bluuebunny/crossref_metadata_2025 huggingface dataset:
Coal burning leaves toxic heavy metal legacy in the Arctic
Authors: McConnell Joseph R. , Edwards Ross
Published: August 2008

Toxic heavy metals emitted by industrial activities in the midlatitudes are transported through the atmosphere and deposited in the polar regions; bioconcentration and biomagnification in the food chain mean that even low levels of atmospheric deposition may threaten human health and Arctic ecosystems. Little is known about sources and long-term trends of most heavy metals before ≈1980, when modern measurements began, although heavy-metal pollution in the Arctic was widespread during recent decades. Lacking detailed, long-term measurements until now, ecologists, health researchers, and policy makers generally have assumed that contamination was highest during the 1960s and 1970s peak of industrial activity in North America and Europe. We present continuous 1772–2003 monthly and annually averaged deposition records for highly toxic thallium, cadmium, and lead from a Greenland ice core showing that atmospheric deposition was much higher than expected in the early 20th century, with tenfold increases from preindustrial levels by the early 1900s that were two to five times higher than during recent decades. Tracer measurements indicate that coal burning in North America and Europe was the likely source of these metals in the Arctic after 1860. Although these results show that heavy-metal pollution in the North Atlantic sector of the Arctic is substantially lower today than a century ago, contamination of other sectors may be increasing because of the rapid coal-driven growth of Asian economies.
Exceptional longevity does not result in excessive levels of disability
Authors: Christensen Kaare , McGue Matt , Petersen Inge , Jeune Bernard , Vaupel James W.
Published: August 2008

Late-life loss of independence in daily living is a central concern for the aging individual and for society. The implications of increased survival to advanced age may be different at the population level than at the individual level. Here we used a longitudinal multi-assessment survey of the entire Danish 1905 cohort from 1998 to 2005 to assess the loss of physical and cognitive independence in the age range of 92 to 100 years. Multiple functional outcomes were studied, including independence, which was defined as being able to perform basic activities of daily living without assistance from other persons and having a MiniMental State Examination (MMSE) score of 23 or higher. In the aggregate, the 1905 cohort had only a modest decline in the proportion of independent individuals at the 4 assessments between age 92 and 100 years: 39%, 36%, 32%, and 33%, with a difference between first and last assessment of 6% [95% confidence interval (CI), −1–14%]. For participants who survived until 2005, however, the prevalence of independence was reduced by more than a factor of 2, from 70% in 1998 to 33% in 2005 (difference, 37%; 95% CI, 28–46%). Similar results were obtained for the other functional outcomes. Analyses of missing data resulting from nonresponse and death suggest that the discrepancy between the population trajectory and the individual trajectory is caused by increased mortality among dependent individuals. For the individual, long life brings an increasing risk of loss of independence. For society, mortality reductions are not expected to result in exceptional levels of disability in cohorts of the very old.
Allopolyploid speciation inPersicaria(Polygonaceae): Insights from a low-copy nuclear region
Authors: Kim Sang-Tae , Sultan Sonia E. , Donoghue Michael J.
Published: August 2008

Using a low-copy nuclear gene region (LEAFYsecond intron) we show multiple instances of allopolyploid speciation inPersicaria(Polygonaceae), which includes many important weeds. Fifteen species seem to be allopolyploids, which is higher than the number found in previous comparisons of chloroplast DNA and nuclear ribosomal internal transcribed spacer (nrITS) phylogenies. This underestimation of the extent of allopolyploidy is due in at least three cases to homogenization of nrITS toward the maternal lineage. One of the diploid species,P. lapathifolia, has been involved in at least six cases of allopolyploid speciation. Of the diploids, this species is the most widespread geographically and ecologically and also bears more numerous and conspicuous flowers, illustrating ecologic factors that may influence hybridization frequency. With a few exceptions, especially the narrowly endemic hexaploid,P. puritanorum, the allopolyploid species also are widespread, plastic, ecological generalists. Hybridization events fostered by human introductions may be fueling the production of new species that have the potential to become aggressive weeds.
The origin recognition complex is dispensable for endoreplication in
Drosophila
Authors: Park So Young , Asano Maki
Published: August 2008

The origin recognition complex (ORC) is an essential component of the prereplication complex (pre-RC) in mitotic cell cycles. The role of ORC as a foundation to assemble the pre-RC is conserved from yeast to human. Furthermore, in metazoans ORC plays a key role in determining the timing of replication initiation and origin usage. In this report we have produced and analyzed a
Drosophila orc1
allele to investigate the roles of ORC1 in three different modes of DNA replication during development. As expected, ORC1 is essential for mitotic replication and proliferation in brains and imaginal discs, as well as for gene amplification in ovarian follicle cells. Surprisingly, however, ORC1 is not required for endoreplication. Decreased cell number in
orc1
mutant salivary glands is consistent with the idea that undetectable levels of maternal ORC1 during embryogenesis fail to support further proliferation. Nevertheless, these cells begin endoreplicating normally and reach a final ploidy of >1000C in the absence of zygotic synthesis of ORC1. The dispensability of ORC is further supported by an examination of other ORC members, whereas Double-parked protein/Cdt1 and minichromosome maintenance proteins are apparently essential for endoreplication, implying that some aspects of initiation are shared among the three modes of DNA replication. This study provides insight into the physiologic roles of ORC during metazoan development and proposes that DNA replication initiation is governed differently in mitotic and endocycles.
Discovering interactions among BRCA1 and other candidate genes associated with sporadic breast cancer
Authors: Lo Shaw-Hwa , Chernoff Herman , Cong Lei , Ding Yuejing , Zheng Tian
Published: August 2008

Analysis of a subset of case-control sporadic breast cancer data, [from the National Cancer Institute's Cancer Genetic Markers of Susceptibility (CGEMS) initiative], focusing on 18 breast cancer-related genes with 304 SNPs, indicates that there are many interesting interactions that form two- and three-way networks in which
BRCA1
plays a dominant and central role. The apparent interactions of
BRCA1
with many other genes suggests the conjecture that
BRCA1
serves as a protective gene and that some mutations in it or in related genes may prevent it from carrying out this protective function even if the patients are not carriers of known cancer-predisposing
BRCA1
mutations. The method of analysis features the evaluation of the effect of a gene by averaging the effects of the SNPs covered by that gene. Marginal methods that test one gene at a time fail to show any effect. That may be related to the fact that each of these 18 genes adds very little to the risk of cancer. Analysis that relates the ratio of interactions to the maximum of the first-order effects discovers significant gene pairs and triplets.
SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins
Authors: Mueller Britta , Klemm Elizabeth J. , Spooner Eric , Claessen Jasper H. , Ploegh Hidde L.
Published: August 2008

Membrane and secretory proteins that fail to pass quality control in the endoplasmic reticulum are discharged into the cytosol and degraded by the proteasome. Many of the mammalian components involved in this process remain to be identified. We performed a biochemical search for proteins that interact with SEL1L, a protein that is part of the mammalian HRD1 ligase complex and involved in substrate recognition. SEL1L is crucial for dislocation of Class I major histocompatibility complex heavy chains by the human cytomegalovirus US11 protein. We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important components of this degradation complex in mammalian cells, as confirmed by mutagenesis and dominant negative versions of these proteins.
Ecological changes in Miocene mammalian record show impact of prolonged climatic forcing
Authors: Badgley Catherine , Barry John C. , Morgan Michèle E. , Nelson Sherry V. , Behrensmeyer Anna K. , Cerling Thure E. , Pilbeam David
Published: August 2008

Geohistorical records reveal the long-term impacts of climate change on ecosystem structure. A 5-myr record of mammalian faunas from floodplain ecosystems of South Asia shows substantial change in species richness and ecological structure in relation to vegetation change as documented by stable isotopes of C and O from paleosols. Between 8.5 and 6.0 Ma, C4savannah replaced C3forest and woodland. Isotopic historical trends for 27 mammalian herbivore species, in combination with ecomorphological data from teeth, show three patterns of response. Most forest frugivores and browsers maintained their dietary habits and disappeared. Other herbivores altered their dietary habits to include increasing amounts of C4plants and persisted for >1 myr during the vegetation transition. The few lineages that persisted through the vegetation transition show isotopic enrichment of δ13C values over time. These results are evidence for long-term climatic forcing of vegetation structure and mammalian ecological diversity at the subcontinental scale.
Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn
2+
and NR1 antagonist
Authors: Madry Christian , Betz Heinrich , Geiger Jörg R. P. , Laube Bodo
Published: August 2008

Coassembly of the glycine-binding NMDA receptor subunits NR1 and NR3A results in excitatory glycine receptors of low efficacy. Here, we report that micromolar concentrations of the divalent cation Zn
2+
produce a 10-fold potentiation of NR1/NR3A receptor responses, which resembles that seen upon antagonizing glycine binding to the NR1 subunit. Coapplication of both Zn
2+
and NR1 antagonist caused a supralinear potentiation, resulting in a >120-fold increase of glycine-activated currents. At concentrations >50 μM, Zn
2+
alone generated receptor currents with similar efficacy as glycine, implying that NR1/NR3A receptors can be activated by different agonists. Point mutations in the NR1 and NR3A glycine-binding sites revealed that both the potentiating and agonistic effects of Zn
2+
are mediated by the ligand-binding domain of the NR1 subunit. In conclusion, Zn
2+
acts as a potent positive modulator and agonist at the NR1 subunit of NR1/NR3A receptors. Our results suggest that this unconventional member of the NMDA receptor family may
in vivo
be gated by the combined action of glycine and Zn
2+
or a yet unknown second ligand.
In defence of anonymity: Rejoining the criticism
Authors: Kelly Anthony
Published: August 2008

This article is a response to the growing criticisms of the British Educational Research Association (BERA) and Economic and Social Research Council (ESRC) ethical guidelines on anonymity and pseudonymity as default positions for participants in qualitative educational research. It discusses and responds to those criticisms under four headings—illusion, impossibility and undesirability, access and quality—and extends the explication of difficulties to quantitative approaches using an example from value‐added effectiveness research. The article discusses potential flaws in the arguments made against anonymous and pseudonymous research, and presents some issues for the research community to take forward. Finally, some suggestions are offered for a modified code of practice regarding anonymity and pseudonymity, which attempts a more subtle capture of difficulties in the field and qualifies the existing rationale to take account of previously unconsidered technical concerns.
Synthetic phonics and the teaching of reading
Authors: Wyse Dominic , Goswami Usha
Published: August 2008

A review of the teaching of early reading in England commissioned by the UK Government recommended that synthetic phonics should be the preferred approach for young English learners. In response, all English schools have been told to put in place a discrete synthetic phonics programme as the key means for teaching high‐quality phonic work. In this paper we analyse the evidence presented by the review to support the change to synthetic phonics. We show that the review provided no reliable empirical evidence that synthetic phonics offers the vast majority of beginners the best route to becoming skilled readers. We analyse the available empirical evidence in English, and show instead that the data support approaches based on systematic tuition in phonics. There is also evidence that contextualised systematic phonics instruction is effective. However, more research is needed, particularly with typically developing readers, in order to determine whether contextualised systematic phonics is more effective than discrete systematic phonics.
Theoretical Modeling in Hemodynamics of Microcirculation
Authors: LEE JACK , SMITH NICOLAS P.
Published: August 2008

Over the past decades, theoretical modeling has become an indispensable component of research into the hemodynamics of microcirculation. Numerous studies rely on modeling to provide quantitative insights into the interacting biophysical mechanisms that govern microcirculatory flow. The mechanical deformation of hematocytes has been addressed by continuum and molecular‐informed computational models based on a growing body of experimental information. Theoretical analyses of single‐vessel flow and blood rheology have led to a range of modeling approaches. Until recently, computational constraints limited direct simulations of multi‐particle flows involving deformation and/or aggregation, but recent studies have begun to address this challenge. Network‐level analyses have provided insights into the biophysical principles underlying the design of the microcirculation. This approach has been used to complement available experimental data and to derive empirical models of microvascular blood rheology. Continued increases in computational performance applied to current modeling techniques will enable larger scale simulations. In order to exploit this opportunity, integration of diverse theoretical approaches within a multi‐scale framework is needed.
Neutrophil Recruitment under Shear Flow: It's All about Endothelial Cell Rings and Gaps
Authors: ALCAIDE PILAR , AUERBACH SCOTT , LUSCINSKAS FRANCIS W.
Published: August 2008

Leukocyte recruitment to tissues and organs is an essential component of host defense. The molecular mechanisms controlling this process are complex and remain under active investigation. The combination of biochemical techniques and live cell imaging using in vivo and in vitro flow‐model approaches have shed light on several aspects of neutrophil transmigration through the vascular endothelial lining of blood vessels. Here, we focus on the role of adhesion molecule signaling in endothelial cells and their downstream targets during the process of transendothelial migration at cell‐cell borders (paracellular transmigration). An emerging model involves the leukocyte β2 integrin engagement of endothelial cell ICAM‐1, which triggers integrin‐ICAM‐1 clustering (rings) and stabilizes leukocyte adhesion at cell‐cell junctions. This step recruits nonreceptor tyrosine kinases that phosphorylate key tyrosine residues in the cytoplasmic tail of VE‐cadherin, which destabilizes its linkage to catenins and the actin cytoskeleton, triggering the transient opening of VE‐cadherin homodimers to form a gap in the cell junction, through which the neutrophil transmigrates. Interestingly, the signaling events that lead to neutrophil transmigration occur independently of shear flow in vitro.
A study of the relationship between personality traits and theoretical orientation preferences
Authors: Ogunfowora Babatunde , Drapeau Martin
Published: August 2008

This study explored the relationship between personality and theoretical orientation preferences in two separate samples of psychotherapy practitioners and students. A total of 493 participants (274 practitioners and 219 students) completed a web‐based survey. Preference for theoretical orientation was assessed using a measure adapted from the Theoretical Orientation Profile Scale‐Revised, while personality was assessed with the HEXACO Personality Inventory. After controlling for the effects of gender, profession, and degree type, personality was found to predict preference for the humanistic/existential, cognitive‐behavioural, psychodynamic, and feminist theoretical orientations across both samples. Personality also predicted preference for the multicultural, family systems, and neuropsychological orientations, although these findings were applicable to only one sample. Implications for future research, psychotherapy training, and practice are discussed.
Learning from experience: Examining the impact of client work upon two trainee therapists
Authors: Turner Sarah , Gibson Neil , Bennetts Christine , Hunt Cheryl
Published: August 2008

This qualitative research study, focusing on the learning and change of two trainee therapists over a nine‐month period, was conducted by the trainees themselves. In collecting and analysing their data, the researchers made use of the heuristic methodology, to which some of the principles of the co‐operative inquiry methodology were added. The findings shed light on some of the ways in which trainee counsellors and psychotherapists might learn through their work with clients, the forms and contexts in which this learning may arise, and how the learning might affect the trainees. The findings additionally highlight some of the possible benefits of engaging in research for trainee counsellors and psychotherapists, in terms of their roles as practitioners. These include positive changes in the ways in which they work with clients, and changes in the ways they think about their practice.
Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied
Authors: Brito Daniela A. , Yang Zhenye , Rieder Conly L.
Published: August 2008

When the spindle assembly checkpoint (SAC) cannot be satisfied, cells exit mitosis via mitotic slippage. In microtubule (MT) poisons, slippage requires cyclin B proteolysis, and it appears to be accelerated in drug concentrations that allow some MT assembly. To determine if MTs accelerate slippage, we followed mitosis in human RPE-1 cells exposed to various spindle poisons. At 37°C, the duration of mitosis in nocodazole, colcemid, or vinblastine concentrations that inhibit MT assembly varied from 20 to 30 h, revealing that different MT poisons differentially depress the cyclin B destruction rate during slippage. The duration of mitosis in Eg5 inhibitors, which induce monopolar spindles without disrupting MT dynamics, was the same as in cells lacking MTs. Thus, in the presence of numerous unattached kinetochores, MTs do not accelerate slippage. Finally, compared with cells lacking MTs, exit from mitosis is accelerated over a range of spindle poison concentrations that allow MT assembly because the SAC becomes satisfied on abnormal spindles and not because slippage is accelerated.
The transcription factor NFATc2 controls IL-6–dependent T cell activation in experimental colitis
Authors: Weigmann Benno , Lehr Hans A. , Yancopoulos George , Valenzuela David , Murphy Andrew , Stevens Sean , Schmidt Jan , Galle Peter R. , Rose-John Stefan , Neurath Markus F.
Published: August 2008

The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell–dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6–dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.
CD4+FoxP3+ regulatory T cells confer infectious tolerance in a TGF-β–dependent manner
Authors: Andersson John , Tran Dat Q. , Pesu Marko , Davidson Todd S. , Ramsey Heather , O'Shea John J. , Shevach Ethan M.
Published: August 2008

CD4+FoxP3+ regulatory T (T reg) cells comprise a separate lineage of T cells that are essential for maintaining immunological tolerance to self. The molecular mechanism(s) by which T reg cells mediate their suppressive effects remains poorly understood. One molecule that has been extensively studied in T reg cell suppression is transforming growth factor (TGF)-β, but its importance remains controversial. We found that TGF-β complexed to latency-associated peptide (LAP) is expressed on the cell surface of activated but not resting T reg cells. T reg cell LAP–TGF-β plays an important role in the suppression of the proliferation of activated T cells, but it is not required for the suppression of naive T cell activation. More importantly, T reg cell–derived TGF-β could generate de novo CD4+FoxP3+ T cells in vitro from naive precursors in a cell contact–dependent, antigen-presenting cell–independent and αV integrin–independent manner. The newly induced CD4+FoxP3+ T cells are suppressive both in vitro and in vivo. Transfer of activated antigen-specific T reg cells with naive antigen-specific responder T cells to normal recipients, followed by immunization, also results in induction of FoxP3 expression in the responder cells. T reg cell–mediated generation of functional CD4+FoxP3+ cells via this TGF-β–dependent pathway may represent a major mechanism as to how T reg cells maintain tolerance and expand their suppressive abilities.
Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans
Authors: Jaensson Elin , Uronen-Hansson Heli , Pabst Oliver , Eksteen Bertus , Tian Jiong , Coombes Janine L. , Berg Pia-Lena , Davidsson Thomas , Powrie Fiona , Johansson-Lindbom Bengt , Agace William W.
Published: August 2008

A functionally distinct subset of CD103+ dendritic cells (DCs) has recently been identified in murine mesenteric lymph nodes (MLN) that induces enhanced FoxP3+ T cell differentiation, retinoic acid receptor signaling, and gut-homing receptor (CCR9 and α4β7) expression in responding T cells. We show that this function is specific to small intestinal lamina propria (SI-LP) and MLN CD103+ DCs. CD103+ SI-LP DCs appeared to derive from circulating DC precursors that continually seed the SI-LP. BrdU pulse-chase experiments suggested that most CD103+ DCs do not derive from a CD103− SI-LP DC intermediate. The majority of CD103+ MLN DCs appear to represent a tissue-derived migratory population that plays a central role in presenting orally derived soluble antigen to CD8+ and CD4+ T cells. In contrast, most CD103− MLN DCs appear to derive from blood precursors, and these cells could proliferate within the MLN and present systemic soluble antigen. Critically, CD103+ DCs with similar phenotype and functional properties were present in human MLN, and their selective ability to induce CCR9 was maintained by CD103+ MLN DCs isolated from SB Crohn's patients. Thus, small intestinal CD103+ DCs represent a potential novel target for regulating human intestinal inflammatory responses.
Repertoire-based selection into the marginal zone compartment during B cell development
Authors: Carey John B. , Moffatt-Blue Chantelle S. , Watson Lisa C. , Gavin Amanda L. , Feeney Ann J.
Published: August 2008

Marginal zone (MZ) B cells resemble fetally derived B1 B cells in their innate-like rapid responses to bacterial pathogens, but the basis for this is unknown. We report that the MZ is enriched in “fetal-type” B cell receptors lacking N regions (N−). Mixed bone marrow (BM) chimeras, made with adult terminal deoxynucleotidyl transferase (TdT)+/+ and TdT−/− donor cells, demonstrate preferential repertoire-based selection of N− B cells into the MZ. Reconstitution of irradiated mice with adult TdT+/+ BM reveals that the MZ can replenish N− B cells in adult life via repertoire-based selection and suggest the possibility of a TdT-deficient precursor population in the adult BM. The mixed chimera data also suggest repertoire-based bifurcations into distinct BM and splenic maturation pathways, with mature “recirculating” BM B cells showing a very strong preference for N+ complementarity-determining region (CDR) 3 compared with follicular B cells. Because the T1 and MZ compartments are both the most enriched for N− H-CDR3, we propose a novel direct T1→MZ pathway and identify a potential T1–MZ precursor intermediate. We demonstrate progressive but discontinuous repertoire-based selection throughout B cell development supporting multiple branchpoints and pathways in B cell development. Multiple differentiation routes leading to MZ development may contribute to the reported functional heterogeneity of the MZ compartment.
Automated Surveillance for Central Line–Associated Bloodstream Infection in Intensive Care Units
Authors: Woeltje Keith F. , Butler Anne M. , Goris Ashleigh J. , Tutlam Nhial T. , Doherty Joshua A. , Westover M. Brandon , Ferris Vicky , Bailey Thomas C.
Published: August 2008

Objective.

To develop and evaluate computer algorithms with high negative predictive values that augment traditional surveillance for central line–associated bloodstream infection (CLABSI).

Setting.

Barnes-Jewish Hospital, a 1,250-bed tertiary care academic hospital in Saint Louis, Missouri.

Methods.

We evaluated all adult patients in intensive care units who had blood samples collected during the period from July 1, 2005, to June 30,2006, that were positive for a recognized pathogen on culture. Each isolate recovered from culture was evaluated using the definitions for nosocomial CLABSI provided by the National Healthcare Safety Network of the Centers for Disease Control and Prevention. Using manual surveillance by infection prevention specialists as the gold standard, we assessed the ability of various combinations of dichotomous rules to determine whether an isolate was associated with a CLABSI. Sensitivity, specificity, and predictive values were calculated.

Results.

Infection prevention specialists identified 67 cases of CLABSI associated with 771 isolates recovered from blood samples. The algorithms excluded approximately 40%-62% of the isolates from consideration as possible causes of CLABSI. The simplest algorithm, with 2 dichotomous rules (ie, the collection of blood samples more than 48 hours after admission and the presence of a central venous catheter within 48 hours before collection of blood samples), had the highest negative predictive value (99.4%) and the lowest specificity (44.2%) for CLABSI. Augmentation of this algorithm with rules for common skin contaminants confirmed by another positive blood culture result yielded in a negative predictive value of 99.2% and a specificity of 68.0%.

Conclusions.

An automated approach to surveillance for CLABSI that is characterized by a high negative predictive value can accurately identify and exclude positive culture results not representing CLABSI from further manual surveillance.
Discordant QuantiFERON-TB Gold Test Results Among US Healthcare Workers With Increased Risk of Latent Tuberculosis Infection: A Problem or Solution?
Authors: Pollock Nira R. , Campos-Neto Antonio , Kashino Suely , Napolitano Danielle , Behar Samuel M. , Shin Daniel , Sloutsky Alex , Joshi Swati , Guillet Jasmine , Wong Michael , Nardell Edward
Published: August 2008

Objective.

In late 2006, our hospital implemented use of the QuantiFERON-TB Gold (QFT-G) assay, a whole-blood interferon-γ release assay, for detection of tuberculosis infection. All newly hired healthcare workers (HCWs) with positive Mantoux tuberculin skin test (TST) results were routinely tested with the QFT-G assay, to take advantage of its higher specificity. We then undertook a quality assurance review to evaluate the QFT-G test results in HCWs with multiple risk factors for latent tuberculosis infection (LTBI).

Methods.

The clinical records for TST-positive HCWs tested with the QFT-G assay were reviewed. HCWs with 2 or more risk factors commonly associated with LTBI were classified as “increased risk” (IR). IR HCWs who had negative QFT-G test results underwent repeat QFT-G testing and were offered testing with a different interferon-γ release assay (T-SPOT.TB) and with extended T cell stimulation assays.

Results.

Ofl43 TST-positive HCWs tested with the QFT-G assay, 26 (18%) had positive results, 115 (81%) had negative results, and 2 (1 %) had indeterminate results. Of 82 IR HCWs, 23 (28%) had positive QFT-G test results, and 57 (70%) had negative results. Of the 57 IR HCWs with negative results, 43 underwent repeat QFT-G testing: 41 had negative results again, and 2 had positive results. These 43 HCWs were also offered additional testing with the T-SPOT.TB diagnostic, and 36 consented: 31/36 tested negative, and 5/36 tested positive. Extended assays using the antigens ESAT-6 and CFP-10 confirmed the positive results detected by the overnight assays and yielded positive results for an additional 7/36 (19%) of individuals; strikingly, all 36 HCWs had strongly positive test results with assays using purified protein derivative.

Conclusions.

The extreme discordance between the results of our clinical diagnostic algorithm and the results of QFT-G testing raises concern about the sensitivity of the QFT-G assay for detection of LTBI in our HCWs. Results of extended stimulation assays suggest that many of our IR HCWs have indeed been sensitized to Mycobacterium tuberculosis. It is possible that the QFT-G assay identifies those at higher reactivation risk rather than all previously infected, but, in the absence of long-term follow-up data, we should interpret negative QFT-G results with some caution.
Computation in Coxeter groups II. Constructing minimal roots
Authors: Casselman Bill
Published: August 2008

In an earlier paper (Casselman, 2002) I described how a number of ideas due to Fokko du Cloux and myself could be incorporated into a reasonably efficient program to carry out multiplication in arbitrary Coxeter groups. At the end of that paper I discussed how this algorithm could be used to build the reflection table of minimal roots, which could in turn form the basis of a much more efficient multiplication algorithm. In this paper, following a suggestion of Robert Howlett, I explain how results due to Brigitte Brink can be used to construct the minimal root reflection table directly and more efficiently.
Optimal contact map alignment of protein–protein interfaces
Authors: Pulim Vinay , Berger Bonnie , Bienkowska Jadwiga
Published: August 2008

The long-standing problem of constructing protein structure alignments is of central importance in computational biology. The main goal is to provide an alignment of residue correspondences, in order to identify homologous residues across chains. A critical next step of this is the alignment of protein complexes and their interfaces. Here, we introduce the program CMAPi, a two-dimensional dynamic programming algorithm that, given a pair of protein complexes, optimally aligns the contact maps of their interfaces: it produces polynomial-time near-optimal alignments in the case of multiple complexes. We demonstrate the efficacy of our algorithm on complexes from PPI families listed in the SCOPPI database and from highly divergent cytokine families. In comparison to existing techniques, CMAPi generates more accurate alignments of interacting residues within families of interacting proteins, especially for sequences with low similarity. While previous methods that use an all-atom based representation of the interface have been successful, CMAPi's use of a contact map representation allows it to be more tolerant to conformational changes and thus to align more of the interaction surface. These improved interface alignments should enhance homology modeling and threading methods for predicting PPIs by providing a basis for generating template profiles for sequence–structure alignment.

Contact:  bab@mit.edu; jbienkowska@gmail.com

Supplementary information: Supplementary data are available at http://theory.csail.mit.edu/cmapi
Accurate sequence-based prediction of catalytic residues
Authors: Zhang Tuo , Zhang Hua , Chen Ke , Shen Shiyi , Ruan Jishou , Kurgan Lukasz
Published: August 2008

Motivation: Prediction of catalytic residues provides useful information for the research on function of enzymes. Most of the existing prediction methods are based on structural information, which limits their use. We propose a sequence-based catalytic residue predictor that provides predictions with quality comparable to modern structure-based methods and that exceeds quality of state-of-the-art sequence-based methods.

Results: Our method (CRpred) uses sequence-based features and the sequence-derived PSI-BLAST profile. We used feature selection to reduce the dimensionality of the input (and explain the input) to support vector machine (SVM) classifier that provides predictions. Tests on eight datasets and side-by-side comparison with six modern structure- and sequence-based predictors show that CRpred provides predictions with quality comparable to current structure-based methods and better than sequence-based methods. The proposed method obtains 15–19% precision and 48–58% TP (true positive) rate, depending on the dataset used. CRpred also provides confidence values that allow selecting a subset of predictions with higher precision. The improved quality is due to newly designed features and careful parameterization of the SVM. The features incorporate amino acids characterized by the highest and the lowest propensities to constitute catalytic residues, Gly that provides flexibility for catalytic sites and sequence motifs characteristic to certain catalytic reactions. Our features indicate that catalytic residues are on average more conserved when compared with the general population of residues and that highly conserved amino acids characterized by high catalytic propensity are likely to form catalytic sites. We also show that local (with respect to the sequence) hydrophobicity contributes towards the prediction.

Availability:  http://biomine.ece.ualberta.ca/CRpred/CRpred.htm

Contact:  lkurgan@ece.ualberta.ca

Supplementary information:  Supplementary data are available at Bioinformatics online.
spolTools: online utilities for analyzing spoligotypes of the Mycobacterium tuberculosis complex
Authors: Tang Chaka , Reyes Josephine F. , Luciani Fabio , Francis Andrew R. , Tanaka Mark M.
Published: August 2008

spolTools is a collection of online programs designed to manipulate and analyze spoligotype datasets of the Mycobacterium tuberculosis complex. These tools are integrated into a repository currently containing 1179 spoligotypes and 6278 isolates across 30 datasets. Users can search this database to export for external use or to pass on to the integrated tools. These tools include the computation of basic population genetic quantities, the visualization of clusters of spoligotype patterns based on an estimated evolutionary history and a procedure to predict emerging strains – genotypes associated with elevated transmission.

Availability: Database, programs and documentation may be accessed online at http://www.emi.unsw.edu.au/spolTools.

Contact:  j.reyes@student.unsw.edu.au; m.tanaka@unsw.edu.au
Markov model plus k-word distributions: a synergy that produces novel statistical measures for sequence comparison
Authors: Dai Qi , Yang Yanchun , Wang Tianming
Published: August 2008

Motivation: Many proposed statistical measures can efficiently compare biological sequences to further infer their structures, functions and evolutionary information. They are related in spirit because all the ideas for sequence comparison try to use the information on the k-word distributions, Markov model or both. Motivated by adding k-word distributions to Markov model directly, we investigated two novel statistical measures for sequence comparison, called wre.k.r and S2.k.r.

Results: The proposed measures were tested by similarity search, evaluation on functionally related regulatory sequences and phylogenetic analysis. This offers the systematic and quantitative experimental assessment of our measures. Moreover, we compared our achievements with these based on alignment or alignment-free. We grouped our experiments into two sets. The first one, performed via ROC (receiver operating curve) analysis, aims at assessing the intrinsic ability of our statistical measures to search for similar sequences from a database and discriminate functionally related regulatory sequences from unrelated sequences. The second one aims at assessing how well our statistical measure is used for phylogenetic analysis. The experimental assessment demonstrates that our similarity measures intending to incorporate k-word distributions into Markov model are more efficient.

Availability: The software, data and supplement material are freely available at http://math.dlut.edu.cn/daiqi/mplusd.html.

Contact:  daiailiu2004@yahoo.com.cn

Supplementary information:  Supplementary data are available at Bioinformatics online.
Influence of Protein and Energy Intakes on Body Composition of Formula‐fed Preterm Infants After Term
Authors: Roggero P , Giannì ML , Amato O , Orsi A , Piemontese P , Puricelli V , Mosca F
Published: August 2008

The aim of the present study was to evaluate changes in body composition in 48 preterm infants in relation to protein and energy intakes from term up to 3 months of corrected age, using air displacement plethysmography. Protein intake (grams per kilogram per day) was negatively associated with percentage of fat mass at 1 month of corrected age. The high‐protein‐intake group showed greater gain in lean body mass gain than did the low‐protein‐intake group. This finding suggests that during the first month of corrected age, high protein intake results in a significantly different weight gain composition.
Fructose Intolerance in Children Presenting With Abdominal Pain
Authors: Gomara Robert E , Halata Michael S , Newman Leonard J , Bostwick Howard E , Berezin Stuart H , Cukaj Lynnette , See Mary C , Medow Marvin S
Published: August 2008

Objectives:

We determined the occurrence of fructose malabsorption in pediatric patients with previous diagnoses of abdominal pain caused by a functional bowel disorder, whether the restriction of fructose intake changes the reporting of symptoms, the role of fructose dosage, and the severity of resultant symptoms.

Patients and Methods:

We administered a fructose breath test to children presenting with persistent unexplained abdominal pain. Patients randomly received 1, 15, or 45 g fructose, and breath hydrogen was measured for 3 hours after ingestion. Test results were positive when breath hydrogen was 20 ppm greater than baseline and was accompanied by gastrointestinal symptoms.

Results:

A total of 32 patients was enrolled, and none of the 9 who received 1 g had positive results. Three of 10 who received 15 g and 8 of 13 who received 45 g had positive results. All patients with positive test results restricted their fructose intake. Among the group with positive results, 9 of 11 had rapid improvement of their gastrointestinal symptoms. After 2 months, all 9 patients continued to report improvement.

Conclusions:

We concluded that fructose malabsorption may be a significant problem in children and that management of dietary intake can be effective in reducing gastrointestinal symptoms.
Pediatric Gastroenterology Fellows, Class of 2007: How Well Are They Prepared for the Future?
Authors: Qualia Cary M , Baldwin Constance D , Rossi Thomas M , Wang Hongyue , Brown Marilyn R
Published: August 2008

Objectives:

Pediatric gastroenterology fellows are expected to acquire skills as clinicians, researchers, and educators. An e‐mail survey was conducted to examine training experiences of individual fellows; to understand how graduating fellows rate their abilities as clinicians, researchers, and teachers; and to answer whether the size of a pediatric gastroenterology training program affects a fellow's training and future position choice.

Materials and Methods:

A survey was e‐mailed to 76 third‐year pediatric gastroenterology fellows. Respondents were ranked according to the size of their training program.

Results:

Completed surveys were returned by 50 respondents. Of these, 75% planned to pursue careers in academic medicine and 16% in private practice. In all, 68% of trainees participated in some type of basic research and 64% in clinical research. As attending physicians, 22% of fellows hoped to conduct basic science research and 74% clinical research. The majority thought they were competent or proficient teachers, and rated themselves as advanced beginners or competent when asked to evaluate their research skills. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommends that fellows perform 100 colonoscopies, 20 liver biopsies, and 5 paracenteses to be considered competent. We found that regardless of program size, 48% of fellows performed fewer than 100 colonoscopies, 62% performed fewer than 20 liver biopsies, and 80% performed fewer than 5 paracenteses.

Conclusions:

The majority of fellows will pursue academic careers. Trainees may not be performing sufficient numbers of procedures. The number of procedures performed during fellowship was independent of program size.
Rome II Versus Rome III Classification of Functional Gastrointestinal Disorders in Pediatric Chronic Abdominal Pain
Authors: Baber Kari F , Anderson Julia , Puzanovova Martina , Walker Lynn S
Published: August 2008

Objectives:

The updated Rome III criteria for pediatric functional gastrointestinal disorders (FGIDs) include new FGID categories and changes to the Rome II criteria for various FGIDs. To our knowledge, the implications of these revisions for patient classification have not been identified. The purpose of this study was to compare classification results using Rome II versus Rome III criteria for FGIDs associated with chronic abdominal pain.

Patients and Methods:

Participants were 368 pediatric patients whose subspecialty evaluations for chronic abdominal pain yielded no evidence of organic disease. The children's gastrointestinal symptoms were assessed with the parent‐report version of the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGS).

Results:

More patients met the criteria for a pediatric pain‐related FGID according to the Rome III criteria (86.6%) than the Rome II criteria (68.0%). In comparison with the results from the Rome II criteria, the Rome III criteria classified a greater percentage of children as meeting criteria for Abdominal Migraine (23.1% vs 5.7%) and Functional Abdominal Pain (11.4% vs 2.7%). Irritable Bowel Syndrome was the most common diagnosis according to both Rome II (44.0%) and Rome III (45.1%).

Conclusions:

Changes to the Rome criteria make the Rome III criteria more inclusive, allowing classification of 86.6% of pediatric patients with medically unexplained chronic abdominal pain.
High Incidence and Allelic Homogeneity of Wilson Disease in 2 Isolated Populations: A Prerequisite for Efficient Disease Prevention Programs
Authors: Antonietta Zappu , Olympia Magli , Lepori Maria Barbara , Valentina Dessì , Stefania Diana , Simona Incollu , Emmanuel Kanavakis , Polyxeni Nicolaidou , Nina Manolaki , Andreas Fretzayas , Stefano De Virgiliis , Antonio Cao , Georgios Loudianos
Published: August 2008

Objectives:

Herein we report the results of mutation‐based screening for Wilson disease (WD) in 2 isolated populations of Sardinia and the Greek island of Kalymnos.

Patients and Methods:

Mutation analysis was performed in 110 and 9 WD families originating respectively from Sardinia and Kalymons using single‐strand conformation polymorphism and sequencing methods. In Sardinia, a limited screening was performed for −441/−427del in 5290 newborns, whereas in Kalymnos 397 newborns underwent mutation screening for H1069Q and R969Q using appropriate methods.

Results:

In Sardinia, mutation analysis showed the presence of 6 mutations accounting for 85% of chromosomes, 1 of which (−441/−427del) is present in 61.7% of alleles. The screening for −441/−427del in 5290 newborns revealed the presence of 122 heterozygotes, which is equal to an allelic frequency of 1.15%. Assuming the same distribution of WD mutations in the general Sardinian population, we also inferred an allelic frequency of 0.77% for mutations other than −441/−427del, which accounts for an overall frequency of any WD mutation of 1.92%. Assuming Hardy‐Weinberg equilibrium, these data could be translated into a WD incidence of 1 in 2707 live births. In Kalymnos, mutation analysis in 9 WD families revealed the presence of only 2 mutations. The screening of 397 newborns revealed the presence of 18 heterozygotes for H1069Q, 9 for R969Q, and 1 compound heterozygote for these mutations, which is equal to an allele frequency of 3.7%. Assuming Hardy‐Weinberg equilibrium, the expected carrier rate is 7%.

Conclusions:

These data indicate the need for health education for WD prevention in these isolated populations.