bluuebunny/crossref_metadata_2025 huggingface dataset:
An UV photochromic memory effect in proton-based WO3 electrochromic devices
Authors: Zhang Yong , Lee S.-H. , Mascarenhas A. , Deb S. K.
Published: November 2008

We report an UV photochromic memory effect on a standard proton-based WO3 electrochromic device. It exhibits two memory states, associated with the colored and bleached states of the device, respectively. Such an effect can be used to enhance device performance (increasing the dynamic range), re-energize commercial electrochromic devices, and develop memory devices.
Strain-induced low dimensional confinement structures
Authors: Sekkal Nadir , Velasco V. R.
Published: November 2008

We propose here confinement structures similar to heterostructures and superlattices. The present structures can be obtained by applying strain to a single material in a periodic or aperiodic way. The conversion of an indirect gap into an optical active direct or quasidirect gap problem has also been investigated together with the role of zone folding in this phenomenon.
ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage
Authors: Chang Lufen , Zhou Bingsen , Hu Shuya , Guo Robin , Liu Xiyong , Jones Stephen N. , Yen Yun
Published: November 2008

Ribonucleotide reductase small subunit p53R2 was identified as a p53 target gene that provides dNTP for DNA damage repair. However, the slow transcriptional induction of p53R2 in RNA may not be rapid enough for prompt DNA damage repair, which has to occur within a few hours of damage. Here, we demonstrate that p53R2 becomes rapidly phosphorylated at Ser
72
by ataxia telangiectasia mutated (ATM) within 30 min after genotoxic stress. p53R2, as well as its heterodimeric partner RRM1, are associated with ATM
in vivo
. Mutational studies further indicate that ATM-mediated Ser
72
phosphorylation is essential for maintaining p53R2 protein stability and conferring resistance to DNA damage. The mutation of Ser
72
on p53R2 to alanine results in the hyperubiquitination of p53R2 and reduces p53R2 stability. MDM2, a ubiquitin ligase for p53, interacts and facilitates ubiquitination of the S72A-p53R2 mutant more efficiently than WT-p53R2 after DNA damage
in vivo
. Our results strongly suggest a novel mechanism for the regulation of p53R2 activity via ATM-mediated phosphorylation at Ser
72
and MDM2-dependent turnover of p53R2 dephosphorylated at the same residue.
Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis
Authors: Jiang Lei , You Jia , Yu Xinxin , Gonzalez Lety , Yu Yue , Wang Qiong , Yang Guoqing , Li Wenjun , Li Cai , Liu Yong
Published: November 2008

Leptin regulates energy balance and glucose metabolism by activation of multiple signaling cascades mediated by the long-form leptin receptor Ob-Rb. However, the whole spectrum of signaling actions through the 3 cytoplasmic tyrosines of mouse Ob-Rb remains to be completely defined in vivo. Here, we generated 2 knockin lines of mice expressing mutant leptin receptors with phenylalanine substitution for all 3 tyrosines (Y123F) or for Tyr
1138
alone (Y3F). Y123F animals developed overt obesity similar to that of Y3F animals with abrogated hypothalamic activation of STAT3 by leptin, but they exhibited more severe impairment in glucose tolerance. In striking contrast to
db
/
db
mice, however, both Y123F and Y3F mice showed attenuated adiposity with reduced hyperphagia, marked improvement in physical activity and adaptive thermogenesis, and significantly ameliorated glycemic control. Further, Y123F mice had hypothalamic neuropeptide Y/agouti-related protein expression maintained at prominently lower levels compared with
db
/
db
mice. Thus, these results provide direct physiological evidence that Ob-Rb exerts crucial metabolic actions not only through tyrosine-dependent, but also tyrosine-independent mechanisms in control of energy balance and glucose homeostasis.
Early photon tomography allows fluorescence detection of lung carcinomas and disease progression in mice in vivo
Authors: Niedre Mark J. , de Kleine Ruben H. , Aikawa Elena , Kirsch David G. , Weissleder Ralph , Ntziachristos Vasilis
Published: November 2008

Imaging of targeted fluorescent probes offers significant advantages for investigating disease and tissue function in animal models in vivo. Conversely, macroscopic tomographic imaging is challenging because of the high scatter of light in biological tissue and the ill-posed nature of the reconstruction mathematics. In this work, we use the earliest-transmitted photons through Lewis Lung Carcinoma bearing mice, thereby dramatically reducing the effect of tissue scattering. By using a fluorescent probe sensitive to cysteine proteases, the method yielded outstanding imaging performance compared with conventional approaches. Accurate visualization of biochemical abnormalities was achieved, not only in the primary tumor, but also in the surrounding tissue related to cancer progression and inflammatory response at the organ level. These findings were confirmed histologically and with ex vivo fluorescence microscopy. The imaging fidelity demonstrated underscores a method that can use a wide range of fluorescent probes to accurately visualize cellular- and molecular-level events in whole animals in vivo.
Stochastic models for convective momentum transport
Authors: Majda Andrew J. , Stechmann Samuel N.
Published: November 2008

The improved parameterization of unresolved features of tropical convection is a central challenge in current computer models for long-range ensemble forecasting of weather and short-term climate change. Observations, theory, and detailed smaller-scale numerical simulations suggest that convective momentum transport (CMT) from the unresolved scales to the resolved scales is one of the major deficiencies in contemporary computer models. Here, a combination of mathematical and physical reasoning is utilized to build simple stochastic models that capture the significant intermittent upscale transports of CMT on the large scales due to organized unresolved convection from squall lines. Properties of the stochastic model for CMT are developed below in a test column model environment for the large-scale variables. The effects of CMT from the stochastic model on a large-scale convectively coupled wave in an idealized setting are presented below as a nontrivial test problem. Here, the upscale transports from stochastic effects are significant and even generate a large-scale mean flow which can interact with the convectively coupled wave.
Materials and noncoplanar mesh designs for integrated circuits with linear elastic responses to extreme mechanical deformations
Authors: Kim Dae-Hyeong , Song Jizhou , Choi Won Mook , Kim Hoon-Sik , Kim Rak-Hwan , Liu Zhuangjian , Huang Yonggang Y. , Hwang Keh-Chih , Zhang Yong-wei , Rogers John A.
Published: November 2008

Electronic systems that offer elastic mechanical responses to high-strain deformations are of growing interest because of their ability to enable new biomedical devices and other applications whose requirements are impossible to satisfy with conventional wafer-based technologies or even with those that offer simple bendability. This article introduces materials and mechanical design strategies for classes of electronic circuits that offer extremely high stretchability, enabling them to accommodate even demanding configurations such as corkscrew twists with tight pitch (e.g., 90° in ≈1 cm) and linear stretching to “rubber-band” levels of strain (e.g., up to ≈140%). The use of single crystalline silicon nanomaterials for the semiconductor provides performance in stretchable complementary metal-oxide-semiconductor (CMOS) integrated circuits approaching that of conventional devices with comparable feature sizes formed on silicon wafers. Comprehensive theoretical studies of the mechanics reveal the way in which the structural designs enable these extreme mechanical properties without fracturing the intrinsically brittle active materials or even inducing significant changes in their electrical properties. The results, as demonstrated through electrical measurements of arrays of transistors, CMOS inverters, ring oscillators, and differential amplifiers, suggest a valuable route to high-performance stretchable electronics.
Ancient DNA, Strontium isotopes, and osteological analyses shed light on social and kinship organization of the Later Stone Age
Authors: Haak Wolfgang , Brandt Guido , Jong Hylke N. de , Meyer Christian , Ganslmeier Robert , Heyd Volker , Hawkesworth Chris , Pike Alistair W. G. , Meller Harald , Alt Kurt W.
Published: November 2008

In 2005 four outstanding multiple burials were discovered near Eulau, Germany. The 4,600-year-old graves contained groups of adults and children buried facing each other. Skeletal and artifactual evidence and the simultaneous interment of the individuals suggest the supposed families fell victim to a violent event. In a multidisciplinary approach, archaeological, anthropological, geochemical (radiogenic isotopes), and molecular genetic (ancient DNA) methods were applied to these unique burials. Using autosomal, mitochondrial, and Y-chromosomal markers, we identified genetic kinship among the individuals. A direct child-parent relationship was detected in one burial, providing the oldest molecular genetic evidence of a nuclear family. Strontium isotope analyses point to different origins for males and children versus females. By this approach, we gain insight into a Late Stone Age society, which appears to have been exogamous and patrilocal, and in which genetic kinship seems to be a focal point of social organization.
Connecting actin monomers by iso-peptide bond is a toxicity mechanism of the
Vibrio cholerae
MARTX toxin
Authors: Kudryashov Dmitri S. , Durer Zeynep A. Oztug , Ytterberg A. Jimmy , Sawaya Michael R. , Pashkov Inna , Prochazkova Katerina , Yeates Todd O. , Loo Rachel R. Ogorzalek , Loo Joseph A. , Satchell Karla J. Fullner , Reisler Emil
Published: November 2008

The Gram-negative bacterium
Vibrio cholerae
is the causative agent of a severe diarrheal disease that afflicts three to five million persons annually, causing up to 200,000 deaths. Nearly all
V. cholerae
strains produce a large multifunctional-autoprocessing RTX toxin (MARTX

Vc

), which contributes significantly to the pathogenesis of cholera in model systems. The actin cross-linking domain (ACD) of MARTX

Vc

directly catalyzes a covalent cross-linking of monomeric G-actin into oligomeric chains and causes cell rounding, but the nature of the cross-linked bond and the mechanism of the actin cytoskeleton disruption remained elusive. To elucidate the mechanism of ACD action and effect on actin, we identified the covalent cross-link bond between actin protomers using limited proteolysis, X-ray crystallography, and mass spectrometry. We report here that ACD catalyzes the formation of an intermolecular iso-peptide bond between residues E270 and K50 located in the hydrophobic and the DNaseI-binding loops of actin, respectively. Mutagenesis studies confirm that no other residues on actin can be cross-linked by ACD both in vitro and in vivo. This cross-linking locks actin protomers into an orientation different from that of F-actin, resulting in strong inhibition of actin polymerization. This report describes a microbial toxin mechanism acting via iso-peptide bond cross-linking between host proteins and is, to the best of our knowledge, the only known example of a peptide linkage between nonterminal glutamate and lysine side chains.
Integrating epidemiology, psychology, and economics to achieve HPV vaccination targets
Authors: Basu Sanjay , Chapman Gretchen B. , Galvani Alison P.
Published: November 2008

Human papillomavirus(HPV) vaccines provide an opportunity to reduce the incidence of cervical cancer. Optimization of cervical cancer prevention programs requires anticipation of the degree to which the public will adhere to vaccination recommendations. To compare vaccination levels driven by public perceptions with levels that are optimal for maximizing the community's overall utility, we develop an epidemiological game-theoretic model of HPV vaccination. The model is parameterized with survey data on actual perceptions regarding cervical cancer, genital warts, and HPV vaccination collected from parents of vaccine-eligible children in the United States. The results suggest that perceptions of survey respondents generate vaccination levels far lower than those that maximize overall health-related utility for the population. Vaccination goals may be achieved by addressing concerns about vaccine risk, particularly those related to sexual activity among adolescent vaccine recipients. In addition, cost subsidizations and shifts in federal coverage plans may compensate for perceived and real costs of HPV vaccination to achieve public health vaccination targets.
Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice
Authors: Louvet Cédric , Szot Gregory L. , Lang Jiena , Lee Michael R. , Martinier Nicolas , Bollag Gideon , Zhu Shirley , Weiss Arthur , Bluestone Jeffrey A.
Published: November 2008

The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results were observed with sunitinib (Sutent), an additional approved multikinase inhibitor, suggesting that the primary target of imatinib, c-Abl, was not essential in blocking disease in this model. Additional studies with another TK inhibitor, PLX647 (targeting c-Kit and c-Fms) or an anti-c-Kit mAb showed only marginal efficacy whereas a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFRβIg, rapidly reversed diabetes. These findings strongly suggest that inhibition of PDGFR is critical to reverse diabetes and highlight a crucial role of inflammation in the development of T1D. These conclusions were supported by the finding that the adaptive immune system was not significantly affected by imatinib treatment. Finally, and most significantly, imatinib treatment led to durable remission after discontinuation of therapy at 10 weeks in a majority of mice. Thus, long-term efficacy and tolerance is likely to depend on inhibiting a combination of tyrosine kinases supporting the use of selective kinase inhibitors as a new, potentially very attractive approach for the treatment of T1D.
Revisiting the mechanism of macrolide-antibiotic resistance mediated by ribosomal protein L22
Authors: Moore Sean D. , Sauer Robert T.
Published: November 2008

Bacterial antibiotic resistance can occur by many mechanisms. An intriguing class of mutants is resistant to macrolide antibiotics even though these drugs still bind to their targets. For example, a 3-residue deletion (ΔMKR) in ribosomal protein L22 distorts a loop that forms a constriction in the ribosome exit tunnel, apparently allowing nascent-chain egress and translation in the presence of bound macrolides. Here, however, we demonstrate that ΔMKR and wild-type ribosomes show comparable macrolide sensitivity in vitro. In
Escherichia coli
, we find that this mutation reduces antibiotic occupancy of the target site on ribosomes in a manner largely dependent on the AcrAB-TolC efflux system. We propose a model for antibiotic resistance in which ΔMKR ribosomes alter the translation of specific proteins, possibly via changes in programmed stalling, and modify the cell envelope in a manner that lowers steady-state macrolide levels.
Building vocabulary knowledge and phonological awareness skills in children with specific language impairment through hybrid language intervention: a feasibility study
Authors: Munro Natalie , Lee Kerrie , Baker Elise
Published: November 2008

Background & Aims: Preschool and early school‐aged children with specific language impairment not only have spoken language difficulties, but also are at risk of future literacy problems. Effective interventions targeting both spoken language and emergent literacy skills for this population are limited. This paper reports a feasibility study of a hybrid language intervention approach that targets vocabulary knowledge and phonological awareness skills within the context of oral narrative, storybook reading, and drill‐based games. This study also reports on two novel, experimental assessments that were developed to expand options for measuring changes in lexical skills in children.

Methods & Procedures: Seventeen children with specific language impairment participated in a pilot within‐group evaluation of a hybrid intervention programme. The children's performance at pre‐ and post‐intervention was compared on a range of clinical and experimental assessment measures targeting both spoken language and phonological awareness skills. Each child received intervention for six one‐hour sessions scheduled on a weekly basis. Intervention sessions focused on training phonological awareness skills as well as lexical–semantic features of words within the context of oral and storybook narrative and drill‐based games.

Outcomes & Results: The children significantly improved on clinical measures of phonological awareness, spoken vocabulary and oral narrative. Lexical–semantic and sublexical vocabulary knowledge also significantly improved on the experimental measures used in the study.

Conclusions: The results of this feasibility study suggest that a larger scale experimental trial of an integrated spoken language and emergent literacy intervention approach for preschool and early school‐aged children with specific language impairment is warranted.
Basketball game‐related statistics that discriminate between teams’ season‐long success
Authors: Ibáñez Sergio J. , Sampaio Jaime , Feu Sebastian , Lorenzo Alberto , Gómez Miguel A. , Ortega Enrique
Published: November 2008

The aim of the present study was to identify the game‐related statistics that discriminate between season‐long successful and unsuccessful basketball teams participating in the Spanish Basketball League (LEB1). The sample included all 145 average records per season from the 870 games played between the 2000–2001 and the 2005–2006 regular seasons. The following game‐related statistics were gathered from the official box scores of the Spanish Basketball Federation: 2‐ and 3‐point field‐goal attempts (both successful and unsuccessful), free‐throws (both successful and unsuccessful), defensive and offensive rebounds, assists, steals, turnovers, blocks (both made and received), and fouls (both committed and received). To control for season variability, all results were normalized to minutes played each season and then converted to z‐scores. The results allowed discrimination between best and worst teams’ performances through the following game‐related statistics: assists (SC=0.47), steals (SC=0.34), and blocks (SC=0.30). The function obtained correctly classified 82.4% of the cases. In conclusion, season‐long performance may be supported by players’ and teams’ passing skills and defensive preparation.
Assessment of ice hockey performance in real‐game conditions
Authors: Nadeau Luc , Godbout Paul , Richard Jean‐François
Published: November 2008

The aim of this study was to adapt a performance measurement tool, the Team Sport Assessment Procedure (TSAP), to ice hockey during match‐play. In addition to the six categories included in the original observational procedure, the ice hockey TSAP contained four new categories. Twelve Pee‐Wee ice hockey matches were video‐recorded during a regional championship tournament. The game play of 103 of the 11‐ to 12‐year‐old players was then analysed on video by three trained observers, based on all 10 ice hockey TSAP categories. The observational data were thereafter used to compute, for each player, a “volume of play per minute” and an efficiency index. Finally, volume of play per minute and the efficiency index were combined to obtain a composite score, the TSAP performance score. Additional measurements for each player were playing time during the observed matches, coaches’ assessments (dominant, good, less decisive), and player tournament statistics (number of points, based on assists and goals). The mean TSAP performance score was substantially higher for players rated by their coaches as dominant and for players who accumulated more than one tournament point, findings that provide evidence of the validity of the TSAP measure. In inter‐observer reliability analyses of TSAP observational data provided by the trained observersfrom video recordings, the level of agreement between each pair of observers was 80–82%. Reliability correlations over a series of three matches (r=0.26, 0.59, and 0.16 respectively) showed that the TSAP performance score was relatively unstable. Ice hockey coaches may use this adapted Team Sport Assessment Procedure to better understand the offensive implication of each player in a given match, since the 10 observational variables provide more extensive information on performance than traditional statistical measures. Due to low performance stability of the TSAP performance score, coaches ought to use the observational assessment data for the formative rather than the summative assessment of their players unless they cumulate information over a series of several matches. Formative assessment can be conducted either during training camps or even during the regular season.
T cell receptor contact to restricting MHC molecules is a prerequisite for peripheral interclonal T cell competition
Authors: Agenès Fabien , Dangy Jean-Pierre , Kirberg Jörg
Published: November 2008

T cell survival and homeostatic proliferation in the periphery requires T cell receptor (TCR) binding to restricting major histocompatability complex (MHC)−encoded molecules, as well as the availability of certain lymphokines. However, the exact mechanisms by which these signals interrelate and contribute to homeostasis are not understood. By performing T cell transfers into TCR transgenic hosts we detected a hierarchical order of homeostatic proliferation for T cells differing in MHC restriction, such that OT1 cells (Kb restricted) proliferated in P14 (Db-restricted TCR) recipients, but not vice versa. Using Kb mutant mice, we demonstrated that proliferation of OT1 cells in P14 recipients, as well as the ability of host OT1 cells to hinder the proliferation of donor P14 cells, were dependent on OT1-TCR binding to Kb molecules. However, interclonal T cell competition was not mediated simply by competition for physical access to the MHC-bearing cell. This was shown in parabiotic pairs of OT1 and Kb mutant mice in which P14 cells failed to proliferate, even though the OT1 cells could not interact with half of the APCs in the system. Thus, we conclude that the interaction between the TCR and restricting MHC molecule influences the ability to compete for trophic resources not bound to the stimulating APC. This mechanism allows a local competitiveness that extends beyond a T cell's specificity.
Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance
Authors: Yano Masashi , Kuroda Noriyuki , Han Hongwei , Meguro-Horike Makiko , Nishikawa Yumiko , Kiyonari Hiroshi , Maemura Kentaro , Yanagawa Yuchio , Obata Kunihiko , Takahashi Satoru , Ikawa Tomokatsu , Satoh Rumi , Kawamoto Hiroshi , Mouri Yasuhiro , Matsumoto Mitsuru
Published: November 2008

The roles of autoimmune regulator (Aire) in the expression of the diverse arrays of tissue-restricted antigen (TRA) genes from thymic epithelial cells in the medulla (medullary thymic epithelial cells [mTECs]) and in organization of the thymic microenvironment are enigmatic. We approached this issue by creating a mouse strain in which the coding sequence of green fluorescent protein (GFP) was inserted into the Aire locus in a manner allowing concomitant disruption of functional Aire protein expression. We found that Aire+ (i.e., GFP+) mTECs were the major cell types responsible for the expression of Aire-dependent TRA genes such as insulin 2 and salivary protein 1, whereas Aire-independent TRA genes such as C-reactive protein and glutamate decarboxylase 67 were expressed from both Aire+ and Aire− mTECs. Remarkably, absence of Aire from mTECs caused morphological changes together with altered distribution of mTECs committed to Aire expression. Furthermore, we found that the numbers of mTECs that express involucrin, a marker for terminal epidermal differentiation, were reduced in Aire-deficient mouse thymus, which was associated with nearly an absence of Hassall's corpuscle-like structures in the medulla. Our results suggest that Aire controls the differentiation program of mTECs, thereby organizing the global mTEC integrity that enables TRA expression from terminally differentiated mTECs in the thymic microenvironment.
Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sjögren's syndrome–like autoimmune exocrinopathy
Authors: Ishimaru Naozumi , Arakaki Rieko , Yoshida Satoko , Yamada Akiko , Noji Sumihare , Hayashi Yoshio
Published: November 2008

Although several autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmunity remain unclear. Recently, we found that retinoblastoma-associated protein 48 (RbAp48) induces tissue-specific apoptosis in the exocrine glands depending on the level of estrogen deficiency. In this study, we report that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sjögren's syndrome. CD4+ T cell–mediated autoimmune lesions were aggravated with age, in association with autoantibody productions. Surprisingly, we obtained evidence that salivary and lacrimal epithelial cells can produce interferon-γ (IFN-γ) in addition to interleukin-18, which activates IFN regulatory factor-1 and class II transactivator. Indeed, autoimmune lesions in Rag2−/− mice were induced by the adoptive transfer of lymph node T cells from RbAp48-Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-γ, resulting in loss of local tolerance before developing gender-based autoimmunity.
A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity
Authors: Terashima Asuka , Watarai Hiroshi , Inoue Sayo , Sekine Etsuko , Nakagawa Ryusuke , Hase Koji , Iwamura Chiaki , Nakajima Hiroshi , Nakayama Toshinori , Taniguchi Masaru
Published: November 2008

Airway hypersensitive reaction (AHR) is an animal model for asthma, which is caused or enhanced by environmental factors such as allergen exposure. However, the precise mechanisms that drive AHR remain unclear. We identified a novel subset of natural killer T (NKT) cells that expresses the interleukin 17 receptor B (IL-17RB) for IL-25 (also known as IL-17E) and is essential for the induction of AHR. IL-17RB is preferentially expressed on a fraction of CD4+ NKT cells but not on other splenic leukocyte populations tested. IL-17RB+ CD4+ NKT cells produce predominantly IL-13 and Th2 chemokines upon stimulation with IL-25 in vitro. IL-17RB+ NKT cells were detected in the lung, and depletion of IL-17RB+ NKT cells by IL-17RB–specific monoclonal antibodies or NKT cell–deficient Jα18−/− mice failed to develop IL-25–dependent AHR. Cell transfer of IL-17RB+ but not IL-17RB− NKT cells into Jα18−/− mice also successfully reconstituted AHR induction. These results strongly suggest that IL-17RB+ CD4+ NKT cells play a crucial role in the pathogenesis of asthma.
TIMs: central regulators of immune responses
Authors: Hafler David A. , Kuchroo Vijay
Published: November 2008

Exhaustion of T cell responses during chronic viral infections has been observed in both mouse and man and has been attributed to up-regulation of PD-1 on the surface of exhausted T cells. In patients with chronic human HIV infection, T cell exhaustion leads to opportunistic infections associated with AIDS. However, not all the exhausted T cells express PD-1, suggesting that other molecules may be involved in the phenotype. A new study now demonstrates a central role for T cell immunoglobulin and mucin domain–containing protein-3 (TIM-3) in T cell exhaustion during chronic HIV infection and suggests that TIM-3 may be a novel therapeutic target in chronic viral diseases.
EchoLOCATION: an in silico analysis of the subcellular locations of Escherichia coli proteins and comparison with experimentally derived locations
Authors: Horler Richard S. P. , Butcher Andrew , Papangelopoulos Nikitas , Ashton Peter D. , Thomas Gavin H.
Published: November 2008

Summary:  EchoLOCATION is a database that provides a comprehensive analysis of the subcellular locations of Escherichia coli K-12 proteins. Locations are predicted by integrating data from a range of publicly available algorithms combined with extensive curation of experimental literature. The data can be searched in a variety of ways and can generate lists of subcellular proteomes for analysis. Experimental evidence supports the locations of over 500 envelope proteins (periplasm, inner and outer membrane). From analysis of disagreements between in silico predictions and experimental data, we provide an analysis of protein types where subcellular prediction algorithms are currently not accurate.

Availability:  http://www.ecoli-york.org/

Contact:  ght2@york.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
A SILAC-based DNA protein interaction screen that identifies candidate binding proteins to functional DNA elements
Authors: Mittler Gerhard , Butter Falk , Mann Matthias
Published: November 2008

Determining the underlying logic that governs the networks of gene expression in higher eukaryotes is an important task in the post-genome era. Sequence-specific transcription factors (TFs) that can read the genetic regulatory information and proteins that interpret the information provided by CpG methylation are crucial components of the system that controls the transcription of protein-coding genes by RNA polymerase II. We have previously described Stable Isotope Labeling by Amino acids in Cell culture (SILAC) for the quantitative comparison of proteomes and the determination of protein–protein interactions. Here, we report a generic and scalable strategy to uncover such DNA protein interactions by SILAC that uses a fast and simple one-step affinity capture of TFs from crude nuclear extracts. Employing mutated or nonmethylated control oligonucleotides, specific TFs binding to their wild-type or methyl-CpG bait are distinguished from the vast excess of copurifying background proteins by their peptide isotope ratios that are determined by mass spectrometry. Our proof of principle screen identifies several proteins that have not been previously reported to be present on the fully methylated CpG island upstream of the human metastasis associated 1 family, member 2 gene promoter. The approach is robust, sensitive, and specific and offers the potential for high-throughput determination of TF binding profiles.
Inferring genomic flux in bacteria
Authors: Didelot Xavier , Darling Aaron , Falush Daniel
Published: November 2008

Acquisition and loss of genetic material are essential forces in bacterial microevolution. They have been repeatedly linked with adaptation of lineages to new lifestyles, and in particular, pathogenicity. Comparative genomics has the potential to elucidate this genetic flux, but there are many methodological challenges involved in inferring evolutionary events from collections of genome sequences. Here we describe a model-based method for using whole-genome sequences to infer the patterns of genome content evolution. A fundamental property of our model is that it allows the rates at which genetic elements are gained or lost to vary in time and from one lineage to another. Our approach is purely sequence based, and does not rely on gene identification. We show how inference can be performed under our model and illustrate its use on three datasets fromFrancisella tularensis, Streptococcus pyogenes, andEscherichia coli. In all three examples, we found interesting variations in the rates of genetic material gain and loss, which strongly correlate with their lifestyle. The algorithms we describe are implemented in a computer software named GenoPlast.
Mapping DNA structural variation in dogs
Authors: Chen Wei-Kang , Swartz Joshua D. , Rush Laura J. , Alvarez Carlos E.
Published: November 2008

DNA structural variation (SV) comprises a major portion of genetic diversity, but its biological impact is unclear. We propose that the genetic history and extraordinary phenotypic variation of dogs make them an ideal mammal in which to study the effects of SV on biology and disease. The hundreds of existing dog breeds were created by selection of extreme morphological and behavioral traits. And along with those traits, each breed carries increased risk for different diseases. We used array CGH to create the first map of DNA copy number variation (CNV) or SV in dogs. The extent of this variation, and some of the gene classes affected, are similar to those of mice and humans. Most canine CNVs affect genes, including disease and candidate disease genes, and are thus likely to be functional. We identified many CNVs that may be breed or breed class specific. Cluster analysis of CNV regions showed that dog breeds tend to group according to breed classes. Our combined findings suggest many CNVs are (1) in linkage disequilibrium with flanking sequence, and (2) associated with breed-specific traits. We discuss how a catalog of structural variation in dogs will accelerate the identification of the genetic basis of canine traits and diseases, beginning with the use of whole genome association and candidate-CNV/gene approaches.
Interaction between CD14−159C>T polymorphism and Helicobacter pylori is associated with serum total immunoglobulin E
Authors: Virta M. , Pessi T. , Helminen M. , Seiskari T. , Kondrashova A. , Knip M. , Hyöty H. , Hurme M.
Published: November 2008

Background
Total serum IgE is regulated by both environmental and genetic factors. Association and linkage studies have suggested a role of CD14−159C>T polymorphism in the regulation of serum total IgE, but the results have been contradictory. It seems that gene–environment interactions are involved in this regulation.

Objective
The aim of this study was to examine the possible gene–environment interactions among Toxoplasma gondii, Helicobacter pylori, CD14−159C>T and Toll‐like receptor (TLR) 4+896A>G polymorphism on serum total IgE. For this study, we expanded the scope of our earlier comparison of allergic sensitization and microbial load between Finland and Russian Karelia by studying the CD14−159C>T and TLR4+896A>G polymorphism in a cohort of Russian Karelian children.

Methods
For this study, CD14−159C>T and TLR4+896A>G polymorphisms were analysed in 264 healthy Russian Karelian children. Serum total IgE levels and H. pylori and T. gondii antibodies were also measured.

Results
We constructed a multiway anova model to analyse the gene–environment interactions among T. gondii seropositivity, H. pylori seropositivity, CD14−159C>T and TLR4+896A>G polymorphisms on serum total IgE. The model showed that there was an interaction between the CD14−159 allele T carrier status and H. pylori antibodies on serum total IgE (P=0.004). No other interactions were found.

Conclusion
Our results further emphasize the role of gene–environment interaction in the regulation of serum total IgE.
Comparison of cysteinyl leukotriene concentrations between exhaled breath condensate and bronchoalveolar lavage fluid
Authors: Ono E. , Mita H. , Taniguchi M. , Higashi N. , Tsuburai T. , Miyazaki E. , Kumamoto T. , Akiyama K.
Published: November 2008

Background
Collection of exhaled breath condensate (EBC) is a simple, non‐invasive method of obtaining samples from the airways and it can be repeated in short intervals without side effects; therefore, it provides an opportunity to monitor the changes in concentration of inflammatory mediators in the airways. However, EBC analysis still has several unresolved issues.

Objective
To better understand the characteristics of EBC, we compared cysteinyl leukotriene (CysLT) concentrations between bronchoalveolar lavage fluid (BALF) and EBC. We also attempted to correct CysLT concentrations in BALF and EBC diluted with saline and water vapour using biological markers.

Methods
EBC was collected from 14 patients with idiopathic pulmonary fibrosis before bronchoscopy. We measured CysLT concentrations and also quantified tyrosine, urea and total protein as possible biomarkers for correcting dilution.

Results
(1) We have validated the quantification of CysLTs in EBC. (2) Although a significant correlation was observed among tyrosine and urea concentrations in BALF, urea and total protein concentrations were below the detection limit in EBC. (3) CysLT concentrations were higher in BALF than in EBC (median, 15.96 pg/mL vs. 5.5 pg/mL; P=0.001) and there was no correlation of CysLT concentrations in BALF with those in EBC. A significant correlation of the ratio of total CysLT concentration to tyrosine concentration (CysLT/Y) in EBC with that in BALF was observed (r=0.547, P=0.043). (4) CysLT/Y in EBC correlated with serum KL‐6 concentration and total cell count in BALF, and CysLT/Y in BALF also correlated with exhaled NO concentration and %VC.

Conclusions
CysLT/Y in EBC significantly correlated with that in BALF and some clinical parameters correlated with CysLT/Y. Tyrosine concentration may be used to correct the dilution error for CysLT concentrations, and CysLT/Y in EBC can be a surrogate marker for CysLT concentrations in BALF.
Incremental build‐up food challenge – a new diagnostic approach to evaluate pseudoallergic reactions in chronic urticaria: a pilot study
Authors: Bunselmeyer B. , Laubach H. J. , Schiller M. , Stanke M. , Luger T. A. , Brehler R.
Published: November 2008

Background
The remission rate of patients with chronic urticaria (CU) due to elimination diets varies between 31% and 71%. However, the diagnostic value of subsequent traditional oral provocation tests with food additives in capsules remains unsatisfactory.

Objectives
A newly incremental build‐up food challenge (IBUF) for patients with CU was designed and implemented in an open pilot study. Primary endpoint was the percentage of patients developing urticaria during at least one step of IBUF after an initial complete remission due to a pseudoallergen‐free elimination diet.

Methods
In total, 153 patients with CU were submitted for 5 weeks to a pseudoallergen‐free diet. All patients with remission were included to the 6‐week IBUF protocol, containing pseudoallergen‐rich foods in a systematic and additive manner. The recurrence and severity of CU was evaluated by urticaria score. Subjective disturbance and quality of life were evaluated by patients' diary, visual analogue scale and quality of life questionnaire (CU‐Q2oL). Subsequently, patients were followed up for 3–24 months after IBUF by a telephone interview.

Results
A total of 104 patients completed the pseudoallergen‐free diet, whereby 51% reported partial, 17% complete and 32% no remission due to the diet. All diet responders showed a decrease in subjective impairment, urticaria and quality of life score (P<0.001 each). Eighty‐six percent (12/14) of the patients reaching complete remission, showed a recurrence of urticaria symptoms during the IBUF protocol. Fifty‐eight percent (7/12) of these patients still remained free of symptoms due to avoidance of IBUF‐identified foods at telephone follow‐up. In patients with partial remission to pseudoallergen‐free diet, however, IBUF did not provide information about the cause of urticaria symptoms.

Conclusions
The newly developed IBUF protocol seemed to be a promising method for identifying individually incompatible foods in some CU patients. IBUF should be verified by randomized controlled trials to gain additional evidence for its diagnostic value.
Mass mortality in Northwestern Mediterranean rocky benthic communities: effects of the 2003 heat wave
Authors: GARRABOU J. , COMA R. , BENSOUSSAN N. , BALLY M. , CHEVALDONNÉ P. , CIGLIANO M. , DIAZ D. , HARMELIN J. G. , GAMBI M. C. , KERSTING D. K. , LEDOUX J. B. , LEJEUSNE C. , LINARES C. , MARSCHAL C. , PÉREZ T. , RIBES M. , ROMANO J. C. , SERRANO E. , TEIXIDO N. , TORRENTS O. , ZABALA M. , ZUBERER F. , CERRANO C.
Published: November 2008

Late in summer 2003, extensive mass mortality of at least 25 rocky benthic macro‐invertebrate species (mainly gorgonians and sponges) was observed in the entire Northwestern (NW) Mediterranean region, affecting several thousand kilometers of coastline. We were able to characterize the mortality event by studying six areas covering the main regions of the NW Mediterranean basin. The degree of impact on each study area was quantified at 49 sites by estimating the proportion of colonies affected in populations of several gorgonian species compared with reference data obtained in years without mortality signs. According to these data, the western areas (Catalan coast and Balearic Islands) were the least affected, while the central areas (Provence coast and Corsica‐Sardinia) showed a moderate impact. The northernmost and eastern areas (Gulf of Genoa and Gulf of Naples) displayed the highest impact, with almost 80% of gorgonian colonies affected. The heat wave of 2003 in Europe caused an anomalous warming of seawater, which reached the highest temperatures ever recorded in the studied regions, between 1 and 3 °C above the climatic values (mean and maximum). Because this exceptional warming was observed in the depth ranges most affected by the mortality, it seems likely that the 2003 anomalous temperature played a key role in the observed mortality event. A correlation analysis between temperature conditions and degree of impact seems to support this hypothesis. Under the present climate warming trend, new mass mortality events may occur in the near future, possibly driving a major biodiversity crisis in the Mediterranean Sea.
Reconciling the influence of global climate phenomena on macrofaunal temporal dynamics at a variety of spatial scales
Authors: HEWITT J. E. , THRUSH S. F.
Published: November 2008

Determining the relative importance of environmental forces on population dynamics is a fundamental question for ecologists. Growing concern over the ecological effects of climate change emphasizes the importance of defining whether broad‐scale environmental forces uniformly act upon local populations (hierarchy theory) or cross‐scale interactions influence local responses (multiscale theory). This study analyses 13 years of data on species abundances at six sites within a large harbour to determine the effect of the El Niño Southern Oscillation (ENSO). Environmental variables both directly and indirectly related to ENSO were observed to be important predictors of the temporal dynamics of abundance in many species, but the observed effects were not consistent across sites or species. While nearly all species were affected by large temporal and spatial scale variability, smaller temporal scale, location‐specific environmental variables (such as wind‐generated wave exposure and turbidity) were also generally important, increasing the variability explained by our models by up to 25%. As with many other broad‐scale variables, generality of response to ENSO is affected by interactions across time and space with smaller scale heterogeneity. This study therefore suggests that the degree of interaction between broad‐scale climatic factors, such as ENSO, with smaller scale variability, will determine the consistency of responses over large spatial scales, and control our ability to predict effects of climate change on coastal and estuarine communities.
Cooking DNA: the effect of ‘domestic’ cooking methods on detection of GM potato
Authors: Van Der Colff Loraine , Podivinsky Ellen
Published: November 2008

The ability to detect GM material in otherwise unprocessed foods cooked using domestic methods is important should ‘ready‐to‐eat’ foods require labelling. This study addresses the issue of DNA degradation in foods as a result of cooking. A number of ‘domestic’ cooking methods were shown to affect the length of DNA sequences able to be PCR amplified from potato samples and the degree of degradation was treatment‐specific. However, a. real‐time PCR assay was developed and. GM material was positively identified in all cooked GM potato samples. This confirms that GM material should be able to be detected in otherwise unprocessed food samples cooked using domestic methods, even if the cooking process has partially degraded the DNA. Results indicate, however, that there may be implications of the cooking process on the ability to accurately quantify GM content in some cooked samples.
Traceability in the meat industry – the farm to plate continuum
Authors: Shackell Grant H
Published: November 2008

Traceability of meat and meat products is a major issue in the meat industry with the two main drivers being food safety/risk management and authentication. Increasingly, the world marketplace is indicating that traceability systems for food products derived from individual animals (e.g. steak, chops etc.) is required now or will be required in the near future. Traceability requirements for compound products, such as ground beef, are usually less strict and are frequently limited to date and place of manufacture. As global competition increases it is imperative that technologies are available that protect against, and deter, fraudulent labelling of inferior product. Traceability offers more than marketing advantages. It can be applied at every stage of the meat production continuum and can be just as valuable to farmers and processors as it is to marketers and consumers.
Biofilms in the food industry: problems and potential solutions
Authors: Brooks John D. , Flint Steve H.
Published: November 2008

Contamination of food by spoilage and pathogenic micro‐organisms costs the food industry millions of dollars annually. Much of this contamination may be attributed to the presence of biofilms in the processing plant. In this review, we examine the properties of micro‐organisms and the surfaces of processing equipment that influence the formation of biofilms. Of particular concern is the increased resistance of biofilms to cleaning and disinfection processes. Alternative means of controlling biofilm development are described and some aspects where more information is required are identified.
Effect of different starches on rheological and microstructural properties of (II) commercial processed cheese
Authors: Trivedi Darshan , Bennett Rod J. , Hemar Yacine , Reid David C. W. , Lee Siew Kim , Illingworth David
Published: November 2008

A range of commercial processed cheese samples containing starch were prepared on a Rapid Visco Analyser (RVA) and on a pilot plant scale. This work clearly demonstrated that it was possible to manufacture processed cheese with part of the protein replaced with potato starch, while maintaining similar rheological attributes (firmness) to those of the control and an acceptable melt index. Sensory evaluation showed that, although the reduced‐protein cheese samples had a good, clean, fresh flavour that was comparable with that of the control, at high starch concentrations the starch‐containing processed cheese had a pasty texture and tended to stick to the wrapper.