bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in equipment sharing in injecting drug users in Sydney 1989–1990
Authors: ROSS MICHAEL W. , STOWE AARON , WODAK ALEX , GOLD JULIAN
Published: July 2006

We investigated levels of equipment sharing in injecting drug users in Sydney, Australia, in two consecutive samples recruited in a non‐treatment setting using similar methodology in 1989 (n = 1,245) and 1990 (n = 550). Comparison between the two waves of the study indicated that there were consistent and major reductions in percentage of time used equipment was re‐used, and number of people from whom used equipment had been accepted. There was a corresponding significant and major increase in use of sterile injection equipment, obtained more frequently in the second sample from needle and syringe exchanges. The proportion of respondents reporting they had never shared equipment rose significantly. These data suggest that there is a continuing increase in the adoption of safer injecting practices and utilisation of needle and syringe exchanges over time in response to the threat of HIV transmission in injecting drug users.
Alcoholic hangover and performance: a review
Authors: LEMON JIM
Published: July 2006

The study of alcoholic hangover is reviewed, with particular concern given to its effects upon skills performance. Different models of hangover, and the evidence gathered in their support, are surveyed. Several factors appear to contribute to hangover, and individuals may be differentially susceptible to these influences. The severity of hangover is affected by dose, coproducts of manufacture, and a number of psychological variables. Hangover is differentiated from post‐intoxication effects on performance, and the results of a variety of studies on these effects are considered. Post‐intoxication effects have been found in a variety of tasks, but no tasks have been consistently affected in a number of studies. This may reflect the fact that few studies have used the same tasks to assess performance. Proposed mechanisms of post‐intoxication effects are considered, and the most consistent symptom accompanying impaired performance is found to be fatigue. This notion finds some support in electroencephalographic data collected during the period following intoxication.
Pathophysiologic mechanisms responsible for the reversible (thiamine‐responsive) and irreversible (thiamine non‐responsive) neurological symptoms of Wernicke's encephalopathy
Authors: BUTTERWORTH ROGER F.
Published: July 2006

Chronic alcoholism results in thiamine deficiency as a result of poor nutrition and impaired gastrointestinal absorption of the vitamin. Pyrithiamine‐induced thiamine deficiency in the rat reproduces a neurological syndrome and ultimately neuropathological damage of a nature and distribution that is similar to that encountered in Wernicke's encephalopathy in humans. Pyrithiamine‐induced thiamine deficiency results in selective reversible decreases in activity of the thiamine‐dependent enzymeα‐ketoglutarate dehydrogenase and concomitant reversible changes in brain amino acids. It is proposed that these changes constitute “the biochemical lesion” in thiamine deficiency encephalopathy. If sufficiently severe and prolonged, decreased activities of a‐ketoglutarate dehydrogenase may result in compromised brain energy metabolism and in lactate accumulation in brain, both of which could be responsible for neuronal cell death in this condition. In addition, it has been suggested that cell death results from NMDA‐receptor mediated excitotoxic damage. Similar pathophysiologic mechanisms could be responsible for brain cell death in Wernicke's encephalopathy in humans.
Sociology—the poor relation in alcohol and drug research?
Authors: HAMILTON MARGARET A.
Published: July 2006

As a foundation theoretical discipline, sociology has much to offer the multi‐disciplinary field of alcohol and drug studies. It has, nevertheless, been overshadowed by others such as medicine and, more recently, psychology. This paper maps significant policy issues in the alcohol and drug field over the past decade using Australian experience as an example. It identifies contributions of the social sciences and in doing so, poses a challenge for sociology.
Social change and the control of psychotropic drugs—risk management, harm reduction and ‘postmodernity’
Authors: MUGFORD STEPHEN
Published: July 2006

This paper argues that in order to understand the broad tide of change in drug control in recent times, we need to link these changes to a general understanding of social change. The paper sketches out how modern society arose and how it is giving way to the postmodern. Two themes are then developed. The first concerns the way that the state shrinks in postmodernity and links this to drug control, mentioning the example of random drug testing in the workplace as a good example of the change. It then moves to looking at the related shift in social control regimes from the ‘corporal’ regime of the premodern through the ‘carceral’ regime of the modern to population and risk management in the postmodern. It argues that in society in general there is a tension between carceral discipline and the amoral management of risk and that this is exhibited in drug control as a struggle between individual treatment and law enforcement on the one hand and ‘harm reduction’ on the other. This is illustrated by reference to a persistent tension within the NCADA enterprise.
The relevance of ethnographic understanding to Aboriginal anti‐grog initiatives
Authors: ROWSE TIM
Published: July 2006

Aboriginal initiatives to “beat the grog” may or may not draw on ethnographies of Aboriginal drinking behaviour. The deeper reason for this uncertainty has to do with fundamental ideas of citizenship and (self) governance. What is the relevance of “culture” to individual responsibility? This paper reviews this question at three levels; the political debate about “rights” and “responsibility”, ethnographic depictions of Aborigines as both group‐dominated and individualistic, and through one Aboriginal organization's embracing of the perspectives of Alcoholic's Anonymous.
Beyond Zinberg's ‘social setting’: a processural view of illicit drug use
Authors: MOORE DAVID
Published: July 2006

This article seeks to go beyond existing understandings of ‘social setting’, or social context, in the addictions field. Using drug‐career data, collected during recent ethnographic research, the fluidity and dynamism of recreational drug‐using social scenes are described before introducing a number of anthropological and sociological concepts. These concepts are processural, that is, they seek to describe and analyze social and cultural change. Finally, the theoretical and practical implications of recognizing the diversity and ever‐changing nature of recreational drug‐using social networks are discussed.
Lived fictions: moving from pharmacology to ethnography
Authors: FITZGERALD JOHN L.
Published: July 2006

While positivist science dominates the drug and alcohol research sector, alternative constructivist paradigms of inquiry into drug and alcohol use are also present. The passage of individual researchers through paradigm shifts is often difficult, and rarely documented. Different paradigms of inquiry produce different types of information. The use of the psychoactive drug methylenedioxymetham‐phetamine (MDMA or “Ecstasy”) is discussed in light of a multidisciplinary investigation into the pharmacology and use of MDMA. The role of the author in interpreting data from both positivist and constructivist paradigms is highlighted by documenting a researchers' changes in epistemology whilst undertaking multidisciplinary research. It is concluded that multidisciplinary research into drug and alcohol use could benefit from evaluation of the processes that frame how information from both research paradigms is interpreted and integrated.
Alcohol use among older hospital patients: findings from an Australian study
Authors: Powell Janet E. , McInness Elizabeth
Published: July 2006

Data on alcohol use were obtained from structured interviews with hospital patients aged 65 and over. The cross‐sectional sample (sex by age by region) was drawn from three hospitals in New South Wales, Australia. Multivariate statistics and chi‐square tests of proportion were used to analyse the data. Significant main effects were found for sex and age. The majority (65%) of the sample had consumed alcohol in the past year. Males were more likely than females to be current drinkers and also had a higher mean weekly alcohol intake than females. There was a significant fall in alcohol consumption with age. More males (25%) than females (6%) were found to be hazardous/harmful users of alcohol, and those in the 65‐74‐year age group had a higher incidence of problem alcohol use (20.8%) than those aged 75‐84 (9.8%) and over 85 (4.9%). The results suggest a comparatively high incidence of problem alcohol use among older hospital patients and indicate the need for consumer education.
AIDS and injecting drug use: very risky behaviour in a Perth sample of injecting drug users
Authors: Loxley Wendy M. , Hawks David V.
Published: July 2006

This research was carried out in 1990 to examine high‐risk injecting and sexual behaviour in a sample of injecting drug users (IDUs) in Perth. The study was a cross‐sectional survey with a convenience sample drawn from drug treatment (54%) and non‐treatment (46%) populations. In the sample of 150 IDUs, there were 11 very risky drug behaviour (VRDB) and 63 very risky sex behaviour (VRSB) respondents. Four respondents fell into both categories. Independent comparisons were made between each risk group and the rest of the sample. The VRDB respondents were heterosexual men, most of whom were in long‐term monogamous relationships, with heavier levels of drug use than the rest of the sample. The VRSB respondents were largely single and mainly heterosexual, with more sexual partners than the rest of the sample. It was concluded that there was little evidence that very risky behaviour was related to a general risk‐taking dimension, to inadequate knowledge about AIDS or to a low assessment of personal vulnerability to AIDS. However, situational influences in association with heavy drug use appeared to be a major component of high‐risk injecting behaviour, while high‐risk sexual behaviour appeared more to be a reflection of community norms about heterosexual sexual behaviour. The study should be replicated with larger samples, particularly as the VRDB group was so small, but if the findings are reproduced in other studies, it suggests that serious attention should be paid to the promotion of safer sex among injecting drug users.
Imagery and craving in alcohol dependent persons
Authors: Felstead Boyce , Love Anthony W. , Pead John , Taylor Stephen
Published: July 2006

There is limited evidence supporting the effectiveness of imagery techniques in exposure‐based treatments for alcohol dependence. Changes in craving for alcohol following imagery instruction, measured by cognitive and physiological indices, have not been demonstrated. Furthermore, the influence of different imagery script content has not been investigated. This study compared levels of craving elicited, measured by self‐report and salivation, under control and imagery conditions, in subjects receiving treatment for alcohol dependence. Imagery script content was varied across three levels. Participants generally reported forming good quality images with strong affective components. Significant effects of imagery treatment were found for changes in self‐reported craving levels, but not for the salivation measure. Significant decay in levels of self‐reported craving was also observed. No differences in effectiveness between the three script types were discovered. Implications of the results for therapy approaches such as cue exposure are considered.
Allocation of research funds in the drug and alcohol field: report of the Consensus Workshop
Authors: Walsh Raoul A. , Sanson‐Fisher Rob
Published: July 2006

Issues concerning the allocation of research funds in the drug and alcohol field have been widely debated. A consensus workshop involving senior researchers and policy makers was convened to examine the appropriateness of current drug and alcohol research activities in Australia. The workshop identified several major barriers restricting research developments including lack of monitoring of research efforts, limited community support, inappropriate allocations of research funds which contributed to a low level of intervention studies, the lack of application of research findings by practitioners and ethical constraints in studies involving Aboriginal populations and in multi‐centre trials. Agreement was reached on 16 recommendations which could increase the amount of high quality research in Australia directed at reducing the harm associated with alcohol, tobacco and other drug use. Strategies which funding bodies could use to encourage intervention studies were identified. A proposal for the Australian Medical and Professional Society on Alcohol and other Drugs to establish a Researchers' Group to encourage implementation of the recommendations was also endorsed by workshop participants.
Minimizing drug‐related harm in Australia—Australia's National Drug Strategy
Authors: Wares Malcolm C.
Published: July 2006

The article describes the nature, origins and development of Australia's recently announced National Drug Strategy (NDS). The NDS aims to minimize the harmful effects of drugs and drug use in Australian society and covers the period 1993‐97. The National Drug Strategic Plan is discussed, and the means by which the NDS will be monitored. The National Campaign Against Drug Abuse (NCADA), the forerunner to the NDS, is reviewed in terms of its major achievements. The Campaign was particularly successful in raising the policy profile of alcohol and tobacco, the drugs causing the most harm in Australian society. The relationship between the latest evaluation of NCADA and the NDS is also described.
Dysarthria and Friedreich's ataxia: what can intelligibility assessment tell us?
Authors: Blaney Bronagh , Hewlett Nigel
Published: July 2006

Background: Friedreich's ataxia is one of the most common hereditary disorders of the nervous system. Dysarthria is a pervasive symptom of Friedreich's ataxia, yet the clinical presentation of speech symptoms remains poorly understood, leaving clinicians without the evidence required to develop therapy interventions.

Aims: The research reported herein had three aims: the first was to document the severity of the intelligibility deficit associated with Friedreich's ataxia dysarthria; the second was to document the phonetic profile of the intelligibility deficit; and the third was to use the results of the phonetic profile to estimate the motor control mechanisms and neurological substrates implicated in Friedreich's ataxia dysarthria.

Methods & Procedures: Eleven adult males with Friedreich's ataxia were recruited. Intelligibility was assessed using a single‐word multiple‐choice task completed by ten listeners.

Outcomes & Results: Intelligibility severity ratings ranged from mild to severe. The majority of subjects fell into the mild category. The phonetic errors revealed a distinctive profile, with word‐final plosive voicing contrast representing the highest source of error. Involvement of cerebro‐cerebellar loops was considered to be compatible with the profile results.

Conclusions: Friedreich's ataxia dysarthria has a distinctive phonetic profile and contains subgroups of different severity. High sources of error identified in the phonetic profile should be considered when developing targets for therapy intervention. Neurological substrates are considered to vary across individuals and to include involvement of cerebro‐cerebellar loops. Further research involving acoustic analysis of final plosive voicing contrasts would provide further insights into the neurological substrates involved.
Neuronal Calcium Sensor-1 and Phosphatidylinositol 4-Kinase β Stimulate Extracellular Signal-regulated Kinase 1/2 Signaling by Accelerating Recycling through the Endocytic Recycling Compartment
Authors: Kapp-Barnea Yaara , Ninio-Many Lihi , Hirschberg Koret , Fukuda Mitsunori , Jeromin Andreas , Sagi-Eisenberg Ronit
Published: July 2006

We demonstrate that recycling through the endocytic recycling compartment (ERC) is an essential step in FcεRI-induced activation of extracellular signal-regulated kinase (ERK)1/2. We show that ERK1/2 acquires perinuclear localization and colocalizes with Rab 11 and internalized transferrin in FcεRI-activated cells. Moreover, a close correlation exists between the amount of ERC-localized ERK1/2 and the amount of phospho-ERK1/2 that resides in the nucleus. We further show that by activating phosphatidylinositol 4-kinase β (PI4Kβ) and increasing the cellular level of phosphatidylinositol(4) phosphate, neuronal calcium sensor-1 (NCS-1), a calmodulin-related protein, stimulates recycling and thereby enhances FcεRI-triggered activation and nuclear translocation of ERK1/2. Conversely, NCS-1 short hairpin RNA, a kinase dead (KD) mutant of PI4Kβ (KD-PI4Kβ), the pleckstrin homology (PH) domain of FAPP1 as well as RNA interference of synaptotagmin IX or monensin, which inhibit export from the ERC, abrogate FcεRI-induced activation of ERK1/2. Consistently, NCS-1 also enhances, whereas both KD-PI4Kβ and FAPP1-PH domain inhibit, FcεRI-induced release of arachidonic acid/metabolites, a downstream target of ERK1/2 in mast cells. Together, our results demonstrate a novel role for NCS-1 and PI4Kβ in regulating ERK1/2 signaling and inflammatory reactions in mast cells. Our results further identify the ERC as a crucial determinant in controlling ERK1/2 signaling.
Dynamic Regulation of Mammalian Numb by G Protein-coupled Receptors and Protein Kinase C Activation: Structural Determinants of Numb Association with the Cortical Membrane
Authors: Dho Sascha E. , Trejo JoAnn , Siderovski David P. , McGlade C. Jane
Published: July 2006

The cell fate determinant Numb is a membrane-associated adaptor protein involved in both development and intracellular vesicular trafficking. It has a phosphotyrosine-binding (PTB) domain and COOH-terminal endocytic-binding motifs for α-adaptin and Eps15 homology domain-containing proteins. Four isoforms of Numb are expressed in vertebrates, two of which selectively associate with the cortical membrane. In this study, we have characterized a cortical pool of Numb that colocalizes with AP2 and Eps15 at substratum plasma membrane punctae and cortical membrane-associated vesicles. Green fluorescent protein (GFP)-tagged mutants of Numb were used to identify the structural determinants required for localization. In addition to the previously described association of the PTB domain with the plasma membrane, we show that the AP2-binding motifs facilitate the association of Numb with cortical membrane punctae and vesicles. We also show that agonist stimulation of G protein-coupled receptors (GPCRs) that are linked to phospholipase Cβ and protein kinase C (PKC) activation causes redistribution of Numb from the cortical membrane to the cytosol. This effect is correlated with Numb phosphorylation and an increase in its Triton X-100 solubility. Live-imaging analysis of mutants identified two regions within Numb that are independently responsive to GPCR-mediated lipid hydrolysis and PKC activation: the PTB domain and a region encompassing at least three putative PKC phosphorylation sites. Our data indicate that membrane localization of Numb is dynamically regulated by GPCR-activated phospholipid hydrolysis and PKC-dependent phosphorylation events.
The Intracellular Domain of ErbB4 Induces Differentiation of Mammary Epithelial Cells
Authors: Muraoka-Cook Rebecca S. , Sandahl Melissa , Husted Carty , Hunter Debra , Miraglia Leah , Feng Shu-mang , Elenius Klaus , Earp H. Shelton
Published: July 2006

Differentiation of mammary epithelium in vivo requires signaling through prolactin- and ErbB4/HER4-dependent mechanisms; how these pathways intersect is unknown. We show herein that HC11 mouse mammary cells undergo ErbB4-dependent lactational differentiation. Prolactin and the ErbB4 ligand HB-EGF each induced STAT5A activation, expression of lactogenic differentiation markers, and lumen formation in three-dimensional Matrigel cultures in HC11 cells. ErbB4 undergoes ligand-dependent transmembrane domain cleavage at Val-675, releasing a soluble 80-kDa intracellular domain (s80HER4) that localizes to nuclei; the physiological relevance of s80HER4 is unknown. A HER4V675A mutant abolishing transmembrane cleavage impaired STAT5A activity, lactogenic gene expression, and lumen formation. Kinase-dead HER4KD was neither cleaved nor able to induce differentiation of HC11 cells. Without treating HC11 cells with prolactin or HB-EGF, s80HER4 (expressed from a cDNA construct) localized to the nucleus, activated STAT5A, and induced three-dimensional lumen formation. Nuclear localization of exogenous s80HER4 required intact kinase activity of s80HER4, as did activation of STAT5A. In contrast, nuclear localization of s80HER4 and STAT5A activation did not require the 16-amino acid region of the ErbB4 intracellular domain specific to the Cyt-1 isoform of ErbB4, and absent in the Cyt-2 isoform. These results suggest that s80HER4 formation contributes to ErbB4-dependent differentiation of mammary epithelial cells.
A Global, Myosin Light Chain Kinase-dependent Increase in Myosin II Contractility Accompanies the Metaphase–Anaphase Transition in Sea Urchin Eggs
Authors: Lucero Amy , Stack Christianna , Bresnick Anne R. , Shuster Charles B.
Published: July 2006

Myosin II is the force-generating motor for cytokinesis, and although it is accepted that myosin contractility is greatest at the cell equator, the temporal and spatial cues that direct equatorial contractility are not known. Dividing sea urchin eggs were placed under compression to study myosin II-based contractile dynamics, and cells manipulated in this manner underwent an abrupt, global increase in cortical contractility concomitant with the metaphase–anaphase transition, followed by a brief relaxation and the onset of furrowing. Prefurrow cortical contractility both preceded and was independent of astral microtubule elongation, suggesting that the initial activation of myosin II preceded cleavage plane specification. The initial rise in contractility required myosin light chain kinase but not Rho-kinase, but both signaling pathways were required for successful cytokinesis. Last, mobilization of intracellular calcium during metaphase induced a contractile response, suggesting that calcium transients may be partially responsible for the timing of this initial contractile event. Together, these findings suggest that myosin II-based contractility is initiated at the metaphase–anaphase transition by Ca2+-dependent myosin light chain kinase (MLCK) activity and is maintained through cytokinesis by both MLCK- and Rho-dependent signaling. Moreover, the signals that initiate myosin II contractility respond to specific cell cycle transitions independently of the microtubule-dependent cleavage stimulus.
BLOC-1 Interacts with BLOC-2 and the AP-3 Complex to Facilitate Protein Trafficking on Endosomes
Authors: Di Pietro Santiago M. , Falcón-Pérez Juan M. , Tenza Danièle , Setty Subba R.G. , Marks Michael S. , Raposo Graça , Dell’Angelica Esteban C.
Published: July 2006

The adaptor protein (AP)-3 complex is a component of the cellular machinery that controls protein sorting from endosomes to lysosomes and specialized related organelles such as melanosomes. Mutations in an AP-3 subunit underlie a form of Hermansky-Pudlak syndrome (HPS), a disorder characterized by abnormalities in lysosome-related organelles. HPS in humans can also be caused by mutations in genes encoding subunits of three complexes of unclear function, named biogenesis of lysosome-related organelles complex (BLOC)-1, -2, and -3. Here, we report that BLOC-1 interacts physically and functionally with AP-3 to facilitate the trafficking of a known AP-3 cargo, CD63, and of tyrosinase-related protein 1 (Tyrp1), a melanosomal membrane protein previously thought to traffic only independently of AP-3. BLOC-1 also interacts with BLOC-2 to facilitate Tyrp1 trafficking by a mechanism apparently independent of AP-3 function. Both BLOC-1 and -2 localize mainly to early endosome-associated tubules as determined by immunoelectron microscopy. These findings support the idea that BLOC-1 and -2 represent hitherto unknown components of the endosomal protein trafficking machinery.
Substring selection for biomedical document classification
Authors: Han Bo , Obradovic Zoran , Hu Zhang-Zhi , Wu Cathy H. , Vucetic Slobodan
Published: July 2006

Motivation: Attribute selection is a critical step in development of document classification systems. As a standard practice, words are stemmed and the most informative ones are used as attributes in classification. Owing to high complexity of biomedical terminology, general-purpose stemming algorithms are often conservative and could also remove informative stems. This can lead to accuracy reduction, especially when the number of labeled documents is small. To address this issue, we propose an algorithm that omits stemming and, instead, uses the most discriminative substrings as attributes.

Results: The approach was tested on five annotated sets of abstracts from iProLINK that report on the experimental evidence about five types of protein post-translational modifications. The experiments showed that Naive Bayes and support vector machine classifiers perform consistently better [with area under the ROC curve (AUC) accuracy in range 0.92–0.97] when using the proposed attribute selection than when using attributes obtained by the Porter stemmer algorithm (AUC in 0.86–0.93 range). The proposed approach is particularly useful when labeled datasets are small.

Contact:  vucetic@ist.temple.edu

Supplementary Information: The supplementary data are available from
Mutagenic probability estimation of chemical compounds by a novel molecular electrophilicity vector and support vector machine
Authors: Zheng Mingyue , Liu Zhiguo , Xue Chunxia , Zhu Weiliang , Chen Kaixian , Luo Xiaomin , Jiang Hualiang
Published: July 2006

Motivation: Mutagenicity is among the toxicological end points that pose the highest concern. The accelerated pace of drug discovery has heightened the need for efficient prediction methods. Currently, most available tools fall short of the desired degree of accuracy, and can only provide a binary classification. It is of significance to develop a discriminative and informative model for the mutagenicity prediction.

Results: Here we developed a mutagenic probability prediction model addressing the problem, based on datasets covering a large chemical space. A novel molecular electrophilicity vector (MEV) is first devised to represent the structure profile of chemical compounds. An extended support vector machine (SVM) method is then used to derive the posterior probabilistic estimation of mutagenicity from the MEVs of the training set. The results show that our model gives a better performance than TOPKAT () and other previously published methods. In addition, a confidence level related to the prediction can be provided, which may help people make more flexible decisions on chemical ordering or synthesis.

Availability: The binary program (ZGTOX_1.1) based on our model and samples of input datasets on Windows PC are available at upon request from the authors.

Contact:  hljiang@mail.shcnc.ac.cn; xmluo@mail.shcnc.ac.cn
VISTAL—a new 2D visualization tool of protein 3D structural alignments
Authors: Kolodny Rachel , Honig Barry
Published: July 2006

Summary: We offer a tool, denoted VISTAL, for two-dimensional visualization of protein structural alignments. VISTAL describes aligned structures as a series of matched secondary structure elements, colored according to the three-dimensional distance of their Cα atoms.

Availability: VISTAL can be downloaded from

Contact:  bh6@columbia.edu
An initial strategy for comparing proteins at the domain architecture level
Authors: Lin Kui , Zhu Lei , Zhang Da-Yong
Published: July 2006

Motivation: Ideally, only proteins that exhibit highly similar domain architectures should be compared with one another as homologues or be classified into a single family. By combining three different indices, the Jaccard index, the Goodman-Kruskal γ function and the domain duplicate index, into a single similarity measure, we propose a method for comparing proteins based on their domain architectures.

Results: Evaluation of the method using the eukaryotic orthologous groups of proteins (KOGs) database indicated that it allows the automatic and efficient comparison of multiple-domain proteins, which are usually refractory to classic approaches based on sequence similarity measures. As a case study, the PDZ and LRR_1 domains are used to demonstrate how proteins containing promiscuous domains can be clearly compared using our method. For the convenience of users, a web server was set up where three different query interfaces were implemented to compare different domain architectures or proteins with domain(s), and to identify the relationships among domain architectures within a given KOG from the Clusters of Orthologous Groups of Proteins database.

Conclusion: The approach we propose is suitable for estimating the similarity of domain architectures of proteins, especially those of multidomain proteins.

Availability:  

Contact:  linkui@bnu.edu.cn

Supplementary Information: Supplementary data are available at Bioinformatics online.
RBR: library-less repeat detection for ESTs
Authors: Malde Ketil , Schneeberger Korbinian , Coward Eivind , Jonassen Inge
Published: July 2006

Motivation: Repeat sequences in ESTs are a source of problems, in particular for clustering. ESTs are therefore commonly masked against a library of known repeats. High quality repeat libraries are available for the widely studied organisms, but for most other organisms the lack of such libraries is likely to compromise the quality of EST analysis.

Results: We present a fast, flexible and library-less method for masking repeats in EST sequences, based on match statistics within the EST collection. The method is not linked to a particular clustering algorithm. Extensive testing on datasets using different clustering methods and a genomic mapping as reference shows that this method gives results that are better than or as good as those obtained using RepeatMasker with a repeat library.

Availability: The implementation of RBR is available under the terms of the GPL from

Contact:  ketil.malde@bccs.uib.no

Supplementary Information: Supplementary data are available at Bioinformatics online.
Interpolated variable order motifs for identification of horizontally acquired DNA: revisiting the Salmonella pathogenicity islands
Authors: Vernikos Georgios S. , Parkhill Julian
Published: July 2006

Motivation: There is a growing literature on the detection of Horizontal Gene Transfer (HGT) events by means of parametric, non-comparative methods. Such approaches rely only on sequence information and utilize different low and high order indices to capture compositional deviation from the genome backbone; the superiority of the latter over the former has been shown elsewhere. However even high order k-mers may be poor estimators of HGT, when insufficient information is available, e.g. in short sliding windows. Most of the current HGT prediction methods require pre-existing annotation, which may restrict their application on newly sequenced genomes.

Results: We introduce a novel computational method, Interpolated Variable Order Motifs (IVOMs), which exploits compositional biases using variable order motif distributions and captures more reliably the local composition of a sequence compared with fixed-order methods. For optimal localization of the boundaries of each predicted region, a second order, two-state hidden Markov model (HMM) is implemented in a change-point detection framework. We applied the IVOM approach to the genome of Salmonella enterica serovar Typhi CT18, a well-studied prokaryote in terms of HGT events, and we show that the IVOMs outperform state-of-the-art low and high order motif methods predicting not only the already characterized Salmonella Pathogenicity Islands (SPI-1 to SPI-10) but also three novel SPIs (SPI-15, SPI-16, SPI-17) and other HGT events.

Availability: The software is available under a GPL license as a standalone application at

Contact:  gsv@sanger.ac.uk

Supplementary Information: Supplementary data are available at Bioinformatics online.
Detecting functional modules in the yeast protein–protein interaction network
Authors: Chen Jingchun , Yuan Bo
Published: July 2006

Motivation: Identification of functional modules in protein interaction networks is a first step in understanding the organization and dynamics of cell functions. To ensure that the identified modules are biologically meaningful, network-partitioning algorithms should take into account not only topological features but also functional relationships, and identified modules should be rigorously validated.

Results: In this study we first integrate proteomics and microarray datasets and represent the yeast protein–protein interaction network as a weighted graph. We then extend a betweenness-based partition algorithm, and use it to identify 266 functional modules in the yeast proteome network. For validation we show that the functional modules are indeed densely connected subgraphs. In addition, genes in the same functional module confer a similar phenotype. Furthermore, known protein complexes are largely contained in the functional modules in their entirety. We also analyze an example of a functional module and show that functional modules can be useful for gene annotation.

Contact:  yuan.33@osu.edu

Supplementary Information: Supplementary data are available at Bioinformatics online
Ocean climate prior to breeding affects the duration of the nestling period in the Atlantic puffin
Authors: Durant Joël M , Anker-Nilssen Tycho , Stenseth Nils Chr
Published: July 2006

Time-series covering 23 years for a long-lived seabird, the Atlantic puffin (
Fratercula arctica
L.) at Røst, northern Norway, was used to explore any indirect effects of climatic variations on chick production. By fitting statistical models on the duration of the nestling period, we found that it may be estimated using the average sea temperature and salinity at 0–20 m depth in March (having a positive and a negative effect, respectively). We propose that when the phytoplankton bloom occurs in early spring, adverse oceanographic conditions, i.e. low temperature and high salinity in March, have a negative effect on puffin reproduction by degradation of the prey availability (mainly
Clupea harengus
) for chick-feeding adults three months later.
Paths swept out by initially slack flexible wires when cutting soft solids; when passing through a very viscous medium; and during regelation
Authors: Dunn P.D , Burton J.D , Xu X , Atkins A.G
Published: July 2006

Flow and fracture of some soft solids may be described by the ‘solid’ mechanical properties of elastic modulus, yield stress and fracture toughness, all being dependent on rate, temperature and environment. Other soft solids behave more like very viscous materials. When cutting soft solids, friction is often high between the blade and the material, and cutting is made easier when performed with a thin wire. The wire may be held taut in a frame like a fretsaw, but cutting is often done using an initially slack wire pulled into the solid by hand or machine. For both types of material behaviours, we investigate the curved shape taken by a loaded wire, elements along which cut into the material both radially and tangentially.

For soft materials displaying solid properties, the treatment is based on the analysis of bi-directional cutting by Atkins
et al
. (Atkins
et al
. 2004
J. Mater. Sci.
39
, 2761–2766), in which it was shown that the ratio
ξ
of tangential to radial displacements strongly influences the cutting forces. The shapes of wires of various lengths arranged as bowstrings, and the loads in the wires, are assessed against experiments on cheddar cheese. The resultant force takes a minimum value for a particular length of the wire, owing to the competition between lower cutting forces, but higher friction at large
ξ
and vice versa.

Passage of a wire through very viscous materials is flow at very low Reynolds number. To determine the path swept out, we make use of the property of all slender bodies of revolution in highly viscous flow, namely, that the drag exerted across the body is approximately twice as large as along. Comparison is made with the experiments on weighted threads falling under gravity in glycerine.

Regelation is another example of passage of a wire through a solid. The mechanism is completely different but, in the context of the present paper, we provide in
appendix A
the solution for the typical hours-long school demonstration where, unlike most reported studies, non-uniform temperature fields develop in the block of ice. Comparison is made with experiment.
Stochastic re-calibration: contextual effects on perceived tilt
Authors: Solomon Joshua A , Morgan Michael J
Published: July 2006

The human visual system exaggerates the difference between the tilts of adjacent lines or grating patches. In addition to this tilt illusion, we found that oblique flanks reduced acuity for small changes of tilt in the centre of the visual field. However, no flanks—regardless of their tilts—decreased sensitivity to contrast. Thus, the foveal tilt illusion should not be attributed to orientation-selective lateral inhibition. Nor is it similar to conventional crowding, which typically does not impair letter recognition in the fovea. Our observers behaved as though the reference orientation (horizontal) had a small tilt in the direction of the flanks. We suggest that the extent of this re-calibration varies randomly over trials, and we demonstrate that this stochastic re-calibration can explain flank-induced acuity loss in the fovea.
Protein motions during catalysis by dihydrofolate reductases
Authors: Allemann Rudolf K , Evans Rhiannon M , Tey Lai-hock , Maglia Giovanni , Pang Jiayun , Rodriguez Robert , Shrimpton Paul J , Swanwick Richard S
Published: July 2006

Dihydrofolate reductase (DHFR) maintains the intracellular pool of tetrahydrofolate through catalysis of hydrogen transfer from reduced nicotinamide adenine dinucleotide to 7,8-dihydrofolate. We report results for pre-steady-state kinetic studies of the temperature dependence of the rates and the hydrogen/deuterium-kinetic isotope effects for the reactions catalysed by the enzymes from the mesophilic
Escherichia coli
and the hyperthermophilic
Thermatoga maritima
. We propose an evolutionary pattern in which catalysis progressed from a relatively rigid active site structure in the ancient thermophilic DHFR to a more flexible and kinetically more efficient structure in
E. coli
that actively promotes hydrogen transfer at physiological pH by modulating the tunnelling distance. The
E. coli
enzyme appeared relatively robust, in that kinetically severely compromised mutants still actively propagated the reaction. The reduced hydrogen transfer rates of the extensively studied Gly121Val mutant of DHFR from
E. coli
were most likely due to sterically unfavourable long-range effects from the introduction of the bulky isopropyl group.
Quantum catalysis in B
12
-dependent methylmalonyl-CoA mutase: experimental and computational insights
Authors: Banerjee Ruma , Dybala-Defratyka Agnieszka , Paneth Piotr
Published: July 2006

B
12
-dependent methylmalonyl-CoA mutase catalyses the interchange of a hydrogen atom and the carbonyl-CoA group on adjacent carbons of methylmalonyl-CoA to give the rearranged product, succinyl-CoA. The first step in this reaction involves the transient generation of cofactor radicals by homolytic rupture of the cobalt–carbon bond to generate the deoxyadenosyl radical and cob(II)alamin. This step exhibits a curious sensitivity to isotopic substitution in the substrate, methylmalonyl-CoA, which has been interpreted as evidence for kinetic coupling. The magnitude of the isotopic discrimination is large and a deuterium isotope effect ranging from 35.6 at 20 °C to 49.9 at 5 °C has been recorded. Arrhenius analysis of the temperature dependence of this isotope effect provides evidence for quantum tunnelling in this hydrogen transfer step. The mechanistic complexity of the observed rate constant for cobalt–carbon bond homolysis together with the spectroscopically silent nature of many of the component steps limits the insights that can be derived by experimental approaches alone. Computational studies using a newly developed geometry optimization scheme that allows determination of the transition state in the full quantum mechanical/molecular mechanical coordinate space have yielded novel insights into the strategy deployed for labilizing the cobalt–carbon bond and poising the resulting deoxyadenosyl radical for subsequent hydrogen atom abstraction.
The role of enzyme dynamics and tunnelling in catalysing hydride transfer: studies of distal mutants of dihydrofolate reductase
Authors: Wang Lin , Goodey Nina M , Benkovic Stephen J , Kohen Amnon
Published: July 2006

Residues M42 and G121 of
Escherichia coli
dihydrofolate reductase (
ec
DHFR) are on opposite sides of the catalytic centre (15 and 19 Å away from it, respectively). Theoretical studies have suggested that these distal residues might be part of a dynamics network coupled to the reaction catalysed at the active site. The
ec
DHFR mutant G121V has been extensively studied and appeared to have a significant effect on rate, but only a mild effect on the nature of H-transfer. The present work examines the effect of M42W on the physical nature of the catalysed hydride transfer step. Intrinsic kinetic isotope effects (KIEs), their temperature dependence and activation parameters were studied. The findings presented here are in accordance with the environmentally coupled hydrogen tunnelling. In contrast to the wild-type (WT), fluctuations of the donor–acceptor distance were required, leading to a significant temperature dependence of KIEs and deflated intercepts. A comparison of M42W and G121V to the WT enzyme revealed that the reduced rates, the inflated primary KIEs and their temperature dependences resulted from an imperfect potential surface pre-arrangement relative to the WT enzyme. Apparently, the coupling of the enzyme's dynamics to the reaction coordinate was altered by the mutation, supporting the models in which dynamics of the whole protein is coupled to its catalysed chemistry.
Protein dynamics and catalysis: the problems of transition state theory and the subtlety of dynamic control
Authors: Pineda J.R.E.T , Schwartz S.D
Published: July 2006

This manuscript describes ongoing research on the nature of chemical reactions in enzymes. We will investigate how protein dynamics can couple to chemical reaction in an enzyme. We first investigate in some detail why transition state theory cannot fully describe the dynamics of chemical reactions catalysed by enzymes. We describe quantum theories of chemical reaction in condensed phase including studies of how the symmetry of coupled vibrational modes differentially affects reaction dynamics. We make reference to previous work in our group on a variety of condensed phase chemical reactions (liquid and crystalline) and a variety of enzymatically catalysed reactions including the reactions of lactate dehydrogenase and purine nucleoside phosphorylase. All the protein motions we have studied have been quite rapid. We will propose methods to find motions over a broad range of time-scales in enzymes that couple to chemical catalysis. We report recent findings which show that conformational fluctuations in lactate dehydrogenase can strongly affect its ability to catalyse reactions through protein motion, and that only a tiny minority of conformations appear to be catalytically competent.
Hydrogen tunnelling in enzyme-catalysed H-transfer reactions: flavoprotein and quinoprotein systems
Authors: Sutcliffe Michael J , Masgrau Laura , Roujeinikova Anna , Johannissen Linus O , Hothi Parvinder , Basran Jaswir , Ranaghan Kara E , Mulholland Adrian J , Leys David , Scrutton Nigel S
Published: July 2006

It is now widely accepted that enzyme-catalysed C–H bond breakage occurs by quantum mechanical tunnelling. This paradigm shift in the conceptual framework for these reactions away from semi-classical transition state theory (TST, i.e. including zero-point energy, but with no tunnelling correction) has been driven over the recent years by experimental studies of the temperature dependence of kinetic isotope effects (KIEs) for these reactions in a range of enzymes, including the tryptophan tryptophylquinone-dependent enzymes such as methylamine dehydrogenase and aromatic amine dehydrogenase, and the flavoenzymes such as morphinone reductase and pentaerythritol tetranitrate reductase, which produced observations that are also inconsistent with the simple Bell-correction model of tunnelling. However, these data—especially, the strong temperature dependence of reaction rates and the variable temperature dependence of KIEs—are consistent with other tunnelling models (termed full tunnelling models), in which protein and/or substrate fluctuations generate a configuration compatible with tunnelling. These models accommodate substrate/protein (environment) fluctuations required to attain a configuration with degenerate nuclear quantum states and, when necessary, motion required to increase the probability of tunnelling in these states. Furthermore, tunnelling mechanisms in enzymes are supported by atomistic computational studies performed within the framework of modern TST, which incorporates quantum nuclear effects.
Classification of stacking faults and their stepwise elimination during the disorder → order transformation of nickel hydroxide
Authors: Ramesh T. N. , Kamath P. Vishnu , Shivakumara C.
Published: July 2006

Nickel hydroxide samples obtained by strong alkali precipitation are replete with stacking faults. The local structures of the stacking faults resemble the stacking patterns of different polytypic modifications that are theoretically possible among the layered hydroxides. This resemblance becomes a basis for the classification of stacking faults into different types. Each type of stacking fault produces a characteristic non-uniform broadening of peaks in the X-ray powder diffraction pattern of nickel hydroxide. DIFFaX simulations aid the classification and quantification of stacking faults. Hydrothermal treatment of a poorly ordered nickel hydroxide slurry at different temperatures (338–473 K) and different durations (5–48 h) shows that the stacking faults are removed in a stepwise manner. The as-precipitated sample has 17–20% stacking faults of the 3R
2 variety, which evolve into the 2H
2 type at 413 K. The 2H
2 stacking faults persist up to 443 K. The stacking faults are completely removed only at 473 K. At this temperature an ordered β-Ni(OH)2 phase is observed.
Structures of (S)-(−)-4-oxo-2-azetidinecarboxylic acid and 3-azetidinecarboxylic acid from powder synchrotron diffraction data
Authors: Mora Asiloé J. , Brunelli Michela , Fitch Andrew N. , Wright Jonathan , Báez Maria E. , López-Carrasquero Francisco
Published: July 2006

The crystal structures of the four-membered heterocycles (S)-(−)-4-oxo-2-azetidinecarboxylic acid (I) and 3-azetidinecarboxylic acid (II) were solved by direct methods using powder synchrotron X-ray diffraction data. The asymmetry of the oxoazetidine and azetidine rings is discussed, along with the hydrogen bonding.