bluuebunny/crossref_metadata_2025 huggingface dataset:
Energy-Aware and Time-Critical Geo-Routing in Wireless Sensor Networks
Authors: Xu Yingqi , Lee Wang-Chien , Xu Jianliang , Mitchell Gail
Published: October 2008

Volunteer forwarding, as an emerging routing idea for large scale, location-aware wireless sensor networks, has recently received significant attention. However, several critical research issues raised by volunteer forwarding, including communication collisions, communication voids, and time-critical routing, have not been well addressed by the existing work. In this paper, we propose a priority-based stateless geo-routing (PSGR) protocol that addresses these issues. Based on PSGR, sensor nodes are able to locally determine their priority to serve as the next relay node using dynamically estimated network density. This effectively suppresses potential communication collisions without prolonging routing delays. PSGR also overcomes the communication void problem using two alternative stateless schemes, rebroadcast and bypass. Meanwhile, PSGR supports routing of time-critical packets with different deadline requirements at no extra communication cost. Additionally, we analyze the energy consumption and the delivery rate of PSGR as functions of the transmission range. Finally, an extensive performance evaluation has been conducted to compare PSGR with competing protocols, including GeRaf, IGF, GPSR, flooding, and MSPEED. Simulation results show that PSGR exhibits superior performance in terms of energy consumption, routing latency, and delivery rate, and soundly outperforms all of the compared protocols.
Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway
Authors: Franchitto Annapaola , Pirzio Livia Maria , Prosperi Ennio , Sapora Orazio , Bignami Margherita , Pichierri Pietro
Published: October 2008

Failure to stabilize and properly process stalled replication forks results in chromosome instability, which is a hallmark of cancer cells and several human genetic conditions that are characterized by cancer predisposition. Loss of WRN, a RecQ-like enzyme mutated in the cancer-prone disease Werner syndrome (WS), leads to rapid accumulation of double-strand breaks (DSBs) and proliferating cell nuclear antigen removal from chromatin upon DNA replication arrest. Knockdown of the MUS81 endonuclease in WRN-deficient cells completely prevents the accumulation of DSBs after fork stalling. Also, MUS81 knockdown in WS cells results in reduced chromatin recruitment of recombination enzymes, decreased yield of sister chromatid exchanges, and reduced survival after replication arrest. Thus, we provide novel evidence that WRN is required to avoid accumulation of DSBs and fork collapse after replication perturbation, and that prompt MUS81-dependent generation of DSBs is instrumental for recovery from hydroxyurea-mediated replication arrest under such pathological conditions.
Membrane lysis during biological membrane fusion: collateral damage by misregulated fusion machines
Authors: Engel Alex , Walter Peter
Published: October 2008

In the canonical model of membrane fusion, the integrity of the fusing membranes is never compromised, preserving the identity of fusing compartments. However, recent molecular simulations provided evidence for a pathway to fusion in which holes in the membrane evolve into a fusion pore. Additionally, two biological membrane fusion models—yeast cell mating and in vitro vacuole fusion—have shown that modifying the composition or altering the relative expression levels of membrane fusion complexes can result in membrane lysis. The convergence of these findings showing membrane integrity loss during biological membrane fusion suggests new mechanistic models for membrane fusion and the role of membrane fusion complexes.
Putting the model to the test: are APC proteins essential for neuronal polarity, axon outgrowth, and axon targeting?
Authors: Rusan Nasser M. , Akong Kathryn , Peifer Mark
Published: October 2008

The highly polarized architecture of neurons is important for their function. Experimental data based on dominant-negative approaches suggest that the tumor suppressor adenomatous polyposis coli (APC), a regulator of Wnt signaling and the cytoskeleton, regulates polarity of neuroectodermal precursors and neurons, helping specify one neurite as the axon, promoting its outgrowth, and guiding axon pathfinding. However, such dominant-negative approaches might affect processes in which APC is not essential. We completely removed both APCs from Drosophila melanogaster larval neural precursors and neurons, testing whether APCs play universal roles in neuronal polarity. Surprisingly, APCs are not essential for asymmetric cell division or the stereotyped division axis of central brain (CB) neuroblasts, although they do affect cell cycle progression and spindle architecture. Likewise, CB, lobular plug, and mushroom body neurons do not require APCs for polarization, axon outgrowth, or, in the latter two cases, axon targeting. These data suggest that proposed cytoskeletal roles for APCs in mammals should be reassessed using loss of function tools.
Elevated levels of placental growth factor represent an adaptive host response in sepsis
Authors: Yano Kiichiro , Okada Yoshiaki , Beldi Guido , Shih Shou-Ching , Bodyak Natalya , Okada Hitomi , Kang Peter M. , Luscinskas William , Robson Simon C. , Carmeliet Peter , Karumanchi S. Ananth , Aird William C.
Published: October 2008

Recently, we demonstrated that circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are increased in sepsis (Yano, K., P.C. Liaw, J.M. Mullington, S.C. Shih, H. Okada, N. Bodyak, P.M. Kang, L. Toltl, B. Belikoff, J. Buras, et al. 2006. J. Exp. Med. 203:1447–1458). Moreover, enhanced VEGF/Flk-1 signaling was shown to contribute to sepsis morbidity and mortality. We tested the hypothesis that PlGF also contributes to sepsis outcome. In mouse models of endotoxemia and cecal ligation puncture, the genetic absence of PlGF or the systemic administration of neutralizing anti-PlGF antibodies resulted in higher mortality compared with wild-type or immunoglobulin G–injected controls, respectively. The increased mortality associated with genetic deficiency of PlGF was reversed by adenovirus (Ad)-mediated overexpression of PlGF. In the endotoxemia model, PlGF deficiency was associated with elevated circulating levels of VEGF, induction of VEGF expression in the liver, impaired cardiac function, and organ-specific accentuation of barrier dysfunction and inflammation. Mortality of endotoxemic PlGF-deficient mice was increased by Ad-mediated overexpression of VEGF and was blocked by expression of soluble Flt-1. Collectively, these data suggest that up-regulation of PlGF in sepsis is an adaptive host response that exerts its benefit, at least in part, by attenuating VEGF signaling.
Position-dependent motif characterization using non-negative matrix factorization
Authors: Hutchins Lucie N. , Murphy Sean M. , Singh Priyam , Graber Joel H.
Published: October 2008

Motivation:  Cis-acting regulatory elements are frequently constrained by both sequence content and positioning relative to a functional site, such as a splice or polyadenylation site. We describe an approach to regulatory motif analysis based on non-negative matrix factorization (NMF). Whereas existing pattern recognition algorithms commonly focus primarily on sequence content, our method simultaneously characterizes both positioning and sequence content of putative motifs.

Results: Tests on artificially generated sequences show that NMF can faithfully reproduce both positioning and content of test motifs. We show how the variation of the residual sum of squares can be used to give a robust estimate of the number of motifs or patterns in a sequence set. Our analysis distinguishes multiple motifs with significant overlap in sequence content and/or positioning. Finally, we demonstrate the use of the NMF approach through characterization of biologically interesting datasets. Specifically, an analysis of mRNA 3′-processing (cleavage and polyadenylation) sites from a broad range of higher eukaryotes reveals a conserved core pattern of three elements.

Contact:  joel.graber@jax.org

Supplementary information:  Supplementary data are available at Bioinformatics online.
Detection and Discrimination of Pratylenchus neglectus and P. thornei in DNA Extracts from Soil
Authors: Yan Guiping , Smiley Richard W. , Okubara Patricia A. , Skantar Andrea , Easley Sandra A. , Sheedy Jason G. , Thompson Alison L.
Published: October 2008

A species-specific polymerase chain reaction (PCR) method was developed to detect and identify the root-lesion nematodes Pratylenchus neglectus and P. thornei from soil. A primer set was designed from Pratylenchus 28S rRNA gene sequences of the D3 expansion domain. Primer specificity was confirmed with 23 isolates of 15 nematode species and other plant-parasitic and non-plant-parasitic nematodes typically present in the soil communities, and with six fungal species commonly associated with wheat root rot. DNA obtained using a commercially available kit and a method developed in our laboratory gave comparable amplification. PCR conditions were optimized and the two species were differentiated by PCR products of 144 bp for P. neglectus and 288 bp for P. thornei. With this assay, we detected a single juvenile in 1 g of sterile, inoculated soil. Examination of 30 field soil samples revealed that this method was applicable to a range of soils naturally infested with these two pathogens in Oregon. This PCR-based method is rapid, efficient, and reliable, does not require expertise in nematode taxonomy and morphology, and could be used as a rapid diagnostic tool for commercial and research applications for disease forecasting and management.
Disease Potential of Soil- and Tuberborne Inocula of Colletotrichum coccodes and Black Dot Severity on Potato
Authors: Nitzan Nadav , Cummings Tom F. , Johnson Dennis A.
Published: October 2008

Inoculum of Colletotrichum coccodes, the cause of potato black dot, is soil- or tuberborne. Understanding the disease potential of sources of inocula is crucial for developing disease management strategies and resistance screening techniques. Two hypotheses were tested in this study: (i) soilborne inoculum causes more disease than tuberborne inoculum and (ii) black dot severity is related to the concentration of soilborne inoculum. Trials were conducted in the greenhouse with standardized inoculum. Plants grown in infested soil had more sclerotia on roots than plants grown from infected tubers in three of four trials. In general, plants grown in infested soil produced fewer tubers and lower yields than the noninoculated plants. Plants grown from infected tubers produced similar numbers of tubers as the noninoculated plants in all trials, and had reduced yields in one of the four trials. Increasing concentrations of soilborne inoculum had a nonlinear association with disease development. Foliar symptoms, sclerotial density on roots, and sclerotial development on stems did not increase when soil inoculum exceeded 0.5 or 1.7 g/liters of soil. In this study, soilborne inoculum caused more disease than tuberborne inoculum and disease severity remained constant above a threshold of soilborne inoculum.
The Influence of Light on Relationships Between Sclerotinia Stem Rot of Soybean in Field and Controlled Environments
Authors: Peltier A. J. , Grau C. R.
Published: October 2008

Interaction phenotypes between soybean and Sclerotinia sclerotiorum observed in controlled and field environments often do not correlate. Resistant and susceptible accessions were selected to study light intensity as a variable that influences interaction phenotype. Objectives were to investigate whether light intensity within a controlled environment influences the ability to: i) distinguish resistant and susceptible accessions; ii) predict field interaction phenotypes; and iii) determine whether the method used for disease assessment influences the outcome of results. Six accessions were evaluated in growth chamber and field disease nursery trials. Five environments ranging from 146 to 434 μmol·m–2·s–1 of photosynthetically active radiation were established in the growth chamber. Inoculum was delivered to cut petioles at the R1 growth stage and interaction phenotypes were assessed for 11 days. For field trials, individual plants were rated at growth stage R7. The breeding line W04.1002 had less disease than NK S19-90 in field environments. Rank correlations of field and light environment interaction phenotypes indicate that light intensity affected the prediction of field performance. Evaluations conducted at 337 μmol·m–2·s–1 of light were most predictive of field interaction phenotypes (rs = 0.83 to 0.94; P = 0.05 to < 0.005). Controlling light intensity is critical to facilitate the identification of resistance to S. sclerotiorum in soybean.
Identification of Phytophthora cryptogea as the Cause of Rapid Decline of Petunia (Petunia × hybrida) in Chile
Authors: Ampuero J. , Latorre B. A. , Torres R. , Chávez E. R.
Published: October 2008

Phytophthora cryptogea was consistently isolated from diseased tissue taken from the crown and necrotic roots of grandiflora type petunia (Petunia × hybrida) that were collected in gardens in five public parks in Santiago, Chile in 2004 and 2005. Symptoms included leaf wilting and foliar chlorosis, followed by partial necrosis, and extensive dark-brown to reddish cankers in the crown. Disease incidence was over 50% and infected plants died within 7 to 10 days after transplanting. This pathogen was identified on the basis of colony morphology, morphological characterization of the sexual and asexual reproductive structures, and temperature range. The identification of Phytophthora cryptogea was further corroborated by the internal transcribed spacer sequence analysis (GenBank accession number EF093534). Isolates of P. cryptogea were pathogenic on 10-week-old white grandiflora petunia plants that were inoculated on the roots or on the crown using mycelium fragments, or via soil inoculation using zoospores. A rapid decline was observed after soil inoculations with zoospores. Root fresh weight decreased significantly and the root rot index and severity of foliage symptoms increased significantly (P ≤ 0.05), relative to noninoculated plants after 14 days of incubation. Two isolates (Ph-1 and Ph-2) were pathogenic on bell pepper and one isolate (Ph-1) was pathogenic on tomato after root inoculation. Two isolates (Ph-2 and Ph-3) were pathogenic on the fruit of avocado, bell pepper, cherry tomato, cucumber, kiwifruit, lemon, pear, pepino, and potato tubers, demonstrating the pathogen's ability to cause postharvest infection of fruit of a wide range of host plants. The efficacy of mefenoxam at 0.1 mg/ml mixed with either chlorothalonil at 1.0 mg/ml or mancozeb at 1.6 mg/ml was demonstrated in this study, whereas chlorothalonil and mancozeb alone did not control disease development. No significant differences were obtained between foliage and soil drench applications. This study demonstrated that P. cryptogea is the cause of the rapid decline found on petunia in Santiago, Chile and, to our knowledge, this is the first report giving a detailed description of a disease caused by P. cryptogea on petunia.
Winter Survival of the Soybean Rust Pathogen, Phakopsora pachyrhizi, in Florida
Authors: Jurick Wayne M. , Narvaez Dario F. , Brennan Meghan M. , Harmon Carrie L. , Marois James J. , Wright David L. , Harmon Philip F.
Published: October 2008

Soybean rust (SBR) survival and host availability (kudzu, Pueraria spp.) were assessed from November 2006 through April 2007 at six sites from the panhandle to southwest Florida. Micro loggers recorded both temperature and relative humidity hourly at each location. Periods of drought and cumulative hours below 0°C correlated with kudzu defoliation. Inoculum potential from detached kudzu leaves was evaluated in vitro under various temperature and relative humidity levels. Kudzu leaves with SBR kept at 4°C produced viable urediniospores with the highest germination at all moisture levels over time. Freezing temperatures (–4 and –20°C) drastically reduced spore germination. However, when leaves were incubated at low (<35%) relative humidity, inoculum potential was prolonged. Results from this study demonstrate that both temperature and relative humidity impact P. pachyrhizi in the field and in vitro, and that detached kudzu leaves have the potential to serve as an inoculum source in kudzu stands.
Virulence of Leptographium serpens on Longleaf Pine Seedlings Under Varying Soil Moisture Regimes
Authors: Matusick G. , Eckhardt L. G. , Enebak S. A.
Published: October 2008

Recently, Leptographium serpens has been recovered from the roots of declining and dead longleaf pine (Pinus palustris) in stands associated with various abiotic stresses. Although most data suggest that L. serpens is pathogenic to various Pinus spp., there is little known of its virulence on longleaf pine or its relationship with abiotic stress in causing disease. These trials examined the effects of L. serpens infection coupled with drought stress. Trials began with wound inoculations of bareroot longleaf pine seedlings in spring 2006 and 2007 at the seedling stress facility at Auburn University. Soon after inoculation, seedlings were also subjected to adequate moisture, moderate drought, or severe drought. Sixteen weeks after inoculation, longleaf pine survival, L. serpens virulence, and seedling growth characteristics were measured. Longleaf pine seedlings inoculated with L. serpens had 33% mortality (138/420) which was significantly greater than nonwounded control seedlings (22%, 47/211). Survival and lesion size on longleaf pine suggests that L. serpens is moderately pathogenic to longleaf pine seedlings. Separately, moisture stress associated with low soil moisture also contributed to seedling mortality. Results suggest that L. serpens infection and moisture stress commonly experienced by southern pines act independently to stress longleaf pine.
Introduction. Pliocene climate, processes and problems
Authors: Haywood Alan M , Dowsett Harry J , Valdes Paul J , Lunt Daniel J , Francis Jane E , Sellwood Bruce W
Published: October 2008

Climate predictions produced by numerical climate models, often referred to as general circulation models (GCMs), suggest that by the end of the twenty-first century global mean annual surface air temperatures will increase by 1.1–6.4°C. Trace gas records from ice cores indicate that atmospheric concentrations of CO
2
are already higher than at any time during the last 650 000 years. In the next 50 years, atmospheric CO
2
concentrations are expected to reach a level not encountered since an epoch of time known as the Pliocene. Uniformitarianism is a key principle of geological science, but can the past also be a guide to the future? To what extent does an examination of the Pliocene geological record enable us to successfully understand and interpret this guide? How reliable are the ‘retrodictions’ of Pliocene climates produced by GCMs and what does this tell us about the accuracy of model predictions for the future? These questions provide the scientific rationale for this Theme Issue.
The epidemiology of kuru: monitoring the epidemic from its peak to its end
Authors: Alpers Michael P
Published: October 2008

Kuru is a fatal transmissible spongiform encephalopathy restricted to the Fore people and their neighbours in a remote region of the Eastern Highlands of Papua New Guinea. When first investigated in 1957 it was found to be present in epidemic proportions, with approximately 1000 deaths in the first 5 years, 1957–1961. The changing epidemiological patterns and other significant findings such as the transmissibility of kuru are described in their historical progression. Monitoring the progress of the epidemic has been carried out by epidemiological surveillance in the field for 50 years. From its peak, the number of deaths from kuru declined to 2 in the last 5 years, indicating that the epidemic is approaching its end. The mode of transmission of the prion agent of kuru was the local mortuary practice of transumption. The prohibition of this practice in the 1950s led to the decline in the epidemic, which has been prolonged into the present century by incubation periods that may exceed 50 years. Currently, the epidemiological surveillance is being maintained and further studies on human genetics and the past mortuary practices are being conducted in the kuru-affected region and in communities beyond it.
Understanding kuru: the contribution of anthropology and medicine
Authors: Lindenbaum Shirley
Published: October 2008

To understand kuru and solve the problems of its cause and transmission required the integration of knowledge from both anthropological and medical research. Anthropological studies elucidated the origin and spread of kuru, the local mortuary practices of endocannibalism, the social effects of kuru, the life of women and child-rearing practices, the kinship system of the Fore and their willingness to incorporate outsiders into it, the myths, folklore and history of the Fore and their neighbours, sorcery as a powerful social phenomenon and way of explaining the causation of disease, and concepts of the treatment of disease. Many scientists from different disciplines, government officers and others have contributed to this chapter of medical history but it is the Fore people who have contributed the most, through their suffering, their cooperative and reliable witness to kuru, and their participation, in various ways, in the research process itself.
Reflections on amyloidosis in Papua New Guinea
Authors: Westermark Per , Westermark Gunilla T
Published: October 2008

The amyloidoses comprise a heterogeneous group of diseases in which 1 out of more than 25 human proteins aggregates into characteristic beta-sheet fibrils with some unique properties. Aggregation is nucleation dependent. Among the known amyloid-forming constituents is the prion protein, well known for its ability to transmit misfolding and disease from one individual to another. There is increasing evidence that other amyloid forms also may be transmissible but only if certain prerequisites are fulfilled. One of these forms is systemic AA-amyloidosis in which an acute-phase reactant, serum AA, is over-expressed and, possibly after cleavage, aggregates into amyloid fibrils, causing disease. In a mouse model, this disorder can easily be transmitted from one animal to another both by intravenous and oral routes. Also, synthetic amyloid-like fibrils made from defined small peptides have this property, indicating a prion-like transmission mechanism. Even some fibrils occurring in the environment can transmit AA-amyloidosis in the murine model. AA-amyloidosis is particularly common in certain areas of Papua New Guinea, probably due to the endemicity of malaria and perhaps genetic predisposition. Now, when kuru is disappearing, more interest should be focused on the potentially lethal systemic AA-amyloidosis.
Early perceptions of an epidemic
Authors: Anderson Warwick H
Published: October 2008

This article surveys some descriptions of the Fore people made on early contact in the 1950s by patrol officers, social anthropologists and medical doctors. Sorcery accusations and cannibalism initially impressed these outside observers, though gradually they came to realize that a strange and fatal condition called kuru was a major affliction of the Fore, especially women and children. Fore attributed kuru to sorcery, anthropologists speculated on psychosomatic causes and medical officers began to wonder if it was a mysterious encephalitis.
Genetic susceptibility, evolution and the kuru epidemic
Authors: Mead Simon , Whitfield Jerome , Poulter Mark , Shah Paresh , Uphill James , Beck Jonathan , Campbell Tracy , Al-Dujaily Huda , Hummerich Holger , Alpers Michael P , Collinge John
Published: October 2008

The acquired prion disease kuru was restricted to the Fore and neighbouring linguistic groups of the Papua New Guinea highlands and largely affected children and adult women. Oral history documents the onset of the epidemic in the early twentieth century, followed by a peak in the mid-twentieth century and subsequently a well-documented decline in frequency. In the context of these strong associations (gender, region and time), we have considered the genetic factors associated with susceptibility and resistance to kuru. Heterozygosity at codon 129 of the human prion protein gene (
PRNP
) is known to confer relative resistance to both sporadic and acquired prion diseases. In kuru, heterozygosity is associated with older patients and longer incubation times. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are predominantly
PRNP
codon 129 heterozygotes and this group show marked Hardy–Weinberg disequilibrium. The deviation from Hardy–Weinberg equilibrium is most marked in elderly women, but is also significant in a slightly younger cohort of men, consistent with their exposure to kuru as boys. Young Fore and the elderly from populations with no history of kuru show Hardy–Weinberg equilibrium. An increasing cline in 129V allele frequency centres on the kuru region, consistent with the effect of selection in elevating the frequency of resistant genotypes in the exposed population. The genetic data are thus strikingly correlated with exposure. Considering the strong coding sequence conservation of primate prion protein genes, the number of global coding polymorphisms in man is surprising. By intronic resequencing in a European population, we have shown that haplotype diversity at
PRNP
comprises two major and divergent clades associated with 129M and 129V. Kuru may have imposed the strongest episode of recent human balancing selection, which may not have been an isolated episode in human history.
Evaluating the robustness of phylogenetic methods to among-site variability in substitution processes
Authors: Holder Mark T , Zwickl Derrick J , Dessimoz Christophe
Published: October 2008

Computer simulations provide a flexible method for assessing the power and robustness of phylogenetic inference methods. Unfortunately, simulated data are often obviously atypical of data encountered in studies of molecular evolution. Unrealistic simulations can lead to conclusions that are irrelevant to real-data analyses or can provide a biased view of which methods perform well. Here, we present a software tool designed to generate data under a complex codon model that allows each residue in the protein sequence to have a different set of equilibrium amino acid frequencies. The software can obtain maximum-likelihood estimates of the parameters of the Halpern and Bruno model from empirical data and a fixed tree; given an arbitrary tree and a fixed set of parameters, the software can then simulate artificial datasets. We present the results of a simulation experiment using randomly generated tree shapes and substitution parameters estimated from 1610 mammalian cytochromebsequences. We tested tree inference at the amino acid, nucleotide and codon levels and under parsimony, maximum-likelihood, Bayesian and distance criteria (for a total of more than 650 analyses on each dataset). Based on these simulations, nucleotide-level analyses seem to be more accurate than amino acid and codon analyses. The performance of distance-based phylogenetic methods appears to be quite sensitive to the choice of model and the form of rate heterogeneity used. Further studies are needed to assess the generality of these conclusions. For example, fitting parameters of the Halpern Bruno model to sequences from other genes will reveal the extent to which our conclusions were influenced by the choice of cytochromeb. Incorporating codon bias and more sources heterogeneity into the simulator will be crucial to determining whether the current results are caused by a bias in the current simulation study in favour of nucleotide analyses.
Efficient computation of the phylogenetic likelihood function on multi-gene alignments and multi-core architectures
Authors: Stamatakis Alexandros , Ott Michael
Published: October 2008

The continuous accumulation of sequence data, for example, due to novel wet-laboratory techniques such as pyrosequencing, coupled with the increasing popularity of multi-gene phylogenies and emerging multi-core processor architectures that face problems of cache congestion, poses new challenges with respect to the efficient computation of the phylogenetic maximum-likelihood (ML) function. Here, we propose two approaches that can significantly speed up likelihood computations that typically represent over 95 per cent of the computational effort conducted by current ML or Bayesian inference programs. Initially, we present a method and an appropriate data structure to efficiently compute the likelihood score on ‘gappy’ multi-gene alignments. By ‘gappy’ we denote sampling-induced gaps owing to missing sequences in individual genes (partitions), i.e. not real alignment gaps. A first proof-of-concept implementation in
RAxML
indicates that this approach can accelerate inferences on large and gappy alignments by approximately one order of magnitude. Moreover, we present insights and initial performance results on multi-core architectures obtained during the transition from an OpenMP-based to a Pthreads-based fine-grained parallelization of the ML function.
A model of evolution and structure for multiple sequence alignment
Authors: Löytynoja Ari , Goldman Nick
Published: October 2008

We have developed a phylogeny-aware progressive alignment method that recognizes insertions and deletions as distinct evolutionary events and thus avoids systematic errors created by traditional alignment methods. We now extend this method to simultaneously model regional heterogeneity and evolution. This novel method can be flexibly adapted to alignment of nucleotide or amino acid sequences evolving under processes that vary over genomic regions and, being fully probabilistic, provides an estimate of regional heterogeneity of the evolutionary process along the alignment and a measure of local reliability of the solution. Furthermore, the evolutionary modelling of substitution process permits adjusting the sensitivity and specificity of the alignment and, if high specificity is aimed at, leaving sequences unaligned when their divergence is beyond a meaningful detection of homology.
The perils of plenty: what are we going to do with all these genes?
Authors: Rodrigo Allen , Bertels Frederic , Heled Joseph , Noder Raphael , Shearman Helen , Tsai Peter
Published: October 2008

This new century's biology promises more of everything—more genes, more organisms, more species and, in short, more data. The flood of data challenges us to find better and quicker ways to summarize and analyse. Here, we present preliminary results and proofs of concept from three of our research projects that are motivated by our search for solutions to the perils of plenty. First, we discuss how models of evolution can accommodate change to better reflect the dynamics of sequence diversity, particularly when it is becoming a lot easier to obtain sequences at different times and across intervals where the probability of new mutations contributing to this diversity is high. Second, we describe our work on the use of a single locus for species delimitation; this research targets the new DNA-barcoding approach that aims to catalogue the entirety of life. We have developed a single-locus test based on the coalescent that tests the null hypothesis of panmixis. Finally, we discuss new sequencing technologies, the types of data available and the efficacy of alignment-free methods to estimate pairwise distances for phylogenetic analyses.
Bayesian analysis of amino acid substitution models
Authors: Huelsenbeck John P , Joyce Paul , Lakner Clemens , Ronquist Fredrik
Published: October 2008

Models of amino acid substitution present challenges beyond those often faced with the analysis of DNA sequences. The alignments of amino acid sequences are often small, whereas the number of parameters to be estimated is potentially large when compared with the number of free parameters for nucleotide substitution models. Most approaches to the analysis of amino acid alignments have focused on the use of fixed amino acid models in which all of the potentially free parameters are fixed to values estimated from a large number of sequences. Often, these fixed amino acid models are specific to a gene or taxonomic group (e.g. the Mtmam model, which has parameters that are specific to mammalian mitochondrial gene sequences). Although the fixed amino acid models succeed in reducing the number of free parameters to be estimated—indeed, they reduce the number of free parameters from approximately 200 to 0—it is possible that none of the currently available fixed amino acid models is appropriate for a specific alignment. Here, we present four approaches to the analysis of amino acid sequences. First, we explore the use of a general time reversible model of amino acid substitution using a Dirichlet prior probability distribution on the 190 exchangeability parameters. Second, we then explore the behaviour of prior probability distributions that are ‘centred’ on the rates specified by the fixed amino acid model. Third, we consider a mixture of fixed amino acid models. Finally, we consider constraints on the exchangeability parameters as partitions, similar to how nucleotide substitution models are specified, and place a Dirichlet process prior model on all the possible partitioning schemes.
A likelihood framework to analyse phyletic patterns
Authors: Cohen Ofir , Rubinstein Nimrod D , Stern Adi , Gophna Uri , Pupko Tal
Published: October 2008

Probabilistic evolutionary models revolutionized our capability to extract biological insights from sequence data. While these models accurately describe the stochastic processes of site-specific substitutions, single-base substitutions represent only a fraction of all the events that shape genomes. Specifically, in microbes, events in which entire genes are gained (e.g. via horizontal gene transfer) and lost play a pivotal evolutionary role. In this research, we present a novel likelihood-based evolutionary model for gene gains and losses, and use it to analyse genome-wide patterns of the presence and absence of gene families. The model assumes a Markovian stochastic process, where gains and losses are represented by the transition between presence and absence, respectively, given an underlying phylogenetic tree. To account for differences in the rates of gain and loss of different gene families, we assume among-gene family rate variability, thus allowing for more accurate description of the data. Using the Bayesian approach, we estimated an evolutionary rate for each gene family. Simulation studies demonstrated that our methodology accurately infers these rates. Our methodology was applied to analyse a large corpus of data, consisting of 4873 gene families spanning 63 species and revealed novel insights regarding the evolutionary nature of genome-wide gain and loss dynamics.
Modelling heterotachy in phylogenetic inference by reversible-jump Markov chain Monte Carlo
Authors: Pagel Mark , Meade Andrew
Published: October 2008

The rate at which a given site in a gene sequence alignment evolves over time may vary. This phenomenon—known as heterotachy—can bias or distort phylogenetic trees inferred from models of sequence evolution that assume rates of evolution are constant. Here, we describe a phylogenetic mixture model designed to accommodate heterotachy. The method sums the likelihood of the data at each site over more than one set of branch lengths on the same tree topology. A branch-length set that is best for one site may differ from the branch-length set that is best for some other site, thereby allowing different sites to have different rates of change throughout the tree. Because rate variation may not be present in all branches, we use a reversible-jump Markov chain Monte Carlo algorithm to identify those branches in which reliable amounts of heterotachy occur. We implement the method in combination with our ‘pattern-heterogeneity’ mixture model, applying it to simulated data and five published datasets. We find that complex evolutionary signals of heterotachy are routinely present over and above variation in the rate or pattern of evolution across sites, that the reversible-jump method requires far fewer parameters than conventional mixture models to describe it, and serves to identify the regions of the tree in which heterotachy is most pronounced. The reversible-jump procedure also removes the need fora posterioritests of ‘significance’ such as the Akaike or Bayesian information criterion tests, or Bayes factors. Heterotachy has important consequences for the correct reconstruction of phylogenies as well as for tests of hypotheses that rely on accurate branch-length information. These include molecular clocks, analyses of tempo and mode of evolution, comparative studies and ancestral state reconstruction. The model is available from the authors' website, and can be used for the analysis of both nucleotide and morphological data.
Phylogenetic mixture models for proteins
Authors: Le Si Quang , Lartillot Nicolas , Gascuel Olivier
Published: October 2008

Standard protein substitution models use a single amino acid replacement rate matrix that summarizes the biological, chemical and physical properties of amino acids. However, site evolution is highly heterogeneous and depends on many factors: genetic code; solvent exposure; secondary and tertiary structure; protein function; etc. These impact the substitution pattern and, in most cases, a single replacement matrix is not enough to represent all the complexity of the evolutionary processes. This paper explores in maximum-likelihood framework phylogenetic mixture models that combine several amino acid replacement matrices to better fit protein evolution. We learn these mixture models from a large alignment database extracted from HSSP, and test the performance using independent alignments fromTreeBase. We compare unsupervised learning approaches, where the site categories are unknown, to supervised ones, where in estimations we use the known category of each site, based on its exposure or its secondary structure. All our models are combined with gamma-distributed rates across sites. Results show that highly significant likelihood gains are obtained when using mixture models compared with the best available single replacement matrices. Mixtures of matrices also improve over mixtures of profiles in the manner of the CAT model. The unsupervised approach tends to be better than the supervised one, but it appears difficult to implement and highly sensitive to the starting values of the parameters, meaning that the supervised approach is still of interest for initialization and model comparison. Using an unsupervised model involving three matrices, the average AIC gain per site withTreeBasetest alignments is 0.31, 0.49 and 0.61 compared with LG (named after Le & Gascuel 2008Mol. Biol. Evol.25, 1307–1320), WAG and JTT, respectively. This three-matrix model is significantly better than LG for 34 alignments (among 57), and significantly worse for 1 alignment only. Moreover, tree topologies inferred with our mixture models frequently differ from those obtained with single matrices, indicating that using these mixtures impacts not only the likelihood value but also the output tree. All our models and a PhyML implementation are available fromhttp://atgc.lirmm.fr/mixtures.
Deaf Children and Young People’s Experiences of Using Specialist Mental Health Services
Authors: Greco Veronica , Beresford Bryony , Sutherland Hilary
Published: October 2008

Deaf children have an increased prevalence of mental health problems compared with hearing children. Generic Child And Adolescent Mental Health Services do not have the skills or expertise to meet the mental health needs of this group of children. Three teams in England provide specialist mental health services for deaf children. This research explored children’s experiences of using these services. Twenty‐four deaf children participated in the study. Overall children valued and benefited from the service. The expertise of the staff and the presence of deaf clinicians were key to these positive experiences.
Child Marriage or Forced Marriage? South Asian Communities in North East England
Authors: Gangoli Geetanjali , McCarry Melanie , Razak Amina
Published: October 2008

This article addresses the links between child marriage and forced marriage in the UK, drawing from a research study on South Asian communities in North East England. It looks at definitional issues through an analysis of UK and South Asian policies. It also analyses how these concepts are understood by service providers, survivors of child marriage and young people from South Asian communities. Finally, concepts such as gender, age, familial and community control reflected in normative marriage practices are addressed.
Regulatory T cells in human immunodeficiency virus-infected patients are elevated and independent of immunological and virological status, as well as initiation of highly active anti-retroviral therapy
Authors: Gaardbo J C , Nielsen S D , Vedel S J , Ersbøll A K , Harritshøj L , Ryder L P , Nielsen J O , Kolte L
Published: October 2008

Infection with human immunodeficiency virus (HIV) causes a dysregulation of the immune system. This is caused by HIV-specific as well as non-specific mechanisms and has not been explained fully. In particular, knowledge is lacking about the potential role of host-mediated immunosuppressive mechanisms. During recent years it has become evident that a subpopulation of T cells [T regulatory (Tregs)] play a major role in sustaining tolerance to self-antigens. To investigate the influence of initiation of highly active anti-retroviral therapy (HAART) on the Treg level in HIV-infected patients we have conducted a prospective study enrolling treatment-naive HIV-infected patients just prior to starting treatment with HAART, measuring levels of Tregs by flow cytometry and mRNA expression of forkhead box P3 (FoxP3) at weeks 0, 4, 12 and 24 of treatment. In this prospective study neither the percentage of CD4+CD25high+ nor the expression of FoxP3 changed significantly during 24 weeks of HAART. Furthermore, HIV patients have higher Tregs measured as percentages of CD4+CD25high+ cells paralleled by higher levels of FoxP3 compared with healthy controls. The elevated level of Tregs was found to be independent of both immunological and virological status, indicating that initiation of HAART has minor effects on the Treg level in HIV-infected patients.
Do cytokines have any role in Wilson's disease?
Authors: Goyal M K , Sinha S , Patil S A , Jayalekshmy V , Taly A B
Published: October 2008

The aim of this study was to determine the serum cytokine levels in patients with Wilson's disease (WD) and correlate with phenotype, therapeutic status and laboratory data. In this cross-sectional study, the serum levels of cytokines were estimated in 34 patients (M : F, 23 : 11; drug-naive, 11) with WD (mean age: 13·8 ± 8·6 and 19·6 ± 9·03 years) and compared with 30 controls. The following serum cytokines were analysed using enzyme-linked immunosorbent assay: (i) tumour necrosis factor (TNF)-α, (ii) interferon (IFN)-γ, (iii) interleukin (IL)-2, (iv) IL-6 and (v) IL-4. Serum TNF-α (P < 0·001), IFN-γ (P = 0·005) and IL-6 (P < 0·001) were detectable in WD compared with controls. However, serum level elevation of IL-4 (P = 0·49) and IL-2 (P = 0·11), although detectable compared with controls, was statistically insignificant. The disease severity and therapeutic status did not affect the cytokines. Presence of anaemia, leucopenia, thrombocytopenia, pancytopenia and hepatic dysfunction did not influence cytokine levels. There was a significant negative correlation between IL-6 and ceruloplasmin (P = 0·04) and anti-inflammatory cytokines (IL-4) and copper level (P = 0·01). Serum cytokines, both proinflammatory and anti-inflammatory subtypes, were elevated significantly in patients with WD. Further studies would establish their role in its pathogenesis.
Calcium ion release from calcium hydroxide stimulated fibronectin gene expression in dental pulp cells and the differentiation of dental pulp cells to mineralized tissue forming cells by fibronectin
Authors: Mizuno M. , Banzai Y.
Published: October 2008

Aim  The effect of calcium ions on dental pulp cells was examined and the mechanism of dentine bridge formation by calcium hydroxide was investigated.

Methodology  Human dental pulp cells were treated with high concentration of calcium or magnesium ions for 24 h and fibronectin gene expression was measured by the quantitative PCR method. Human dental pulp cells were then cultured on fibronecin‐coated dishes for 24 h, and osteocalcin and osteopontin gene expression, which are typical phenotypes of mineralized tissue forming cells, were measured by the quantitative PCR method.

Results  Fibronectin gene expression was stimulated by calcium ions dose‐dependently. On the other hand, magnesium ions did not influence fibronectin gene expression. Furthermore, pulp cells cultured on fibronectin‐coated dishes enhanced the expression of phenotypes of mineralized tissue forming cells.

Conclusions  Calcium ions released from calcium hydroxide stimulates fibronectin synthesis in dental pulp cells. Fibronectin might induce the differentiation of dental pulp cells to mineralized tissue forming cells that are the main cells to form dentine bridges, via contact with cells.
Mechanical behaviour of nickel‐titanium rotary endodontic instruments in simulated clinical conditions: a computational study
Authors: Necchi S. , Taschieri S. , Petrini L. , Migliavacca F.
Published: October 2008

Aim  To develop an accurate finite element (FE) model for studying rotary endodontic instruments and to demonstrate the usefulness of the FE method in improving the knowledge of the mechanical behaviour of these instruments during root canal preparation.

Methodology  An accurate geometrical model of a Ni‐Ti ProTaper F1 instrument was created. The interaction between the rotating instrument and differently shaped root canals during the insertion and removal procedure was studied using FE analyses. The complex thermo‐mechanical behaviour of the Ni‐Ti alloy was reproduced using an ad hoc computational subroutine. With the aim of demonstrating the enhanced performance of the shape memory alloy employment, the same analysis was performed on a ‘virtual’ ProTaper F1 made of stainless steel.

Results  The Ni‐Ti instrument operated in its pseudo‐elastic range and was able to recover its original shape and to follow the canal curvature without deviation. The radius and the position of the canal curvature are the most critical parameters that determined the stress in the instrument with higher stress levels being produced by decreasing the radius and moving from the apical to the mid root position.

Conclusions  The most demanding working conditions were observed in canals with sharp curves, especially in areas where the instruments had larger diameters. To prevent possible damage to instruments and fracture, it is advised that the instruments should be discarded following their use in such canals.