bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired nucleotide excision repair upon macrophage differentiation is corrected by E1 ubiquitin-activating enzyme
Authors: Nouspikel Thierry , Hanawalt Philip C.
Published: October 2006

Global nucleotide excision repair is greatly attenuated in terminally differentiated mammalian cells. We observed this phenomenon in human neurons and in macrophages, noting that the transcription-coupled repair pathway remains functional and that there is no significant reduction in levels of excision repair enzymes. We have discovered that ubiquitin-activating enzyme E1 complements the repair deficiency in macrophage extracts, and although there is no reduction in the concentration of E1 upon differentiation, our results indicate a reduction in phosphorylation of E1. In preliminary studies, we have identified the basal transcription factor TFIIH as the potential target for ubiquitination. We suggest that this unusual type of regulation at the level of the E1 enzyme is likely to affect numerous cellular processes and may represent a strategy to coordinate multiple phenotypic changes upon differentiation by using E1 as a “master switch.”
Enforced expression of the homeobox gene
Mixl1
impairs hematopoietic differentiation and results in acute myeloid leukemia
Authors: Glaser Stefan , Metcalf Donald , Wu Li , Hart Adam H. , DiRago Ladina , Mifsud Sandra , D'Amico Angela , Dagger Samantha , Campo Chiara , Chan Angela C. , Izon David J. , Robb Lorraine
Published: October 2006

Mixl1
, the sole murine homologue of the
Xenopus Mix/Bix
family of homeobox transcription factors, is essential for the patterning of axial mesendodermal structures during early embryogenesis. Gene targeting and overexpression studies have implicated
Mixl1
as a regulator of hematopoiesis arising in differentiating embryonic stem cells. To assess the role of
Mixl1
in the regulation of adult hematopoiesis, we overexpressed
Mixl1
in murine bone marrow using a retroviral transduction/transplantation model. Enforced expression of
Mixl1
profoundly perturbed hematopoietic lineage commitment and differentiation, giving rise to abnormal myeloid progenitors and impairing erythroid and lymphoid differentiation. Moreover, all mice reconstituted with
Mixl1
-transduced bone marrow developed fatal, transplantable acute myeloid leukemia with a mean latency period of 200 days. These observations establish a link between enforced
Mixl1
expression and leukemogenesis in the mouse.
Modeling
CTLA4
-linked autoimmunity with RNA interference in mice
Authors: Chen Zhibin , Stockton John , Mathis Diane , Benoist Christophe
Published: October 2006

The
CTLA4
gene is important for T lymphocyte-mediated immunoregulation and has been associated with several autoimmune diseases, in particular, type 1 diabetes. To model the impact of natural genetic variants of
CTLA4
, we constructed RNA interference (RNAi) “knockdown” mice through lentiviral transgenesis. Variegation of expression was observed in founders but proved surmountable because it reflected parental imprinting, with derepression by transmission from male lentigenics. Unlike the indiscriminate multiorgan autoimmune phenotype of the corresponding knockout mice, Ctla4 knockdown animals had a disease primarily focused on the pancreas, with rapid progression to diabetes. As with the human disease, the knockdown phenotype was tempered by genetic-modifier loci. RNAi should be more pertinent than gene ablation in modeling disease pathogenesis linked to a gene-dosage variation.
A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation
Authors: Fulkerson Patricia C. , Fischetti Christine A. , McBride Melissa L. , Hassman Lynn M. , Hogan Simon P. , Rothenberg Marc E.
Published: October 2006

To clarify the role and regulation of eosinophils, we subjected several key eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in eosinophil development (Δdbl-GATA) and eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1/2 double knockout)] were subjected to
Aspergillus fumigatus
-induced allergic airway inflammation. Allergen-induced eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1/2 double knockout, CCR3 knockout, and Δdbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of eosinophil- and CCR3-deficient mice. The absence of eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was eosinophil- and CCR3-dependent; pathways downstream from eosinophils were identified, including
in situ
activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that eosinophils via CCR3 have a central role in chronic allergic airway disease.
Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines
Authors: Zha Xiang-ming , Wemmie John A. , Green Steven H. , Welsh Michael J.
Published: October 2006

Extracellular proton concentrations in the brain may be an important signal for neuron function. Proton concentrations change both acutely when synaptic vesicles release their acidic contents into the synaptic cleft and chronically during ischemia and seizures. However, the brain receptors that detect protons and their physiologic importance remain uncertain. Using organotypic hippocampal slices and biolistic transfection, we found the acid-sensing ion channel 1a (ASIC1a), localized in dendritic spines where it functioned as a proton receptor. ASIC1a also affected the density of spines, the postsynaptic site of most excitatory synapses. Decreasing ASIC1a reduced the number of spines, whereas overexpressing ASIC1a had the opposite effect. Ca
2+
-mediated Ca
2+
/calmodulin-dependent protein kinase II (CaMKII) signaling was probably responsible, because acid evoked an ASIC1a-dependent elevation of spine intracellular Ca
2+
concentration, and reducing or increasing ASIC1a levels caused parallel changes in CaMKII phosphorylation
in vivo
. Moreover, inhibiting CaMKII prevented ASIC1a from increasing spine density. These data indicate that ASIC1a functions as a postsynaptic proton receptor that influences intracellular Ca
2+
concentration and CaMKII phosphorylation and thereby the density of dendritic spines. The results provide insight into how protons influence brain function and how they may contribute to pathophysiology.
Crystal structure of a photoactivated deprotonated intermediate of rhodopsin
Authors: Salom David , Lodowski David T. , Stenkamp Ronald E. , Trong Isolde Le , Golczak Marcin , Jastrzebska Beata , Harris Tim , Ballesteros Juan A. , Palczewski Krzysztof
Published: October 2006

The changes that lead to activation of G protein-coupled receptors have not been elucidated at the structural level. In this work we report the crystal structures of both ground state and a photoactivated deprotonated intermediate of bovine rhodopsin at a resolution of 4.15 Å. In the photoactivated state, the Schiff base linking the chromophore and Lys-296 becomes deprotonated, reminiscent of the G protein-activating state, metarhodopsin II. The structures reveal that the changes that accompany photoactivation are smaller than previously predicted for the metarhodopsin II state and include changes on the cytoplasmic surface of rhodopsin that possibly enable the coupling to its cognate G protein, transducin. Furthermore, rhodopsin forms a potentially physiologically relevant dimer interface that involves helices I, II, and 8, and when taken with the prior work that implicates helices IV and V as the physiological dimer interface may account for one of the interfaces of the oligomeric structure of rhodopsin seen in the membrane by atomic force microscopy. The activation and oligomerization models likely extend to the majority of other G protein-coupled receptors.
Independent and simultaneous translocation of two substrates by a nucleotide sugar transporter
Authors: Caffaro Carolina E. , Hirschberg Carlos B. , Berninsone Patricia M.
Published: October 2006

Nucleotide sugar transporters play an essential role in protein and lipid glycosylation, and mutations can result in developmental phenotypes. We have characterized a transporter of UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine encoded by theCaenorhabditis elegansgene C03H5.2. Surprisingly, translocation of these substrates occurs in an independent and simultaneous manner that is neither a competitive nor a symport transport. Incubations of Golgi apparatus vesicles ofSaccharomyces cerevisiaeexpressing C03H5.2 protein with these nucleotide sugars labeled with3H and14C in their sugars showed that both substrates enter the lumen to the same extent, whether or not they are incubated alone or in the presence of a 10-fold excess of the other nucleotide sugar. Vesicles containing a deletion mutant of the C03H5.2 protein transport UDP-N-acetylglucosamine at rates comparable with that of wild-type transporter, whereas transport of UDP-N-acetylgalactosamine was decreased by 85–90%, resulting in an asymmetrical loss of substrate transport.
How the headpiece hinge angle is opened: new insights into the dynamics of integrin activation
Authors: Puklin-Faucher Eileen , Gao Mu , Schulten Klaus , Vogel Viola
Published: October 2006

How the integrin head transitions to the high-affinity conformation is debated. Although experiments link activation with the opening of the hinge angle between the βA and hybrid domains in the ligand-binding headpiece, this hinge is closed in the liganded αvβ3 integrin crystal structure. We replaced the RGD peptide ligand of this structure with the 10th type III fibronectin module (FnIII10) and discovered through molecular dynamics (MD) equilibrations that when the conformational constraints of the leg domains are lifted, the βA/hybrid hinge opens spontaneously. Together with additional equilibrations on the same nanosecond timescale in which small structural variations impeded hinge-angle opening, these simulations allowed us to identify the allosteric pathway along which ligand-induced strain propagates via elastic distortions of the α1 helix to the βA/hybrid domain hinge. Finally, we show with steered MD how force accelerates hinge-angle opening along the same allosteric pathway. Together with available experimental data, these predictions provide a novel framework for understanding integrin activation.
Spectrin functions upstream of ankyrin in a spectrin cytoskeleton assembly pathway
Authors: Das Amlan , Base Christine , Dhulipala Srilakshmi , Dubreuil Ronald R.
Published: October 2006

Prevailing models place spectrin downstream of ankyrin in a pathway of assembly and function in polarized cells. We used a transgene rescue strategy in Drosophila melanogaster to test contributions of four specific functional sites in β spectrin to its assembly and function. (1) Removal of the pleckstrin homology domain blocked polarized spectrin assembly in midgut epithelial cells and was usually lethal. (2) A point mutation in the tetramer formation site, modeled after a hereditary elliptocytosis mutation in human erythrocyte spectrin, had no detectable effect on function. (3) Replacement of repetitive segments 4–11 of β spectrin with repeats 2–9 of α spectrin abolished function but did not prevent polarized assembly. (4) Removal of the putative ankyrin-binding site had an unexpectedly mild phenotype with no detectable effect on spectrin targeting to the plasma membrane. The results suggest an alternate pathway in which spectrin directs ankyrin assembly and in which some important functions of spectrin are independent of ankyrin.
Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis
Authors: Ma Yinghua , Li Jianxue , Chiu Isaac , Wang Yawen , Sloane Jacob A. , Lü Jining , Kosaras Bela , Sidman Richard L. , Volpe Joseph J. , Vartanian Timothy
Published: October 2006

Toll receptors in Drosophila melanogaster function in morphogenesis and host defense. Mammalian orthologues of Toll, the Toll-like receptors (TLRs), have been studied extensively for their essential functions in controlling innate and adaptive immune responses. We report that TLR8 is dynamically expressed during mouse brain development and localizes to neurons and axons. Agonist stimulation of TLR8 in cultured cortical neurons causes inhibition of neurite outgrowth and induces apoptosis in a dissociable manner. Our evidence indicates that such TLR8-mediated neuronal responses do not involve the canonical TLR–NF-κB signaling pathway. These findings reveal novel functions for TLR8 in the mammalian nervous system that are distinct from the classical role of TLRs in immunity.
Phosphorylation and activity of the tumor suppressor Merlin and the ERM protein Moesin are coordinately regulated by the Slik kinase
Authors: Hughes Sarah C. , Fehon Richard G.
Published: October 2006

Merlin and Moesin are closely related members of the 4.1 Ezrin/Radixin/Moesin domain superfamily implicated in regulating proliferation and epithelial integrity, respectively. The activity of both proteins is regulated by head to tail folding that is controlled, in part, by phosphorylation. Few upstream regulators of these phosphorylation events are known. In this study, we demonstrate that in Drosophila melanogaster, Slik, a Ste20 kinase, controls subcellular localization and phosphorylation of Merlin, resulting in the coordinate but opposite regulation of Merlin and Moesin. These results suggest the existence of a novel mechanism for coordinate regulation of cell proliferation and epithelial integrity in developing tissues.
BAFF controls B cell metabolic fitness through a PKCβ- and Akt-dependent mechanism
Authors: Patke Alina , Mecklenbräuker Ingrid , Erdjument-Bromage Hediye , Tempst Paul , Tarakhovsky Alexander
Published: October 2006

B cell life depends critically on the cytokine B cell–activating factor of the tumor necrosis factor family (BAFF). Lack of BAFF signaling leads to B cell death and immunodeficiency. Excessive BAFF signaling promotes lupus-like autoimmunity. Despite the great importance of BAFF to B cell biology, its signaling mechanism is not well characterized. We show that BAFF initiates signaling and transcriptional programs, which support B cell survival, metabolic fitness, and readiness for antigen-induced proliferation. We further identify a BAFF-specific protein kinase C β–Akt signaling axis, which provides a connection between BAFF and generic growth factor–induced cellular responses.
Regulation of B1 cell migration by signals through Toll-like receptors
Authors: Ha Seon-ah , Tsuji Masayuki , Suzuki Keiichiro , Meek Bob , Yasuda Nobutaka , Kaisho Tsuneyasu , Fagarasan Sidonia
Published: October 2006

Peritoneal B1 cells are known to generate large amounts of antibodies outside their residential site. These antibodies play an important role in the early defense against bacteria and viruses, before the establishment of adaptive immune responses. Although many stimuli, including antigen, lipopolysaccharide, or cytokines, have been shown to activate B1 cells and induce their differentiation into plasma cells, the molecular signals required for their egress from the peritoneal cavity are not understood. We demonstrate here that direct signals through Toll-like receptors (TLRs) induce specific, rapid, and transient down-regulation of integrins and CD9 on B1 cells, which is required for detachment from local matrix and a high velocity movement of cells in response to chemokines. Thus, we revealed an unexpected role for TLRs in governing the interplay between integrins, tetraspanins, and chemokine receptors required for B1 cell egress and, as such, in facilitating appropriate transition from innate to adaptive immune responses.
Helix Interaction Tool (HIT): a web-based tool for analysis of helix-helix interactions in proteins
Authors: Burba Anne E. Counterman , Lehnert Ursula , Yu Eric Z. , Gerstein Mark
Published: October 2006

Motivation: In many proteins, helix–helix interactions can be critical to establishing protein conformation (folding) and dynamics, as well as determining associations between protein units. However, the determination of a set of rules that guide helix–helix interaction has been elusive. In order to gain further insight into the helix–helix interface, we have developed a comprehensive package of tools for analyzing helix–helix packing in proteins. These tools are available at . They include quantitative measures of the helix interaction surface area and helix crossing angle, as well as several methods for visualizing the helical interaction. These methods can be used for analysis of individual protein conformations or to gain insight into dynamic changes in helix interactions. For the latter purpose, a direct interface from entries in the Molecular Motions Database to the HIT site has been provided.

Contact:  Mark.Gerstein@yale.edu
An algorithm for modularity analysis of directed and weighted biological networks based on edge-betweenness centrality
Authors: Yoon Jeongah , Blumer Anselm , Lee Kyongbum
Published: October 2006

Motivation: Modularity analysis is a powerful tool for studying the design of biological networks, offering potential clues for relating the biochemical function(s) of a network with the ‘wiring’ of its components. Relatively little work has been done to examine whether the modularity of a network depends on the physiological perturbations that influence its biochemical state. Here, we present a novel modularity analysis algorithm based on edge-betweenness centrality, which facilitates the use of directional information and measurable biochemical data.

Contact:  kyongbum.lee@tufts.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
Prediction of oxidoreductase-catalyzed reactions based on atomic properties of metabolites
Authors: Mu Fangping , Unkefer Pat J. , Unkefer Clifford J. , Hlavacek William S.
Published: October 2006

Motivation: Our knowledge of metabolism is far from complete, and the gaps in our knowledge are being revealed by metabolomic detection of small-molecules not previously known to exist in cells. An important challenge is to determine the reactions in which these compounds participate, which can lead to the identification of gene products responsible for novel metabolic pathways. To address this challenge, we investigate how machine learning can be used to predict potential substrates and products of oxidoreductase-catalyzed reactions.

Results: We examined 1956 oxidation/reduction reactions in the KEGG database. The vast majority of these reactions (1626) can be divided into 12 subclasses, each of which is marked by a particular type of functional group transformation. For a given transformation, the local structures of reaction centers in substrates and products can be characterized by patterns. These patterns are not unique to reactants but are widely distributed among KEGG metabolites. To distinguish reactants from non-reactants, we trained classifiers (linear-kernel Support Vector Machines) using negative and positive examples. The input to a classifier is a set of atomic features that can be determined from the 2D chemical structure of a compound. Depending on the subclass of reaction, the accuracy of prediction for positives (negatives) is 64 to 93% (44 to 92%) when asking if a compound is a substrate and 71 to 98% (50 to 92%) when asking if a compound is a product. Sensitivity analysis reveals that this performance is robust to variations of the training data. Our results suggest that metabolic connectivity can be predicted with reasonable accuracy from the presence or absence of local structural motifs in compounds and their readily calculated atomic features.

Availability: Classifiers reported here can be used freely for noncommercial purposes via a Java program available upon request.

Contact: wish@lanl.gov

Supplementary information: Supplementary data are available at Bioinformatics online.
Linkage analysis using sex-specific recombination fractions with GENEHUNTER-MODSCORE
Authors: Dietter Johannes , Mattheisen Manuel , Fürst Robert , Rüschendorf Franz , Wienker Thomas F. , Strauch Konstantin
Published: October 2006

Motivation: Sex-specific marker maps have become increasingly available. We have implemented the usage of sex-specific recombination frequencies in the GENEHUNTER-MODSCORE program that performs multipoint linkage analysis. Furthermore, we have devised a consistent method to choose the combinations of male and female genetic positions at which linkage scores should be calculated. Marker coordinates can be read automatically from publicly available genetic maps.

Results: In a MOD-score analysis of the COGA dataset provided for Genetic Analysis Workshop 14, the highest linkage peak on chromosome 1 further increases when using sex-specific maps, while some smaller peaks are decreased. Simulations confirm that the MOD score can be biased when a sex-averaged instead of the correct sex-specific map is employed. This shows that an adequate modeling of the female:male ratio of genetic distances is important, especially for complex traits.

Availability: The new version of GENEHUNTER-MODSCORE can be downloaded from the following website:

Contact:  dietter@med.uni-marburg.de
SequenceLDhot: detecting recombination hotspots
Authors: Fearnhead Paul
Published: October 2006

Motivation: There is much local variation in recombination rates across the human genome—with the majority of recombination occuring in recombination hotspots—short regions of around ∼2 kb in length that have much higher recombination rates than neighbouring regions. Knowledge of this local variation is important, e.g. in the design and analysis of association studies for disease genes. Population genetic data, such as that generated by the HapMap project, can be used to infer the location of these hotspots. We present a new, efficient and powerful method for detecting recombination hotspots from population data.

Results: We compare our method with four current methods for detecting hotspots. It is orders of magnitude quicker, and has greater power, than two related approaches. It appears to be more powerful than HotspotFisher, though less accurate at inferring the precise positions of the hotspot. It was also more powerful than LDhot in some situations: particularly for weaker hotspots (10–40 times the background rate) when SNP density is lower (< 1/kb).

Availability: Program, data sets, and full details of results are available at:

Contact:  p.fearnhead@lancs.ac.uk
A Gibbs sampler for the identification of gene expression and network connectivity consistency
Authors: Brynildsen Mark P. , Tran Linh M. , Liao James C.
Published: October 2006

Motivation: Data from DNA microarrays and ChIP-chip binding assays often form the basis of transcriptional regulatory analyses. However, experimental noise in both data types combined with environmental dependence and uncorrelation between binding and regulation in ChIP-chip binding data complicate analyses that utilize these complimentary data sources. Therefore, to minimize the impact of these inaccuracies on transcription analyses it is desirable to identify instances of gene expression-ChIP-chip agreement, under the premise that inaccuracies are less likely to be present when separate data sources corroborate each other. Current methods for such identification either make key assumptions that limit their applicability and/or yield high false positive and false negative rates. The goal of this work was to develop a method with a minimal amount of assumptions, and thus widely applicable, that can identify agreement between gene expression and ChIP-chip data at a higher confidence level than current methods.

Results: We demonstrate in Saccharomyces cerevisiae that currently available ChIP-chip binding data explain microarray data from a variety of environments only as well as randomized networks with the same connectivity density. This suggests a high degree of inconsistency between the two data types and illustrates the need for a method that can identify consistency between the two data sources. Here we have developed a Gibbs sampling technique to identify genes whose expression and ChIP-chip binding data are mutually consistent. Compared to current methods that could perform the same task, the Gibbs sampling method developed here exceeds their ability at high levels (>50%) of transcription network and gene expression error, while performing similarly at lower levels. Using this technique, we show that on average 73% more gene expression features can be captured per gene as compared to the unfiltered use of gene expression and ChIP-chip-derived network connectivity data. It is important to note that the method described here can be generalized to other transcription connectivity data (e.g. sequence analysis, etc.).

Availability: Our algorithm is available on request from the authors and soon to be posted on the web. See author's homepage for details,

Contact:  liaoj@ucla.edu

Supplementary information: Supplementary data are available at Bioinformatics Online.
High-resolution spatial normalization for microarrays containing embedded technical replicates
Authors: Yuan Daniel S. , Irizarry Rafael A.
Published: October 2006

Motivation: Microarray data are susceptible to a wide-range of artifacts, many of which occur on physical scales comparable to the spatial dimensions of the array. These artifacts introduce biases that are spatially correlated. The ability of current methodologies to detect and correct such biases is limited.

Results: We introduce a new approach for analyzing spatial artifacts, termed ‘conditional residual analysis for microarrays’ (CRAM). CRAM requires a microarray design that contains technical replicates of representative features and a limited number of negative controls, but is free of the assumptions that constrain existing analytical procedures. The key idea is to extract residuals from sets of matched replicates to generate residual images. The residual images reveal spatial artifacts with single-feature resolution. Surprisingly, spatial artifacts were found to coexist independently as additive and multiplicative errors. Efficient procedures for bias estimation were devised to correct the spatial artifacts on both intensity scales. In a survey of 484 published single-channel datasets, variance fell 4- to 12-fold in 5% of the datasets after bias correction. Thus, inclusion of technical replicates in a microarray design affords benefits far beyond what one might expect with a conventional ‘n = 5’ averaging, and should be considered when designing any microarray for which randomization is feasible.

Availability: CRAM is implemented as version 2 of the hoptag software package for R, which is included in the Supplementary information.

Contact:  dyuan@jhmi.edu

Supplementary information: Supplementary Data are available at Bioinformatics online.
The Use of Herbal Medicine in Alzheimer′s Disease—A Systematic Review
Authors: Santos-Neto Leopoldo Luiz dos , de Vilhena Toledo Maria Alice , Medeiros-Souza Patrícia , de Souza Gustavo Almeida
Published: October 2006

The treatments of choice in Alzheimer′s disease (AD) are cholinesterase inhibitors and NMDA‐receptor antagonists, although doubts remain about the therapeutic effectiveness of these drugs. Herbal medicine products have been used in the treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) but with various responses. The objective of this article was to review evidences from controlled studies in order to determine whether herbs can be useful in the treatment of cognitive disorders in the elderly. Randomized controlled studies assessing AD in individuals older than 65 years were identified through searches of MEDLINE, LILACS, Cochrane Library, dissertation Abstract (USA), ADEAR (Alzheimer′s Disease Clinical Trials Database), National Research Register, Current Controlled trials, Centerwatch Trials Database and PsychINFO Journal Articles. The search combined the terms Alzheimer disease, dementia, cognition disorders, Herbal, Phytotherapy. The crossover results were evaluated by the Jadad′s measurement scale. The systematic review identified two herbs and herbal formulations with therapeutic effects for the treatment of AD: Melissa officinalis, Salvia officinalis and Yi‐Gan San and BDW (Ba Wei Di Huang Wan). Ginkgo biloba was identified in a meta‐analysis study. All five herbs are useful for cognitive impairment of AD. M. officinalis and Yi‐Gan San are also useful in agitation, for they have sedative effects. These herbs and formulations have demonstrated good therapeutic effectiveness but these results need to be compared with those of traditional drugs. Further large multicenter studies should be conducted in order to test the cost‐effectiveness of these herbs for AD and the impact in the control of cognitive deterioration.
The northern geographic range limit of the intertidal limpetCollisella scabra: a test of performance, recruitment, and temperature hypotheses
Authors: Gilman Sarah E.
Published: October 2006

A decline in abundance towards a species' range boundary is often interpreted as evidence of a decline in individual success, and is usually assumed to reflect a decline in suitable environmental conditions. Gradual declines towards high latitude range boundaries are frequently attributed to limitations on organismal tolerance of cold temperature. Rarely have these two assumptions been empirically tested. The intertidal gastropodCollisella scabradeclines monotonically in abundance from 435 to <1 m−2over the northern 300 km of its geographic distribution. I examined temperature, adult performance (survival, growth, reproduction), and recruitment at five locations in this region of decline. Mortality ranged from 4.9 to 11.2% per month, but was highest at the lowest latitude study site. Growth rates ranged from 0 to 5.2 mm yr−1, but were generally lower at lower latitude sites. Gonad development was high in the three populations examined, but the possibility of infrequent spawning at high latitude sites could not be excluded. Finally, a comparison of performance differences among populations with temperature revealed clear effects of temperature on both growth and mortality; however, the patterns were not consistent with a hypothesis of cold stress at the range boundary. Overall there was little evidence for either reduced performance or increasing cold stress in low density high latitude populations. Over the same 300 km, recruitment declined monotonically from a mean of six recruits per 625 cm2to less than one; suggesting that limitations on recruitment, rather that adult performance, are responsible for low abundance in marginal populations. Several hypotheses for the decline in recruitment are discussed in the paper and the most likely explanation appears to be an increase in the distance between populations at the range margin, reducing the chances that dispersing larvae find suitable habitat for settlement.
Null models for species co‐occurrence patterns: assessing bias and minimum iteration number for the sequential swap
Authors: Lehsten Veiko , Harmand Peter
Published: October 2006

The analysis of co‐occurrence matrices is a common practice to evaluate community structure. The observed data are compared with a “null model”, a randomised co‐occurrence matrix derived from the observation by using a statistic, e.g. the C‐score, sensitive to the pattern investigated. The most frequently used algorithm, “sequential swap”, has been criticised for not sampling with equal frequencies thereby calling into question the results of earlier analysis. The bias of the “sequential swap” algorithm when used with the C‐score was assessed by analysing 291 published presence‐absence matrices. In 152 cases, the true p‐value differed by >5% from the p‐value generated by an uncorrected “sequential swap”. However, the absolute value of the difference was rather small. Out of the 291 matrices, there were only 5 cases in which an incorrect statistical decision would have been reached by using the uncorrected p‐value (3 at the p<0.05 and 2 at the p<0.01 level), and in all 5 of these cases, the true p‐value was close to the significance level. Our results confirm analytical studies of Miklos and Podani which show that the uncorrected swap gives slightly conservative results in tests for competitive segregation. However, the bias is very small and should not distort the ecological interpretation. We also estimated the number of iterations needed for the “sequential swap” to generate accurate p‐values. While most authors do not exceed a number of 104 iterations, the suggested minimum number of swaps for 29 out of the 291 tested matrices is greater than 104. We recommend to use 30 000 “sequential swaps” if the required sample size is not assessed otherwise.
Spatial‐pattern analysis in a territorial spider: evidence for multi‐scale effects
Authors: Birkhofer Klaus , R. Henschel Joh , Scheu Stefan
Published: October 2006

Territorial animals maintain a certain distance to neighbouring conspecifics, presumably leading to a regular spatial pattern through social spacing. Nevertheless, most animal populations are assumed to show aggregation at certain distance ranges, reflecting the scale dependency of spatial patterns. Leucorchestris arenicola (Araneae: Sparassidae) is a burrow‐living spider species that shows territorial behaviour against conspecifics. A multi‐scale approach in spatial analysis revealed that territory owners had fewer neighbours than expected under spatial randomness at distances up to 6 m. Behavioural field experiments showed that territory owners were able to perceive and react to burrow constructing neighbours up to at least 4 m distance from their own burrow. At larger distances individuals were often more aggregated than expected under spatial randomness. Analysing adult and immature relationships showed attraction between different development stages at small distances and avoidance at larger distances. The analysis reveals diverse spatial patterns in a territorial and cannibalistic species, showing that both behaviour and environment affect pattern development at different distances. The study outlines the importance of multi‐scale approaches for spatial analysis and the need for accompanying experiments to facilitate the interpretation of results.
Predicting patterns of plant species richness in megadiverse South Africa
Authors: Thuiller Wilfried , F. Midgley Guy , Rougeti Mathieu , M. Cowling Richard
Published: October 2006

Using new tools (boosted regression trees) in predictive biogeography, with extensive spatial 23 distribution data for >19 000 species, we developed predictive models for South African plant species richness patterns. Further, biome level analysis explored possible functional determinants of country‐wide regional species richness. Finally, to test model reliability independently, we predicted potential alien invasive plant species richness with an independent dataset. Amongst the different hypotheses generally invoked to explain species 30 diversity (energy, favorableness, topographic heterogeneity, irregularity and seasonality), results revealed topographic heterogeneity as the most powerful single explanatory variable for indigenous South African plant species richness. Some biome‐specific responses were observed, i.e. two of the five analyzed biomes (Fynbos and Grassland) had richness best explained by the “species‐favorableness” hypothesis, but even in this case, topographic heterogeneity was also a primary predictor. This analysis, the largest conducted on an almost exhaustive species sample in a species‐rich region, demonstrates the preeminence of topographic heterogeneity in shaping the spatial pattern of regional plant species richness. Model reliability was confirmed by the considerable predictive power for alien invasive species richness. It thus appears that topographic heterogeneity controls species richness in two main ways: firstly, by providing an abundance of ecological niches in contemporary space (revealed by alien invasive species richness relationships) and secondly, by facilitating the persistence of ecological niches through time. The extraordinary richness of the South African Fynbos biome, a world‐renowned hotspot of biodiversity with the steepest environmental gradients in South Africa, may thus have arisen through both mechanisms. Comparisons with similar regions of the world outside South Africa are needed to confirm the generality of topographic heterogeneity and favorableness as predictors of plant richness.
Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors
Authors: Reipert Birgit M. , Van Den Helden Pauline M. W. , Schwarz Hans‐Peter , Hausl Christina
Published: October 2006

In its most severe form, haemophilia A is a life‐threatening haemorrhagic bleeding disorder that is caused by mutations in the factor VIII (FVIII) gene. About 25% of patients who receive replacement therapy with intravenous FVIII products develop neutralising antibodies (FVIII inhibitors) that inhibit the function of substituted FVIII. Long‐term application of high or low doses of FVIII has evolved as an effective strategy for eradicating antibodies and inducing long‐lasting immune tolerance. Despite clinical experience with the therapy, little is known about the immunological mechanisms that cause the downmodulation of FVIII‐specific immune responses or the induction of long‐lasting immune tolerance against FVIII. This review summarises current knowledge of the immunological mechanisms that might be involved in the induction of immune tolerance against FVIII in patients with haemophilia A who have FVIII inhibitors. In addition to data from patients with haemophilia A, data from patients who have had organ transplants or have immune‐related disorders, such as autoimmune diseases, are considered as well as data from animal models.
Differential cell division history between neutrophils and macrophages in their development from granulocyte–macrophage progenitors
Authors: Sugimoto Yuka , Katayama Naoyuki , Masuya Masahiro , Miyata Eri , Ueno Masaya , Ohishi Kohshi , Nishii Kazuhiro , Takakura Nobuyuki , Shiku Hiroshi
Published: October 2006

The appearance of monocytes before neutrophils in the blood during haematopoietic recovery in myelosuppressive patients is commonly observed, thus suggesting a difference in the cell division history between these two lineages in the differentiation from granulocyte–macrophage (GM) progenitors. We investigated the cell division histories of murine GM progenitors. When analysed by the dye dilution method, GM progenitors gave rise to Gr‐1+Fms+ and Gr‐1+Fms− cells that passed through similar rounds of cell division during initial 5 d of culture. The Gr‐1+Fms+ cells showed morphological features of monocytes, while Gr‐1+Fms− cells exhibited an immature morphology of neutrophils. In the subsequent culture, a decline in the number of Gr‐1+Fms+ cells was observed, while Gr‐1+Fms− cells increased. The proliferation of Gr‐1+Fms− cells and no cell division of Gr‐1+Fms+ cells were confirmed by DNA staining, Ki‐67 expression, membrane dye staining and bromodeoxyuridine incorporation. These Gr‐1+Fms− cells acquired mature neutrophil morphology, whereas Gr‐1+Fms+ cells became macrophages. These results demonstrate that GM progenitors generate postmitotic monocytes earlier than mature neutrophils. Our data may also offer one explanation for the rapid recovery of monocytes in comparison with neutrophils in the early phase of haematopoietic regeneration.
Research‐based interventions for children and youth with a Fetal Alcohol Spectrum Disorder: revealing the gap
Authors: Premji S. , Benzies K. , Serrett K. , Hayden K. A.
Published: October 2006

Background  Alcohol use during pregnancy can result in a continuum of effects including growth deficits, dysmorphology and/or complex patterns of behavioural and cognitive difficulties that influence an individual’s functioning throughout their lifespan. We conducted a systematic review to identify research‐based interventions for children and youth with a Fetal Alcohol Spectrum Disorder and areas for future study.

Methods  We identified the substantive literature by searching 40 peer‐reviewed and 23 grey literature databases, as well as reference lists. We hand‐searched eight relevant journals, and undertook a systematic search of Internet sites and review of reports and documents received from key stakeholders. Two reviewers independently assessed eligibility and quality, and extracted data. Given the small number of studies that met all inclusion criteria, both experimental and quasi‐experimental studies were included.

Results  Ten intervention studies were identified, of which three were experimental or quasi‐experimental, and four were non‐experimental. Despite multiple attempts, three studies (two in foreign languages and one unpublished) could not be acquired. A meta‐analysis could not be undertaken because the included studies examined different interventions or outcomes. Interventions targeted in the included studies were as follows: (i) psychostimulant medications (methyphenidate, pemoline and dextroamphetamine); and (ii) Cognitive Control Therapy. The identified studies were limited by very small sample sizes and weak designs.

Conclusion  There is limited scientific evidence upon which to draw recommendations regarding efficacious interventions for children and youth with a Fetal Alcohol Spectrum Disorder. Clinicians, researchers, service providers, educators, policy makers, affected children and youth and their families, and others need to urgently collaborate to develop a comprehensive research agenda for this population.
Associations between youth assets and sexual activity: does adult supervision play a role?
Authors: Harris L. , Oman R. F. , Vesely S. K. , Tolma E. L. , Aspy C. B. , Rodine S. , Marshall L. , Fluhr J.
Published: October 2006

Background  Youth participation in sexual risk behaviours continues to be a critically important public health topic. Additionally, as youth are frequently being left alone during the day without adult supervision, there are increased opportunities for sexual risk‐taking behaviour. This study examined how the relationships of nine youth assets and sexual activity may vary according to the stratification of youth into two groups: self‐care and supervised.

Methods  Data were collected through at‐home, in‐person interviews from a random sample of inner‐city youth (mean age = 15.4 years; 51.5% female; 48.8% White; 22.4% Black; 18.5% Hispanic; 10% Native American) and their parents (n = 1079 parent/youth pairs). Nine youth assets were analysed using multiple logistic regression. Examples of assets youth may possess are: positive role models, family communication, school connectedness, constructive use of time and aspirations for the future. The item used to assess sexual intercourse was ‘Have you ever had sexual intercourse (“done it”, “had sex”, “made love”, “gone all the way”)?’. Asset/risk behaviour associations that were unique to one of the two strata were the focus of the study.

Results  Thirty‐seven per cent of youth spent two or more hours per day home alone. Youth who were supervised had a greater number of unique significant associations between assets and sexual activity than youth who were in the self‐care group.

Conclusions  Youth in supervised settings may be less likely to participate in sexual activity because of the presence of assets. Certain assets may also be important in deterring sexual activity for youth who are in self‐care.
Competition between two planktonic rotifer species at different temperatures: an experimental test
Authors: STELZER CLAUS‐PETER
Published: October 2006

1. The effect of temperature on the outcome of resource competition between two planktonic rotifers (Synchaeta pectinata and Brachionus calyciflorus) was investigated in laboratory experiments. In addition to the competition experiments, several physiological variables and their temperature‐dependence were characterised, including ingestion rate and starvation tolerance.

2. Because of a lower threshold food level (TFL) for population growth for the food algae Cryptomonas erosa, Synchaeta was predicted to be the superior competitor at low temperatures (12 °C). In contrast, Brachionus had a lower TFL at 20 °C and was predicted to be competitively superior at this temperature.

3. In both rotifer species, ingestion rates increased with temperature, but the increase was much more pronounced in Brachionus. Ingestion rates of Brachionus at temperatures from 8 to 24 °C were always higher than in Synchaeta (up to 4.6‐fold).

4. Starvation resistance reduced with temperature in both rotifer species. At all temperatures investigated (12, 16 and 20 °C) Brachionus could survive starvation for longer than Synchaeta. This difference was strongest at 12 °C (5.8 days versus 2.5 days).

5. In the first competition experiment, food was supplied at 48 h‐intervals. Brachionus displaced Synchaeta at both experimental temperatures (12 and 20 °C). Competitive exclusion of Synchaeta at the lower temperature was probably because of large fluctuations in algal densities that resulted from the long intervals between feeding, a condition that favoured Brachionus because of its higher starvation resistance.

6. In the second competition experiment, one third of the food suspension was renewed every 8 h, resulting in a much better approximation to a continuous resource supply. At 12 °C Synchaeta and Brachionus coexisted for more than 1 month and the densities of both rotifer species were significantly lower in the presence of their competitor. In contrast to expectations, Brachionus was able to persist even when Cryptomonas concentrations fell below its TFL. This was probably because Brachionus was using detritus and associated bacteria as additional food sources, which were present in the cultures during the later phase of the experiment.

7. Autocorrelation analysis of the temporal changes in egg ratios revealed significant periodic cycles in Synchaeta during the second competition experiment. A possible explanation for this is the fecundity schedule of Synchaeta, in which reproduction is highly concentrated in a few age classes. According to demographic theory, such a life cycle feature can cause slower convergence to a stable age distribution.