of grouping anonymous DNA sequences that may encode proteins.

Results

"Mixed COGs" of ORFs (clusters in which some sequences correspond to annotated genes and some do not) are attractive targets when seeking errors of gene predicion. Examination of mixed COGs reveals some situations in which genes appear to have been missed in current annotations and a smaller number of regions that appear to have been annotated as gene loci erroneously. This technique can also be used to detect potential pseudogenes or sequencing errors. Our method uses an adjustable parameter for degree of conservation among the studied genomes (stringency). We detail results for one level of stringency at which we found 83 potential genes which had not previously been identified, 60 potential pseudogenes, and 7 sequences with existing gene annotations that are probably incorrect.

Conclusion

Systematic study of sequence conservation offers a way to improve existing annotations by identifying potentially homologous regions where the annotation of the presence or absence of a gene is inconsistent among genomes.
A domain-oriented approach to the reduction of combinatorial complexity in signal transduction networks
Authors: Conzelmann Holger , Saez-Rodriguez Julio , Sauter Thomas , Kholodenko Boris N , Gilles Ernst D
Published: January 2006

Background:

Receptors and scaffold proteins possess a number of distinct domains and bind multiple partners. A common problem in modeling signaling systems arises from a combinatorial explosion of different states generated by feasible molecular species. The number of possible species grows exponentially with the number of different docking sites and can easily reach several millions. Models accounting for this combinatorial variety become impractical for many applications.

Results:

Our results show that under realistic assumptions on domain interactions, the dynamics of signaling pathways can be exactly described by reduced, hierarchically structured models. The method presented here provides a rigorous way to model a large class of signaling networks using macro-states (macroscopic quantities such as the levels of occupancy of the binding domains) instead of micro-states (concentrations of individual species). The method is described using generic multidomain proteins and is applied to the molecule LAT.

Conclusion:

The presented method is a systematic and powerful tool to derive reduced model structures describing the dynamics of multiprotein complex formation accurately.
Finding biological process modifications in cancer tissues by mining gene expression correlations
Authors: Gamberoni Giacomo , Storari Sergio , Volinia Stefano
Published: January 2006

Background

Through the use of DNA microarrays it is now possible to obtain quantitative measurements of the expression of thousands of genes from a biological sample. This technology yields a global view of gene expression that can be used in several ways. Functional insight into expression profiles is routinely obtained by using Gene Ontology terms associated to the cellular genes. In this paper, we deal with functional data mining from expression profiles, proposing a novel approach that studies the correlations between genes and their relations to Gene Ontology (GO). By using this "functional correlations comparison" we explore all possible pairs of genes identifying the affected biological processes by analyzing in a pair-wise manner gene expression patterns and linking correlated pairs with Gene Ontology terms.

Results

We apply here this "functional correlations comparison" approach to identify the existing correlations in hepatocarcinoma (161 microarray experiments) and to reveal functional differences between normal liver and cancer tissues. The number of well-correlated pairs in each GO term highlights several differences in genetic interactions between cancer and normal tissues. We performed a bootstrap analysis in order to compute false detection rates (FDR) and confidence limits.

Conclusion

Experimental results show the main advantage of the applied method: it both picks up general and specific GO terms (in particular it shows a fine resolution in the specific GO terms). The results obtained by this novel method are highly coherent with the ones proposed by other cancer biology studies. But additionally they highlight the most specific and interesting GO terms helping the biologist to focus his/her studies on the most relevant biological processes.