bluuebunny/crossref_metadata_2025 huggingface dataset:
Heritable and stable gene knockdown in rats
Authors: Dann Christina Tenenhaus , Alvarado Alma L. , Hammer Robert E. , Garbers David L.
Published: July 2006

The rat has served as an excellent model for studies on animal physiology and as a model for human diseases such as diabetes and alcoholism; however, genetic studies have been limited because of the inability to knock out genes. Our goal was to produce heritable deficiencies in specific gene function in the rat using RNA interference to knock down gene expression
in vivo
. Lentiviral-mediated transgenesis was used to produce rats expressing a short hairpin RNA targeting
Dazl
, a gene expressed in germ cells and required for fertility in mice [Ruggiu, M., Speed, R., Taggart, M., McKay, S. J., Kilanowski, F., Saunders, P., Dorin, J. & Cooke, H. J. (1997)
Nature
389, 73–77]. Germ-line transmission of the transgene occurred, and its expression correlated with significant reductions in DAZL protein levels and male sterility, and the knockdown was stable over multiple generations (F
1
–F
3
). This study demonstrates an efficient system by which directed reverse genetic analysis can now be performed in the rat.
Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation
Authors: Koga Fumitaka , Xu Wanping , Karpova Tatiana S. , McNally James G. , Baron Roland , Neckers Len
Published: July 2006

Hsp90 plays an essential role in maintaining stability and activity of its clients, including oncogenic signaling proteins that regulate key signal transduction nodes. Hsp90 inhibitors interfere with diverse signaling pathways by destabilizing and attenuating activity of such proteins, and thus they exhibit antitumor activity. However, Hsp90 inhibition has recently been reported to activate Akt and Erk and potentiate Akt activation induced by insulin-like growth factor 1 and insulin, raising the concern that clinical use of Hsp90 inhibitors might promote tumor progression under certain circumstances. Here, we show that the prototypical Hsp90 inhibitor geldanamycin induces Akt and Erk activation that is independent of PTEN status and is mediated by transient activation of Src kinase. Activated Src phosphorylates Cbl, which recruits the p85 subunit of phosphatidylinositol 3-kinase, resulting in phosphatidylinositol 3-kinase activation and eventually the activation of Akt and Erk. We show that geldanamycin rapidly disrupts Src association with Hsp90, suggesting that Src activation results directly from dissociation of the chaperone. These data suggest that, under certain circumstances, dual inhibition of Hsp90 and Src may be warranted.
A two-dimensional view of the folding energy landscape of cytochrome
c
Authors: Werner James H. , Joggerst Raymond , Dyer R. Brian , Goodwin Peter M.
Published: July 2006

Time-correlated single photon counting (TCSPC) was combined with fluorescence correlation spectroscopy (FCS) to study the transition between acid-denatured states and the native structure of cytochrome
c
(Cyt
c
) from
Saccharomyces cerevisiae
. The use of these techniques in concert proved to be more powerful than either alone, yielding a two-dimensional picture of the folding energy landscape of Cyt
c
. TCSPC measured the distribution of distances between the heme of the protein and a covalently attached dye molecule at residue C102 (one folding reaction coordinate), whereas FCS measured the hydrodynamic radius (a second folding reaction coordinate) of the protein over a range of pH values. These two independent measurements provide complimentary information regarding protein conformation. We see evidence for a well defined folding intermediate in the acid renaturation folding pathway of this protein reflected in the distribution of lifetimes needed to fit the TCSPC data. Moreover, FCS studies revealed this intermediate state to be in dynamic equilibrium with unfolded structures, with conformational fluctuations into and out of this intermediate state occurring on an ≈30-μs time scale.
Biophysical model of self-organized spindle formation patterns without centrosomes and kinetochores
Authors: Schaffner Stuart C. , José Jorge V.
Published: July 2006

Eukaryotic cell division and chromosome segregation depend crucially on the mitotic spindle pattern formation. The usual pathway for spindle production involves microtubule polymerization from two centrosomes. However, experiments using
Xenopus
extracts with micrometer-sized chromatin-coated beads found, remarkably, that spindle patterns can form in the absence of centrosomes, kinetochores, and duplicated chromosomes. Here we introduce a previously undescribed biophysical model inspired by the heuristic interpretations of the experiments that provides a quantitative explanation and constraints for this type of experiment. The model involves plus-directed (chromokinesin and Eg5) and minus-directed (cytoplasmic dynein oligomers) motors walking on microtubules and the boundary conditions caused by the chromatin-coated spheres. This model combines the effects of the plus-directed cross-linking motor Eg5 and any chromokinesin on the chromatin-covered beads, reflecting current uncertainties in the division of function between the two kinds of motors. The model can nucleate dynamically a variety of self-organized spindle patterns over a wide range of biological parameter values. Our calculations show that spindles will form over a wide range of parameter values. Some parameter values cause a monaster to form instead of a bipolar spindle. Varying the processivity and the dynein microtubule attachment and detachment rates, we find stability parameters for spindle formations. These results not only constrain the possible parameter values, but they point toward the proper division of function between Eg5 and chromokinesin in this spindle formation pathway. The model results suggest experiments that would further enhance our understanding of the basic elements needed for spindle pattern formation in this pathway.
Single-molecule dynamics of phytochrome-bound fluorophores probed by fluorescence correlation spectroscopy
Authors: Miller Abigail E. , Fischer Amanda J. , Laurence Ted , Hollars Christopher W. , Saykally Richard J. , Lagarias J. Clark , Huser Thomas
Published: July 2006

Fluorescence correlation spectroscopy (FCS) was used to investigate the hydrodynamic and photophysical properties of PR1 (phytofluor red 1), an intensely red fluorescent biliprotein variant of the truncated cyanobacterial phytochrome 1 (Cph1Δ, which consists of the N-terminal 514 amino acids). Single-molecule diffusion measurements showed that PR1 has excellent fluorescence properties at the single-molecule level, making it an interesting candidate for red fluorescent protein fusions. FCS measurements for probing dimer formation in solution over a range of protein concentrations were enabled by addition of Cph1Δ apoprotein (apoCph1Δ) to nanomolar solutions of PR1. FCS brightness analysis showed that heterodimerization of PR1 with apoCph1Δ altered the chemical environment of the PR1 chromophore to further enhance its fluorescence emission. Fluorescence correlation measurements also revealed interactions between apoCph1Δ and the red fluorescent dyes Cy5.18 and Atto 655 but not Alexa Fluor 660. The concentration dependence of protein:dye complex formation indicated that Atto 655 interacted with, or influenced the formation of, the apoCph1 dimer. These studies presage the utility of phytofluor tags for probing single-molecule dynamics in living cells in which the fluorescence signal can be controlled by the addition of various chromophores that have different structures and photophysical properties, thereby imparting different types of information, such as dimer formation or the presence of open binding faces on a protein.
Parasites dominate food web links
Authors: Lafferty Kevin D. , Dobson Andrew P. , Kuris Armand M.
Published: July 2006

Parasitism is the most common animal lifestyle, yet food webs rarely include parasites. The few earlier studies have indicated that including parasites leads to obvious increases in species richness, number of links, and food chain length. A less obvious result was that adding parasites slightly reduced connectance, a key metric considered to affect food web stability. However, reported reductions in connectance after the addition of parasites resulted from an inappropriate calculation. Two alternative corrective approaches applied to four published studies yield an opposite result: parasites increase connectance, sometimes dramatically. In addition, we find that parasites can greatly affect other food web statistics, such as nestedness (asymmetry of interactions), chain length, and linkage density. Furthermore, whereas most food webs find that top trophic levels are least vulnerable to natural enemies, the inclusion of parasites revealed that mid-trophic levels, not low trophic levels, suffered the highest vulnerability to natural enemies. These results show that food webs are very incomplete without parasites. Most notably, recognition of parasite links may have important consequences for ecosystem stability because they can increase connectance and nestedness.
Benefit of farnesoid X receptor inhibition in obstructive cholestasis
Authors: Stedman Catherine , Liddle Christopher , Coulter Sally , Sonoda Junichiro , Alvarez Jacqueline G. , Evans Ronald M. , Downes Michael
Published: July 2006

The nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor have been implicated in regulating bile acid, lipid, carbohydrate, and xenobiotic metabolism. Bile duct ligation was used to increase endogenous bile acids and evaluate the roles of these receptors in modulating cholestatic liver injury. FXR knockout (KO) mice were found to be protected from obstructive cholestasis. Concurrent deletion of FXR also could ameliorate an increase in liver injury that is seen usually in pregnane X receptor KO mice with cholestasis. Mechanisms proposed for this protection include the lowering of bile acid concentrations and altered expression of the hepatic transporters Mdr1, Mdr2, BSEP, and Mrp4. FXR KO mice also exhibit a biphasic lipid profile after bile duct ligation, with an increase in high-density lipoprotein cholesterol and triglycerides by day 6. The expression of apolipoprotein AV was reduced in these mice, implicating FXR in triglyceride regulation. We show that FXR modulates cholestasis by controlling bile acids within the hepatocyte and is involved in bile acid synthesis, bile excretion via BSEP, and serum export via Mrp4. This study strongly suggests a potential clinical role for FXR antagonists in the treatment of obstructive cholestatic liver disorders.
Glycolipid α-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice
Authors: Fujii Shin-ichiro , Shimizu Kanako , Hemmi Hiroaki , Fukui Mikiko , Bonito Anthony J. , Chen Guangwu , Franck Richard W. , Tsuji Moriya , Steinman Ralph M.
Published: July 2006

α-Galactosylceramide (α-GalCer) is the prototype compound for studying the presentation of glycolipids on CD1d molecules to natural killer T (NKT) lymphocytes. A single i.v. dose of glycolipid triggers a cascade of events involving the production of several cytokines over the course of a day, a short-lived activation of NKT and natural killer (NK) cells, and a more prolonged adaptive T cell immune response if certain antigens are given together with α-GalCer. We find that a recently described analogue, α-C-galactosylceramide (α-C-GalCer), more potently induces these innate and adaptive immune responses in mice. α-C-GalCer acts as a more effective trigger for IL-12 and IFN-γ production, although it minimally elicits IL-4 and TNF-α release into the serum. Also, α-C-GalCer better mobilizes NKT and natural killer cells to resist B16 melanoma. To help understand these effects, we find that α-C-GalCer binds more stably to dendritic cells than α-GalCer and that dendritic cells loaded with α-C-GalCer induce larger and more long lasting NKT cell responses
in vivo
. When glycolipid is targeted to dendritic cells in spleen together with antigens in dying cells, such as irradiated tumor cells, α-C-GalCer is active as an adjuvant for T cell-mediated immunity at lower doses, just 20 ng per mouse, where it is also able to up-regulate the required CD40L costimulatory molecule on NKT cells. Therefore, α-C-GalCer represents a glycolipid that binds more stably to dendritic cells and acts as a more effective link between innate and adaptive immunity
in vivo
.
Dietary α-linolenic acid and health-related outcomes: a metabolic perspective
Authors: Burdge Graham C , Calder Philip C
Published: July 2006

α-Linolenic acid (αLNA; 18: 3n-3) is essential in the human diet, probably because it is the substrate for the synthesis of longer-chain, more unsaturatedn-3 fatty acids, principally EPA (20: 5n-3) and DHA (22: 6n-3), which confer important biophysical properties on cell membranes and so are required for tissue function. The extent to which this molecular transformation occurs in man is controversial. The present paper reviews the recent literature on the metabolism of αLNA in man, including the use of dietary αLNA in β-oxidation, recycling of carbon by fatty acid synthesisde novoand conversion to longer-chain PUFA. Sex differences in αLNA metabolism and the possible biological consequences are discussed. Increased consumption of EPA and DHA in fish oil has a number of well-characterised beneficial effects on health. The present paper also reviews the efficacy of increased αLNA consumption in increasing the concentrations of EPA and DHA in blood and cell lipid pools, and the extent to which such dietary interventions might be protective against CVD and inflammation. Although the effects on CVD risk factors and inflammatory markers are variable, where beneficial effects have been reported these are weaker than have been achieved from increasing consumption of EPA+DHA or linoleic acid. Overall, the limited capacity for conversion to longer-chainn-3 fatty acids, and the lack of efficacy in ameliorating CVD risk factors and inflammatory markers in man suggests that increased consumption of αLNA may be of little benefit in altering EPA+DHA status or in improving health outcomes compared with other dietary interventions.
Nutrition-based health in animal production
Authors: Adams Clifford A
Published: July 2006

Events such as BSE, foot and mouth disease and avian influenza illustrate the importance of animal health on a global basis. The only practical solution to deal with such problems has usually been mass culling of millions of animals at great effort and expense. Serious consideration needs to be given to nutrition as a practical solution for health maintenance and disease avoidance of animals raised for food. Health or disease derives from a triad of interacting factors; diet–disease agent, diet–host and disease agent–host. Various nutrients and other bioactive feed ingredients, nutricines, directly influence health by inhibiting growth of pathogens or by modulating pathogen virulence. It is possible to transform plant-based feed ingredients to produce vaccines against important diseases and these could be fed directly to animals. Nutrients and nutricines contribute to three major factors important in the diet–host interaction; maintenance of gastrointestinal integrity, support of the immune system and the modulation of oxidative stress. Nutrition-based health is the next challenge in modern animal production and will be important to maintain economic viability and also to satisfy consumer demands in terms of food quality, safety and price. This must be accomplished largely through nutritional strategies making optimum use of both nutrients and nutricines.
Aspects of anthocyanin absorption, metabolism and pharmacokinetics in humans
Authors: Kay Colin D
Published: July 2006

Interest in the health-promoting properties of berry anthocyanins is intensifying; however, findings are primarily based onin vitrocharacteristics, leaving mechanisms associated with absorption, metabolism and pharmacokinetics largely unexplored. The present review integrates the available anthocyanin literature with that of similar flavonoids or polyphenols in order to form hypotheses regarding absorption, metabolism and clearance in humans. Of the limited available literature regarding the absorption and clearance kinetics of anthocyanins, maximum plasma concentrations are reported anywhere between 1·4 and 592 nmol/l and occur at 0·5–4 h post-consumption (doses; 68–1300 mg). Average urinary excretion is reported between 0·03 and 4 % of the ingested dose, having elimination half-lives of 1·5–3 h. In addition, much is unknown regarding the metabolism of anthocyanins. The most commonly cited conjugation reactions involved in the metabolism of other flavonoids include glucuronidation, methylation and sulfation. It is reasonable to suspect that anthocyanins are metabolised in much the same manner; however, until recently, there was little evidence to suggest that anthocyanins were metabolised to any significant extent. New evidence now suggests that anthocyanins are absorbed and transported in human serum and urine primarily as metabolites, with recent studies documenting as much as 68–80 % of anthocyanins as metabolised derivatives in human urine. Further research is required to resolve mechanisms associated with the absorption, metabolism and clearance of anthocyanins in order to establish their true biological activities and health effects. The presented evidence will hopefully focus future research, refining study design and propagating a more complete understanding of anthocyanins' biological significance in humans.
Different dietary strategies for weight loss in obesity: role of energy and macronutrient content
Authors: Abete I , Parra M. D , Zulet M. A , Martínez J. A
Published: July 2006

Obesity is a chronic disorder caused by an imbalance of the energy metabolism with high associated burdens. Therefore, huge efforts are being currently devoted in studying new types of hypoenergetic diets and their composition, in order to characterise more specific, long-lasting and safe slimming protocols. A number of investigations are trying to determine the specific influence of the macronutrient distribution in energy-restricted diets on the management of excessive body weight. In this context, very-low-energy diets supplying between 1670 and 3350 kJ (400 and 800 kcal)/d have been beneficial in short-term treatments causing a weight loss of 300–500 g/d. Such strategies place more emphasis on energy restriction than on the macronutrient composition of the diet prescription. Weight loss produced by either low-carbohydrate or low-fat moderately energy-restricted diets ranges from 0·5 to 1·0 kg/week, while diets with high or moderately high protein content have also been applied in weight-reducing programmes by inducing losses of 0·2–0·4 kg/week. Other factors that determine weight loss by dieting are sex, age, initial body weight, race, genetics, regional fat deposition, etc, which must be taken into account to explain the variability in the outcomes of different low-energy diets. Therefore, more research is needed about the impact of diets with different fuel substrates and foods on the characteristics of the weight-loss process.
Are the health benefits of fish oils limited by products of oxidation?
Authors: Turner Rufus , McLean Carlene H , Silvers Karen M
Published: July 2006

Human clinical trials have shown that fish oils reduce the risk of a variety of disorders including CVD. Despite this, results have been inconsistent. Fish oils are easily oxidised and some fish oils contain higher than recommended levels of oxidised products, but their effects have not been investigated. Recent evidence indicates that dietary oxidised fats can contribute to the development of atherosclerosis and thrombosis. This review summarises findings from cellular, animal and human trials that have examined the effects of oxidised lipids and their potential to affect health outcomes, and proposes that oxidised products in fish oils may attenuate their beneficial effects. More research is required to determine the magnitude of negative effects of fish oil on health outcomes in clinical trials.
Parameters controlling the glycaemic response to breads
Authors: Fardet Anthony , Leenhardt Fanny , Lioger Delphine , Scalbert Augustin , Rémésy Christian
Published: July 2006

Bread is one of the most widely consumed staple foods worldwide. White-wheat bread, largely consumed in France, is made from highly refined flour, which leads to a low nutrient density. Due to a highly porous structure and gelatinised starch, it is easily broken down during digestion, leading to a rapid increase of glucose released into the bloodstream. Low glycaemic responses are considered favourable to health, especially against a background of diabetes. Literature reports show that selection of raw material is an essential factor in decreasing the glycaemic index (GI) of white bread. There are two means of decreasing the rate of starch degradation: either (i) slowing gastric emptying rate and/or glucose diffusion–absorption through the intestinal mucosa, which can be achieved by incorporating soluble fibre or organic acid in bread, or (ii) limiting starch accessibility to α-amylase by using high-amylose cereal varieties and/or incorporating intact cereal grains. Studies on cereal products show that preservation of the food structure during digestion seems to be a more important GI-reducing factor than the degree of starch crystallinity or the presence of soluble fibre. Thus, we should look to produce bread with a more compact food structure or higher density, which is the case in leavened wholewheat bread or bread with intact cereal grains. The baking process should also be improved to achieve this goal, by using, for example, a reduced kneading time or less yeast than usual.
One-carbon metabolism in psychiatric illness
Authors: Sugden C
Published: July 2006

The cost of psychiatric illness to the UK economy was recently estimated at £77 billion annually. Despite years of research no firm aetiological explanation exists, and with no physiological or biochemical markers diagnosis is made entirely on a behavioural basis. All current pharmacological therapies are associated with serious long-term side effects. Substantial evidence supports the involvement of one-carbon cycle dysregulation in psychiatric illness, but this is not currently used as a basis for diagnosis or treatment. The present paper reviews the evidence for one-carbon cycle dysregulation in schizophrenic, bipolar, depressed and autistic patients. Also presented are novel findings from the field of epigenetics, which demonstrate how the one-carbon cycle-derived methyl donorS-adenosylmethionine influences the expression of key genes in the brain affecting memory, learning, cognition and behaviour, genes whose expression is reduced to varying degrees in these patient groups. Clinical evidence that nutritional supplements can rectify one-carbon cycle activity, and restore normal gene expression, suggests a novel approach to the development of biochemical tests and simple, non-harmful treatments for some psychiatric patients. Conversely, evidence from animal studies highlights the dangers of exposing the unborn fetus to very high dietary levels of folic acid, a one-carbon cycle cofactor. Fetal adaptations to a high-folate environment may interfere with folate metabolism postnatally, with serious consequences for the epigenetic regulation of gene expression. The public health implications of these diverse scenarios indicate an urgent need for further research in this field.
Mechanisms involved in the nutritional regulation of mRNA translation: features of the avian model
Authors: Tesseraud Sophie , Abbas Mourad , Duchene Sophie , Bigot Karine , Vaudin Pascal , Dupont Joëlle
Published: July 2006

Abstract:Insulin and amino acids are key factors in regulating protein synthesis. The mechanisms of their action have been widely studied for several years. The insulin signal is mediated by the activation of intracellular kinases such as phosphatidylinositol–3'kinase and the mammalian target of rapamycin (mTOR), affecting the phosphorylation of some major effectors involved in the regulation of translation initiation, i.e. p70 S6 kinase (p70S6K) and the translational repressor eukaryotic initiation factor 4E binding protein (4E-BP1). The amino acid–induced signalling cascade also originates from mTOR and promotes p70S6K and 4E–BP1 activation. However, the mechanisms of regulation are complex and little understood, especiallyin vivo. Elucidating these mechanisms is important for both fundamental physiology and nutritional applications, i.e. better control of the use of nutrients and optimisation of dietary amino acid supplies in various physiological and physiopathological situations. In comparative physiology, the chicken is an interesting model to gain better understanding of the nutritional regulation of mRNA translation because of the very high rates of muscle growth and protein synthesis, and the unusual features compared with mammals. In the present review we provide an overview of the roles of insulin and amino acids as regulators of protein synthesis in both mammals and avian species.
Evolving enzyme technology: impact on commercial poultry nutrition
Authors: Cowieson A. J , Hruby M , Pierson E. E. M
Published: July 2006

The use of exogenous enzymes to improve the nutritional value of poultry diets is a relatively new concept. The technology is rapidly evolving, with new enzymes, enzyme combinations, and novel applications being developed as rapidly as regulatory restrictions will allow. Most researchers in the field of poultry nutrition would consider phytase to be the last significant leap forward in terms of enzyme use in the animal feed industry. However, there is a great deal of ongoing research into the next generation of enzymes with a focus on ingredient quality, predictability of response via least-square models, improvements in food safety, effect of bird age, effect of various side activities and enzyme dose, maximisation of net income and reduction in environmental pollution. It is the purpose of the present review article to summarise the current research in the area of feed enzymes for poultry and to speculate on future applications of enzymes and new enzyme technologies that may be of value to the industry in the coming years.
Nutritional supplements: prevalence of use and contamination with doping agents
Authors: Van Thuyne W , Van Eenoo P , Delbeke F. T
Published: July 2006

Based upon recent sales numbers, nutritional supplements play a key role in the lifestyle of a substantial proportion of the population. As well as products such as vitamins or minerals, several precursors of anabolic steroids are marketed as nutritional supplements. Another group of commercially available supplements are products for weight loss based upon herbal formulations originating fromEphedraspecies. Apart from supplements indicating the presence of these active compounds, numerous non-hormonal nutritional supplements were found that were contaminated with non-labelled anabolic steroids. Stimulating agents other than naturally occurring analogues of ephedrine were detected. A major group using dietary supplements are sportsmen, ranging from amateur level to elite athletes. Besides the possible health risks associated with the use of dietary supplements, athletes should take care not to violate the rules of the World Anti-Doping Agency because athletes remain responsible for substances detected in their biofluids, irrespective of their origin. Several analytical methods have been developed to determine the presence of doping agents as contaminants. The present review attempts to address the issues concerning the use of nutritional supplements and the detection of doping agents as contaminants in dietary supplements.
Influence of dietary components on development of the microbiota in single-stomached species
Authors: Bauer Eva , Williams Barbara A , Smidt Hauke , Mosenthin Rainer , Verstegen Martin W. A
Published: July 2006

After birth, development of a normal microbial community occurs gradually, and is affected by factors such as the composition of the maternal gut microbiota, the environment, and the host genome. Diet also has a direct influence, both on composition and activity of this community. This influence begins with the milk, when specific components exert their growth-promoting effect on a beneficial microbiota, thereby suppressing potential pathogens. For example, breast-fed infants compared with formula-fed babies usually have a microbial community dominated by bifidobacteria. When solid food is introduced (weaning), dramatic changes in microbial composition occur, so pathogens can gain access to the disturbed gastrointestinal (GI) ecosystem. However, use of specific dietary components can alter the composition and activity of the microbiota positively. Of all dietary components, fermentable carbohydrates seem to be most promising in terms of promoting proliferation of beneficial bacterial species. Carbohydrate fermentation results in the production of SCFA which are known for their trophic and health-promoting effects. Fermentation of proteins, on the other hand, is often associated with growth of potential pathogens, and results in production of detrimental substances including NH3and amines. In terms of the GI microbiota, lipids are often associated with the antimicrobial activity of medium-chain fatty acids and their derivatives. The present review aims to provide deeper insights into the composition and development of the neonatal GI microbiota, how this microbiota can be influenced by certain dietary components, and how this might ultimately lead to improvements in host health.
Changes in the initiation of heroin use after a reduction in heroin supply
Authors: DAY CAROLYN , DEGENHARDT LOUISA , HALL WAYNE
Published: July 2006

Increasing heroin use in Australia over the past 30 years has been associated with a decline in the age of initiation to heroin use. The 2001 Australian heroin shortage was used to assess the effects of a reduction in heroin supply on age of initiation into heroin injecting. Data collected from regular injecting drug users (IDU) over the period 1996–2004 as part of the Australian Illicit Drug Reporting System were examined for changes in self‐reported age of first heroin use after the onset of the heroin shortage. Estimates were also made of the number of young people who may not have commenced injecting heroin during the heroin shortage. The proportion of IDU interviewed in the IDRS who were aged ≤24 years decreased from 46% in 1996 to 12% in 2004, with the most marked drop in 2001, the year in which there was an abrupt and marked reduction in heroin availability. Of those who reported first injecting between 1993 and 2000, similar proportions reported heroin and amphetamine as the first drug injected. After 2000, methamphetamine was the drug most often reported as being the first injected. Estimates suggested that between 2745 and 10 560 young people may not have begun to inject heroin in 2001 as a result of reduced heroin supply. If around one in four of these young users had progressed to regular or dependent heroin use, then there may have been a reduction of between 700 and 2500 dependent heroin users. There was an increase in amphetamine injecting but it is unclear to what extent any reduction in heroin injecting has been offset by increased amphetamine injecting. Reduced heroin availability probably resulted in a reduction in the number of new heroin injectors in Australia. Efforts need to be made to reduce the chances that young people who have initiated methamphetamine injecting do not move to heroin injecting when the heroin supply returns.
Unusual presentations for pharmacotherapy—poppy seed dependence*
Authors: LLOYD‐JONES D. M. , BONOMO Y.
Published: July 2006

Two cases of patients presenting with opioid dependence who maintained their dependence with poppy tea are described. There appears to have been an increase in this practice in some groups, although dependent use is uncommon. These cases illustrate significant levels of dependence on a licit, and readily available, source of opiates requiring high doses of pharmacotherapy that match those typically required by individuals who are treated for heroin dependence.
Identification of transcription factor cooperativity via stochastic system model
Authors: Chang Yu-Hsiang , Wang Yu-Chao , Chen Bor-Sen
Published: July 2006

Motivation: Transcription factor binding sites are known to co-occur in the same gene owing to cooperativity of the transcription factors (TFs) that bind to them. Genome-wide location data can help us understand how an individual TF regulates its target gene. Nevertheless, how TFs cooperate to regulate their target genes still needs further study. In this study, genome-wide location data and expression profiles are integrated to reveal how TFs cooperate to regulate their target genes from the stochastic system perspective.

Results: Based on a stochastic dynamic model, a new measurement of TF cooperativity is developed according to the regulatory abilities of cooperative TF pairs and the number of their occurrences. Our method is employed to the yeast cell cycle and reveals successfully many cooperative TF pairs confirmed by previous experiments, e.g. Swi4-Swi6 in G1/S phase and Ndd1-Fkh2 in G2/M phase. Other TF pairs with potential cooperativity mentioned in our results can provide new directions for future experiments. Finally, a cooperative TF network of cell cycle is constructed from significant cooperative TF pairs.

Contact:  bschen@ee.nthu.edu.tw

Supplementary information:
Scoring of predicted GRK2 phosphorylation sites in Nedd4-2
Authors: Arthur Jonathan W. , Sanchez-Perez Angeles , Cook David I.
Published: July 2006

Motivation: Epithelial Na+ channels (ENaC) mediate the transport of sodium (Na) across epithelia in the kidney, gut and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4-2. These ligases bind to proline-rich motifs (PY motifs) present in the C-termini of ENaC subunits. Loss of this inhibition leads to hypertension. We have previously reported that ENaC channels are maintained in the active state by the G protein coupled receptor kinase, GRK2. The enzyme has been implicated in the development of essential hypertension [R. D. Feldman (2002)Mol. Pharmacol., 61, 707–709]. Additional findings in our lab pointed towards a possible role for GRK2 in the phosphorylation and inactivation of Nedd4-2.

Results: We have predicted GRK2 phosphorylation sites on Nedd4-2 by combining sequence analysis, homology modeling and surface accessibility calculations. A total of 24 potential phosphorylation sites were predicted by sequence analysis. Of these, 16 could be modeled using homology modeling and 6 of these were found to have sufficient surface exposure to be accessible to the GRK2 enzyme responsible for the phosphorylation of Nedd4-2. The method provides an ordered list of the most probable GRK2 phosphorylation sites on Nedd4-2 providing invaluable guidance to future experimental studies aimed at mutating certain Nedd4-2 residues in order to prevent phosphorylation by GRK2. The method developed could be applied in a wide variety of biological applications involving the binding of one molecule to a protein. The relative effectiveness of the technique is determined mainly by the quality of the homology model built for the protein of interest.

Contact:  jarthur@med.usyd.edu.au
CART variance stabilization and regularization for high-throughput genomic data
Authors: Papana Ariadni , Ishwaran Hemant
Published: July 2006

Motivation: mRNA expression data obtained from high-throughput DNA microarrays exhibit strong departures from homogeneity of variances. Often a complex relationship between mean expression value and variance is seen. Variance stabilization of such data is crucial for many types of statistical analyses, while regularization of variances (pooling of information) can greatly improve overall accuracy of test statistics.

Results: A Classification and Regression Tree (CART) procedure is introduced for variance stabilization as well as regularization. The CART procedure adaptively clusters genes by variances. Using both local and cluster wide information leads to improved estimation of population variances which improves test statistics. Whereas making use of cluster wide information allows for variance stabilization of data.

Availability: Sufficient details for our CART procedure are given so that the interested reader can program the method for themselves. The algorithm is also accessible within the Java software package BAMarrayTM, which is freely available to non-commercial users at

Contact:  hemant.ishwaran@gmail.com
OrderedList—a bioconductor package for detecting similarity in ordered gene lists
Authors: Lottaz Claudio , Yang Xinan , Scheid Stefanie , Spang Rainer
Published: July 2006

Summary:  OrderedList is a Bioconductor compliant package for meta-analysis based on ordered gene lists like those resulting from differential gene expression analysis. Our package quantifies the similarity between gene lists. The significance of the similarity score is estimated from random scores computed on perturbed data. OrderedList illustrates list similarity in intuitive plots and determines the score-driving genes for further analysis.

Availability:  

Contact:  claudio.lottaz@molgen.mpg.de

Supplementary information: Please visit our webpage on
Gene selection in cancer classification using sparse logistic regression with Bayesian regularization
Authors: Cawley Gavin C. , Talbot Nicola L. C.
Published: July 2006

Motivation: Gene selection algorithms for cancer classification, based on the expression of a small number of biomarker genes, have been the subject of considerable research in recent years. Shevade and Keerthi propose a gene selection algorithm based on sparse logistic regression (SLogReg) incorporating a Laplace prior to promote sparsity in the model parameters, and provide a simple but efficient training procedure. The degree of sparsity obtained is determined by the value of a regularization parameter, which must be carefully tuned in order to optimize performance. This normally involves a model selection stage, based on a computationally intensive search for the minimizer of the cross-validation error. In this paper, we demonstrate that a simple Bayesian approach can be taken to eliminate this regularization parameter entirely, by integrating it out analytically using an uninformative Jeffrey's prior. The improved algorithm (BLogReg) is then typically two or three orders of magnitude faster than the original algorithm, as there is no longer a need for a model selection step. The BLogReg algorithm is also free from selection bias in performance estimation, a common pitfall in the application of machine learning algorithms in cancer classification.

Results: The SLogReg, BLogReg and Relevance Vector Machine (RVM) gene selection algorithms are evaluated over the well-studied colon cancer and leukaemia benchmark datasets. The leave-one-out estimates of the probability of test error and cross-entropy of the BLogReg and SLogReg algorithms are very similar, however the BlogReg algorithm is found to be considerably faster than the original SLogReg algorithm. Using nested cross-validation to avoid selection bias, performance estimation for SLogReg on the leukaemia dataset takes almost 48 h, whereas the corresponding result for BLogReg is obtained in only 1 min 24 s, making BLogReg by far the more practical algorithm. BLogReg also demonstrates better estimates of conditional probability than the RVM, which are of great importance in medical applications, with similar computational expense.

Availability: A MATLAB implementation of the sparse logistic regression algorithm with Bayesian regularization (BLogReg) is available from

Contact:  gcc@cmp.uea.ac.uk
Serial NetEvolve: a flexible utility for generating serially-sampled sequences along a tree or recombinant network
Authors: Buendia Patricia , Narasimhan Giri
Published: July 2006

Summary:  Serial NetEvolve is a flexible simulation program that generates DNA sequences evolved along a tree or recombinant network. It offers a user-friendly Windows graphical interface and a Windows or Linux simulator with a diverse selection of parameters to control the evolutionary model. Serial NetEvolve is a modification of the Treevolve program with the following additional features: simulation of serially-sampled data, the choice of either a clock-like or a variable rate model of sequence evolution, sampling from the internal nodes and the output of the randomly generated tree or network in our newly proposed NeTwick format.

Availability: From website

Contacts:  giri@cis.fiu.edu

Supplementary information: Manual and examples available from
SynView: a GBrowse-compatible approach to visualizing comparative genome data
Authors: Wang Haiming , Su Yanqi , Mackey Aaron J. , Kraemer Eileen T. , Kissinger Jessica C.
Published: July 2006

Summary: We present SynView, a simple and generic approach to dynamically visualize multi-species comparative genome data. It is a light-weight application based on the popular and configurable web-based GBrowse framework. It can be used with a variety of databases and provides the user with a high degree of interactivity. The tool is written in Perl and runs on top of the GBrowse framework. It is in use in the PlasmoDB () and the CryptoDB () projects and can be easily integrated into other cross-species comparative genome projects.

Availability: The program and instructions are freely available at

Contact:  jkissing@uga.edu
Global topological features of cancer proteins in the human interactome
Authors: Jonsson Pall F. , Bates Paul A.
Published: July 2006

Motivation: The study of interactomes, or networks of protein-protein interactions, is increasingly providing valuable information on biological systems. Here we report a study of cancer proteins in an extensive human protein-protein interaction network constructed by computational methods.

Results: We show that human proteins translated from known cancer genes exhibit a network topology that is different from that of proteins not documented as being mutated in cancer. In particular, cancer proteins show an increase in the number of proteins they interact with. They also appear to participate in central hubs rather than peripheral ones, mirroring their greater centrality and participation in networks that form the backbone of the proteome. Moreover, we show that cancer proteins contain a high ratio of highly promiscuous structural domains, i.e., domains with a high propensity for mediating protein interactions. These observations indicate an underlying evolutionary distinction between the two groups of proteins, reflecting the central roles of proteins, whose mutations lead to cancer.

Contact:  paul.bates@cancer.org.uk

Supplementary information: The interactome data are available though the PIP (Potential Interactions of Proteins) web server at . Further additional material is available at
Comparative evaluation of reverse engineering gene regulatory networks with relevance networks, graphical gaussian models and bayesian networks
Authors: Werhli Adriano V. , Grzegorczyk Marco , Husmeier Dirk
Published: July 2006

Motivation: An important problem in systems biology is the inference of biochemical pathways and regulatory networks from postgenomic data. Various reverse engineering methods have been proposed in the literature, and it is important to understand their relative merits and shortcomings. In the present paper, we compare the accuracy of reconstructing gene regulatory networks with three different modelling and inference paradigms: (1) Relevance networks (RNs): pairwise association scores independent of the remaining network; (2) graphical Gaussian models (GGMs): undirected graphical models with constraint-based inference, and (3) Bayesian networks (BNs): directed graphical models with score-based inference. The evaluation is carried out on the Raf pathway, a cellular signalling network describing the interaction of 11 phosphorylated proteins and phospholipids in human immune system cells. We use both laboratory data from cytometry experiments as well as data simulated from the gold-standard network. We also compare passive observations with active interventions.

Results: On Gaussian observational data, BNs and GGMs were found to outperform RNs. The difference in performance was not significant for the non-linear simulated data and the cytoflow data, though. Also, we did not observe a significant difference between BNs and GGMs on observational data in general. However, for interventional data, BNs outperform GGMs and RNs, especially when taking the edge directions rather than just the skeletons of the graphs into account. This suggests that the higher computational costs of inference with BNs over GGMs and RNs are not justified when using only passive observations, but that active interventions in the form of gene knockouts and over-expressions are required to exploit the full potential of BNs.

Availability: Data, software and supplementary material are available from .

Contact:  adriano@bioss.ac.uk, dirk@bioss.ac.uk, Grzegorc@statistik.uni-dortmund.de
Increased recovery of Moraxella catarrhalis and Haemophilus influenzae in association with group A β-haemolytic streptococci in healthy children and those with pharyngo-tonsillitis
Authors: Brook Itzhak , Gober Alan E.
Published: July 2006

The inflamed tonsils harbour numerous types of bacteria, alone or in combination with group A β-haemolytic streptococci (GABHS). The cohabitation of the tonsils by GABHS and certain other bacterial species may contribute to the inflammatory process and the failure of penicillin therapy. This study evaluated the recovery of Moraxella catarrhalis, Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae in association with GABHS in healthy children and those with acute pharyngo-tonsillitis (APT). Pharyngo-tonsillar cultures were obtained from 548 children with APT and 866 healthy children. GABHS was recovered from 112 (20.4 %) children with APT. Of the 114 H. influenzae isolates, 32 were recovered in association with GABHS (29 % of all patients who had GABHS) and 82 were isolated without GABHS (19 %) (P=0.0267). Of the 69 M. catarrhalis isolates, 25 were recovered in association with GABHS (22 % of all patients who had GABHS) and 44 were isolated without GABHS (10 %) (P=0.0012). In contrast, there was no association between the isolation of GABHS and the recovery of Staph. aureus or Strep. pneumoniae. GABHS was recovered from 104 (12 %) healthy children. Of the 69 M. catarrhalis isolates, 24 were recovered in association with GABHS (23 % of all patients who had GABHS) and 80 were isolated without GABHS (10 %) (P=0.006). There was no association between the isolation of GABHS and the recovery of H. influenzae, Staph. aureus or Strep. pneumoniae. This study demonstrates an association between the recovery of GABHS and H. influenzae and M. catarrhalis from pharyngo-tonsillar cultures of patients with APT and M. catarrhalis from pharyngo-tonsillar cultures of healthy children.