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Showing papers by "University of Basel published in 2008"


Journal ArticleDOI
TL;DR: The Compact Muon Solenoid (CMS) detector at the Large Hadron Collider (LHC) at CERN as mentioned in this paper was designed to study proton-proton (and lead-lead) collisions at a centre-of-mass energy of 14 TeV (5.5 TeV nucleon-nucleon) and at luminosities up to 10(34)cm(-2)s(-1)
Abstract: The Compact Muon Solenoid (CMS) detector is described. The detector operates at the Large Hadron Collider (LHC) at CERN. It was conceived to study proton-proton (and lead-lead) collisions at a centre-of-mass energy of 14 TeV (5.5 TeV nucleon-nucleon) and at luminosities up to 10(34)cm(-2)s(-1) (10(27)cm(-2)s(-1)). At the core of the CMS detector sits a high-magnetic-field and large-bore superconducting solenoid surrounding an all-silicon pixel and strip tracker, a lead-tungstate scintillating-crystals electromagnetic calorimeter, and a brass-scintillator sampling hadron calorimeter. The iron yoke of the flux-return is instrumented with four stations of muon detectors covering most of the 4 pi solid angle. Forward sampling calorimeters extend the pseudo-rapidity coverage to high values (vertical bar eta vertical bar <= 5) assuring very good hermeticity. The overall dimensions of the CMS detector are a length of 21.6 m, a diameter of 14.6 m and a total weight of 12500 t.

5,193 citations


Journal ArticleDOI
TL;DR: Emerging research data led to the establishment of collaborative working groups addressing issues like isolated ‘v’ lesion and incorporation of omics‐technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.

1,700 citations


Journal ArticleDOI
Jennifer K. Adelman-McCarthy1, Marcel A. Agüeros2, S. Allam1, S. Allam3  +170 moreInstitutions (65)
TL;DR: The Sixth Data Release of the Sloan Digital Sky Survey (SDS) as discussed by the authors contains images and parameters of roughly 287 million objects over 9583 deg(2), including scans over a large range of Galactic latitudes and longitudes.
Abstract: This paper describes the Sixth Data Release of the Sloan Digital Sky Survey. With this data release, the imaging of the northern Galactic cap is now complete. The survey contains images and parameters of roughly 287 million objects over 9583 deg(2), including scans over a large range of Galactic latitudes and longitudes. The survey also includes 1.27 million spectra of stars, galaxies, quasars, and blank sky ( for sky subtraction) selected over 7425 deg2. This release includes much more stellar spectroscopy than was available in previous data releases and also includes detailed estimates of stellar temperatures, gravities, and metallicities. The results of improved photometric calibration are now available, with uncertainties of roughly 1% in g, r, i, and z, and 2% in u, substantially better than the uncertainties in previous data releases. The spectra in this data release have improved wavelength and flux calibration, especially in the extreme blue and extreme red, leading to the qualitatively better determination of stellar types and radial velocities. The spectrophotometric fluxes are now tied to point-spread function magnitudes of stars rather than fiber magnitudes. This gives more robust results in the presence of seeing variations, but also implies a change in the spectrophotometric scale, which is now brighter by roughly 0.35 mag. Systematic errors in the velocity dispersions of galaxies have been fixed, and the results of two independent codes for determining spectral classifications and red-shifts are made available. Additional spectral outputs are made available, including calibrated spectra from individual 15 minute exposures and the sky spectrum subtracted from each exposure. We also quantify a recently recognized underestimation of the brightnesses of galaxies of large angular extent due to poor sky subtraction; the bias can exceed 0.2 mag for galaxies brighter than r = 14 mag.

1,602 citations


Journal ArticleDOI
TL;DR: A more integrated overview of the key role of these signalling lipids in inflammation, cancer and metabolic disease is attempted, and emerging strategies for therapeutic intervention are discussed.
Abstract: Signalling lipids such as eicosanoids, phosphoinositides, sphingolipids and fatty acids control important cellular processes, including cell proliferation, apoptosis, metabolism and migration. Extracellular signals from cytokines, growth factors and nutrients control the activity of a key set of lipid-modifying enzymes: phospholipases, prostaglandin synthase, 5-lipoxygenase, phosphoinositide 3-kinase, sphingosine kinase and sphingomyelinase. These enzymes and their downstream targets constitute a complex lipid signalling network with multiple nodes of interaction and cross-regulation. Imbalances in this network contribute to the pathogenesis of human disease. Although the function of a particular signalling lipid is traditionally studied in isolation, this review attempts a more integrated overview of the key role of these signalling lipids in inflammation, cancer and metabolic disease, and discusses emerging strategies for therapeutic intervention.

1,134 citations


Journal ArticleDOI
TL;DR: In this paper, a correlation of tectonic units of the Alpine-Carpathian-Dinaridic system of orogens, including the substrate of the Pannonian and Transylvanian basins, is presented in the form of a map.
Abstract: A correlation of tectonic units of the Alpine-Carpathian-Dinaridic system of orogens, including the substrate of the Pannonian and Transylvanian basins, is presented in the form of a map. Combined with a series of crustal-scale cross sections this correlation of tectonic units yields a clearer picture of the three-dimensional architecture of this system of orogens that owes its considerable complexity to multiple overprinting of earlier by younger deformations.

1,028 citations


Journal ArticleDOI
TL;DR: It is revealed that only a few studies provided data on the prevalence of peri-implant diseases, and cross-sectional studies on implant-treated subjects are rare and data from only two study samples were available.
Abstract: OBJECTIVES: The aim of the current review was to describe the prevalence of peri-implant diseases including peri-implant mucositis and peri-implantitis. MATERIAL AND METHODS: A MEDLINE search (PubMed) until December 2007 was conducted and different keywords related to the prevalence of peri-implant diseases were used. Cross-sectional and longitudinal studies including < or =50 implant-treated subjects exhibiting a function time of < or =5 years were considered. RESULTS AND CONCLUSION: The current review revealed that only a few studies provided data on the prevalence of peri-implant diseases. Cross-sectional studies on implant-treated subjects are rare and data from only two study samples were available. Peri-implant mucositis occurred in approximately 80% of the subjects and in 50% of the implants. Peri-implantitis was found in 28% and < or =56% of subjects and in 12% and 43% of implant sites.

1,028 citations


Journal ArticleDOI
31 Jul 2008-Nature
TL;DR: It is demonstrated that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting or blocking of VEG FR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models, implicate VEGfr-3 as a regulator of vascular network formation.
Abstract: Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.

782 citations


Journal ArticleDOI
TL;DR: There is an important mortality effect of heat across Europe from June through August; it is limited to the first week following temperature excess, with evidence of mortality displacement.
Abstract: BACKGROUND: Epidemiologic studies show that high temperatures are related to mortality, but little is known about the exposure-response function and the lagged effect of heat. We report the associations between daily maximum apparent temperature and daily deaths during the warm season in 15 European cities. METHODS: The city-specific analyses were based on generalized estimating equations and the city-specific results were combined in a Bayesian random effects meta-analysis. We specified distributed lag models in studying the delayed effect of exposure. Time-varying coefficient models were used to check the assumption of a constant heat effect over the warm season. RESULTS: The city-specific exposure-response functions have a V shape, with a change-point that varied among cities. The meta-analytic estimate of the threshold was 29.4 degrees C for Mediterranean cities and 23.3 degrees C for north-continental cities. The estimated overall change in all natural mortality associated with a 1 degrees C increase in maximum apparent temperature above the city-specific threshold was 3.12% (95% credibility interval = 0.60% to 5.72%) in the Mediterranean region and 1.84% (0.06% to 3.64%) in the north-continental region. Stronger associations were found between heat and mortality from respiratory diseases, and with mortality in the elderly. CONCLUSIONS: There is an important mortality effect of heat across Europe. The effect is evident from June through August; it is limited to the first week following temperature excess, with evidence of mortality displacement. There is some suggestion of a higher effect of early season exposures. Acclimatization and individual susceptibility need further investigation as possible explanations for the observed heterogeneity among cities.

777 citations


Journal ArticleDOI
TL;DR: Ten key messages to clinicians are highlighted about the role of NP levels in state‐of‐the‐art clinical practice is evolving rapidly.
Abstract: Natriuretic peptide (NP) levels (B-type natriuretic peptide (BNP) and N-terminal proBNP) are now widely used in clinical practice and cardiovascular research throughout the world and have been incorporated into most national and international cardiovascular guidelines for heart failure. The role of NP levels in state-of-the-art clinical practice is evolving rapidly. This paper reviews and highlights ten key messages to clinicians: 1) NP levels are quantitative plasma biomarkers of heart failure (HF). 2) NP levels are accurate in the diagnosis of HF. 3) NP levels may help risk stratify emergency department (ED) patients with regard to the need for hospital admission or direct ED discharge. 4) NP levels help improve patient management and reduce total treatment costs in patients with acute dyspnoea. 5) NP levels at the time of admission are powerful predictors of outcome in predicting death and re-hospitalisation in HF patients. 6) NP levels at discharge aid in risk stratification of the HF patient. 7) NP-guided therapy may improve morbidity and/or mortality in chronic HF. 8) The combination of NP levels together with symptoms, signs and weight gain assists in the assessment of clinical decompensation in HF. 9) NP levels can accelerate accurate diagnosis of heart failure presenting in primary care. 10) NP levels may be helpful to screen for asymptomatic left ventricular dysfunction in high-risk patients.

770 citations


Journal ArticleDOI
TL;DR: In this paper, the authors find that people with longer commuting time report systematically lower subjective well-being than those with shorter commutes, and they mention several possibilities of an extended model of human behavior able to explain this "commuting paradox".
Abstract: People spend a lot of time commuting and often find it a burden. According to standard economics, the burden of commuting is chosen when compensated either on the labor or on the housing market so that individuals’ utility is equalized. However, in a direct test of this strong notion of equilibrium with panel data, we find that people with longer commuting time report systematically lower subjective well-being. This result is robust with regard to a number of alternative explanations. We mention several possibilities of an extended model of human behavior able to explain this “commuting paradox”.

723 citations


Journal ArticleDOI
TL;DR: The concept that activation of the endogenous IFN system in CHC not only is ineffective in clearing the infection but also may impede the response to therapy, most likely by inducing a refractory state of the IFN signaling pathway, is supported.
Abstract: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The current standard therapy for chronic hepatitis C (CHC) consists of a combination of pegylated IFN alpha (pegIFNalpha) and ribavirin. It achieves a sustained viral clearance in only 50-60% of patients. To learn more about molecular mechanisms underlying treatment failure, we investigated IFN-induced signaling in paired liver biopsies collected from CHC patients before and after administration of pegIFNalpha. In patients with a rapid virological response to treatment, pegIFNalpha induced a strong up-regulation of IFN-stimulated genes (ISGs). As shown previously, nonresponders had high expression levels of ISGs before therapy. Analysis of posttreatment biopsies of these patients revealed that pegIFNalpha did not induce expression of ISGs above the pretreatment levels. In accordance with ISG expression data, phosphorylation, DNA binding, and nuclear localization of STAT1 indicated that the IFN signaling pathway in nonresponsive patients is preactivated and refractory to further stimulation. Some features characteristic of nonresponders were more accentuated in patients infected with HCV genotypes 1 and 4 compared with genotypes 2 and 3, providing a possible explanation for the poor response of the former group to therapy. Taken together with previous findings, our data support the concept that activation of the endogenous IFN system in CHC not only is ineffective in clearing the infection but also may impede the response to therapy, most likely by inducing a refractory state of the IFN signaling pathway.

Journal ArticleDOI
TL;DR: Current knowledge on the role of the long-chain polyunsaturated fatty acids, DHA, docosahexaenoic acid and arachidonic acid, in maternal and term infant nutrition as well as infant development is reviewed.
Abstract: This paper reviews current knowledge on the role of the long-chain polyunsaturated fatty acids (LC-PUFA), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, 20:4n-6), in maternal and term infant nutrition as well as infant development. Consensus recommendations and practice guidelines for health-care providers supported by the World Association of Perinatal Medicine, the Early Nutrition Academy, and the Child Health Foundation are provided. The fetus and neonate should receive LC-PUFA in amounts sufficient to support optimal visual and cognitive development. Moreover, the consumption of oils rich in n-3 LC-PUFA during pregnancy reduces the risk for early premature birth. Pregnant and lactating women should aim to achieve an average daily intake of at least 200 mg DHA. For healthy term infants, we recommend and fully endorse breastfeeding, which supplies preformed LC-PUFA, as the preferred method of feeding. When breastfeeding is not possible, we recommend use of an infant formula providing DHA at levels between 0.2 and 0.5 weight percent of total fat, and with the minimum amount of AA equivalent to the contents of DHA. Dietary LC-PUFA supply should continue after the first six months of life, but currently there is not sufficient information for quantitative recommendations.

Book
28 Aug 2008
TL;DR: This is the first book on applied econometrics using the R system for statistical computing and graphics and provides a chapter on programming, including simulations, optimization, and an introduction to R tools enabling reproducible econometric research.
Abstract: Introduction. - Basics. - Linear Regression. - Diagnostics and alternative methods of regression. - Models of microeconometrics. - Time series. - Programming your own analysis. - References. - Index.

Journal ArticleDOI
TL;DR: It is demonstrated that muscle mTORC1 has an unexpected role in the regulation of the metabolic properties and that its function is essential for life.

Journal ArticleDOI
TL;DR: This paper developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases.
Abstract: Background and objectivesDiagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings A systematic process for exclusion of alternative diagnoses has not been defined An International Panel of MS experts developed consensus perspectives on MS differential diagnosisMethodsUsing available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseasesResultsWe present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of “clinically isolated syndromes” (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification schem

Journal ArticleDOI
TL;DR: The current disease-relevant knowledge for isoform-specific PI3K function in the above mentioned diseases is reviewed, and the progress of >400 recent patents covering pharmaceutical targeting ofPI3K is reviewed.

Journal ArticleDOI
TL;DR: This work has created a gecko-inspired tissue adhesive from a biocompatible and biodegradable elastomer combined with a thin tissue-reactive biOCompatible surface coating that significantly increased the interfacial adhesion strength on porcine intestine tissue in vitro and in the rat abdominal subfascial in vivo environment.
Abstract: There is a significant medical need for tough biodegradable polymer adhesives that can adapt to or recover from various mechanical deformations while remaining strongly attached to the underlying tissue We approached this problem by using a polymer poly(glycerol-co-sebacate acrylate) and modifying the surface to mimic the nanotopography of gecko feet, which allows attachment to vertical surfaces Translation of existing gecko-inspired adhesives for medical applications is complex, as multiple parameters must be optimized, including: biocompatibility, biodegradation, strong adhesive tissue bonding, as well as compliance and conformability to tissue surfaces Ideally these adhesives would also have the ability to deliver drugs or growth factors to promote healing As a first demonstration, we have created a gecko-inspired tissue adhesive from a biocompatible and biodegradable elastomer combined with a thin tissue-reactive biocompatible surface coating Tissue adhesion was optimized by varying dimensions of the nanoscale pillars, including the ratio of tip diameter to pitch and the ratio of tip diameter to base diameter Coating these nanomolded pillars of biodegradable elastomers with a thin layer of oxidized dextran significantly increased the interfacial adhesion strength on porcine intestine tissue in vitro and in the rat abdominal subfascial in vivo environment This gecko-inspired medical adhesive may have potential applications for sealing wounds and for replacement or augmentation of sutures or staples

Journal ArticleDOI
TL;DR: In this article, a basic framework for the prediction of health-related behavior which combines reflective influences (as measured via self-report), impulsive influences and implicit measures is proposed.
Abstract: Often, health behavior seems to be governed not only by reasoned attitudes and goal-directed behavior but also by impulsive influences. The notion of a conflict between reflective and impulsive processing which is incorporated in prominent dual-system accounts (e.g., Metcalfe & Mischel, 1999; Strack & Deutsch, 2004) may yield important benefits for the understanding and prediction of health-related behavior. In this article, we suggest a basic framework for the prediction of health-related behavior which combines (a) reflective influences (as measured via self-report), (b) impulsive influences (as measured via implicit measures), and (c) situational or dispositional moderators that shift the weight between reflective and impulsive influences. The practical utility of such a framework is demonstrated by drawing on recent evidence from several areas of health psychology such as eating, drinking, drug abuse, and sexual behavior. Implications for the understanding of health behavior and applied healt...

Journal ArticleDOI
TL;DR: In this article, the authors used data from the Sloan Digital Sky Survey (SDSS) Data Release 5 to explore the overall structure and substructure of the stellar halo of the Milky Way using ~4 million color-selected main-sequence turnoff stars.
Abstract: We have used data from the Sloan Digital Sky Survey (SDSS) Data Release 5 to explore the overall structure and substructure of the stellar halo of the Milky Way using ~4 million color-selected main-sequence turnoff stars with -->0.2 18.5 ? r 0.5 3.7 ? 1.2 ? 108 M?. The density profile of the stellar halo is approximately -->? r??, where ? -->2 > ? > ? 4. Yet, we found that all smooth and symmetric models were very poor fits to the distribution of stellar halo stars because the data exhibit a great deal of spatial substructure. We quantified deviations from a smooth oblate/triaxial model using the rms of the data around the model profile on scales 100 pc, after accounting for the (known) contribution of Poisson uncertainties. Within the DR5 area of the SDSS, the fractional rms deviation ?/total of the actual stellar distribution from any smooth, parameterized halo model is 40%: hence, the stellar halo is highly structured. We compared the observations with simulations of galactic stellar halos formed entirely from the accretion of satellites in a cosmological context by analyzing the simulations in the same way as the SDSS data. While the masses, overall profiles, and degree of substructure in the simulated stellar halos show considerable scatter, the properties and degree of substructure in the Milky Way's halo match well the properties of a typical stellar halo built exclusively out of the debris from disrupted satellite galaxies. Our results therefore point toward a picture in which an important fraction of the stellar halo of the Milky Way has been accreted from satellite galaxies.

Journal ArticleDOI
TL;DR: The results demonstrate the importance of working memory capacity for everyday self-regulation and suggest an individual differences perspective on dual-process or dual-system theories of human behavior.
Abstract: In the present research, the authors investigated how individual differences in working memory capacity moderate the relative influence of automatic versus controlled precursors on self-regulatory behavior. In 2 studies, on sexual interest behavior (Study 1) and the consumption of tempting food (Study 2), automatic attitudes toward the temptation of interest had a stronger influence on behavior for individuals who scored low rather than high in working memory capacity. Analogous results emerged in Study 3 on anger expression in a provoking situation when a measure of the automatic personality trait of angriness was employed. Conversely, controlled dispositions such as explicit attitudes (Study 1) and self-regulatory goals (Studies 2 and 3) were more effective in guiding behavior for participants who scored high rather than low in working memory capacity. Taken together, these results demonstrate the importance of working memory capacity for everyday self-regulation and suggest an individual differences perspective on dual-process or dual-system theories of human behavior.

Journal ArticleDOI
TL;DR: It is suggested that adipose mTORC1 is a regulator of adipose metabolism and, thereby, controls whole-body energy homeostasis.

Journal ArticleDOI
TL;DR: The quantification of the construct of mindfulness—as derived from Buddhist psychology—has recently gained prominence as studies of mindfulnessbased interventions have become increasingly accepted in psychosomatic medicine and psychology.

Journal ArticleDOI
Jean Pieters1
TL;DR: Mycobacterium tuberculosis is a highly efficient pathogen, killing millions of infected people annually and understanding M. tuberculosis virulence strategies will not only define novel targets for drug development but will also help to uncover previously unknown signaling pathways related to the host's response to M. TB.

Journal ArticleDOI
TL;DR: Cryo-electron microscopy of vitreous sections is used to perform a detailed ultrastructural analysis of three species belonging to the Corynebacterineae suborder and shows a direct visualization of an outer membrane, analogous to that found in gram-negative bacteria, in the three bacterial species examined.
Abstract: The cell envelope of mycobacteria, which include the causative agents of tuberculosis and leprosy, is crucial for their success as pathogens. Despite a continued strong emphasis on identifying the multiple chemical components of this envelope, it has proven difficult to combine its components into a comprehensive structural model, primarily because the available ultrastructural data rely on conventional electron microscopy embedding and sectioning, which are known to induce artifacts. The existence of an outer membrane bilayer has long been postulated but has never been directly observed by electron microscopy of ultrathin sections. Here we have used cryo-electron microscopy of vitreous sections (CEMOVIS) to perform a detailed ultrastructural analysis of three species belonging to the Corynebacterineae suborder, namely, Mycobacterium bovis BCG, Mycobacterium smegmatis, and Corynebacterium glutamicum, in their native state. We provide new information that accurately describes the different layers of the mycobacterial cell envelope and challenges current models of the organization of its components. We show a direct visualization of an outer membrane, analogous to that found in gram-negative bacteria, in the three bacterial species examined. Furthermore, we demonstrate that mycolic acids, the hallmark of mycobacteria and related genera, are essential for the formation of this outer membrane. In addition, a granular layer and a low-density zone typifying the periplasmic space of gram-positive bacteria are apparent in CEMOVIS images of mycobacteria and corynebacteria. Based on our observations, a model of the organization of the lipids in the outer membrane is proposed. The architecture we describe should serve as a reference for future studies to relate the structure of the mycobacterial cell envelope to its function.

Journal ArticleDOI
TL;DR: The relative contributions of explicitly measured attitudes and general restraint standards are investigated as two distinct, but complementing constructs that are dependent on control resources.
Abstract: Recent theories in social psychology suggest that explicitly measured attitudes are particularly valuable for the prediction of deliberate, controlled behaviour. In contrast, implicitly measured attitudes are assumed to be more important for the prediction of less controlled, more impulsive behaviour. Yet, conclusive evidence for the differential predictive validity of both measures is scarce. We hypothesized that limitations of different control resources would lead to functionally equivalent effects. In Study 1, cognitive capacity moderated the predictive validity of both explicit and implicit attitude measures in a choice task. Self-regulatory resources led to similar patterns for eating (Study 2) and drinking behaviour (Study 3). In addition to the predictive validity of implicit and explicit attitude measures, in Study 3 we more closely investigated the relative contributions of explicitly measured attitudes and general restraint standards as two distinct, but complementing constructs that are dependent on control resources.

Journal ArticleDOI
TL;DR: It is demonstrated that DL4 is the essential and nonredundant N1 ligand responsible for T cell lineage commitment and strongly suggest that N1-expressing thymic progenitors interact with DL4- expressing TECs to suppress B lineage potential and to induce the first steps of intrathymic T cell development.
Abstract: Thymic T cell lineage commitment is dependent on Notch1 (N1) receptor-mediated signaling. Although the physiological ligands that interact with N1 expressed on thymic precursors are currently unknown, in vitro culture systems point to Delta-like 1 (DL1) and DL4 as prime candidates. Using DL1- and DL4-lacZ reporter knock-in mice and novel monoclonal antibodies to DL1 and DL4, we show that DL4 is expressed on thymic epithelial cells (TECs), whereas DL1 is not detected. The function of DL4 was further explored in vivo by generating mice in which DL4 could be specifically inactivated in TECs or in hematopoietic progenitors. Although loss of DL4 in hematopoietic progenitors did not perturb thymus development, inactivation of DL4 in TECs led to a complete block in T cell development coupled with the ectopic appearance of immature B cells in the thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional N1 mutant mice. Collectively, our results demonstrate that DL4 is the essential and nonredundant N1 ligand responsible for T cell lineage commitment. Moreover, they strongly suggest that N1-expressing thymic progenitors interact with DL4-expressing TECs to suppress B lineage potential and to induce the first steps of intrathymic T cell development.

Journal ArticleDOI
TL;DR: Assessment of FOXP3+ cell density can contribute to the prediction of outcome in diffuse large B-cell lymphoma, fallicular lymphoma and classical Hodgkin’s lymphoma.
Abstract: Background The tumor microenvironment is important for the behavior of cancer. We assessed the distribution and biological significance of FOXP3+ regulatory T-cells (Treg) in lymphomas.Design and Methods The absolute number of intratumoral FOXP3+ cells was immunohistochemically studied on lymphoma tissue microarrays from 1019 cases of different types of lymphomas and correlated to phenotypic and clinical parameters in uni- and multivariate models. Receiver operating characteristic -curves were used to determine prognostic cut-off values of FOXP3+ cell density.Results Of the 1019 cases, 926 (91%) were evaluable. FOXP3+ cell density varied between the lymphoma entities, and was highest in follicular lymphoma. An increased number of tumor-infiltrating FOXP3+ cells over the receiver operating characteristic-determined cut-offs positively influenced both disease-specific and failure-free survival in follicular lymphoma (p=0.053) and disease-specific survival in germinal center-like diffuse large B-cell lymphoma (p=0.051) and overall and failure-free survival in classical Hodgkin’s lymphoma (p=0.004), but had a negative prognostic effect in non-germinal center diffuse large B-cell lymphoma (p=0.059). In a Cox regression model, considering stage and age, the amount of FOXP3+ cells was of independent prognostic significance for failure-free survival in classical Hodgkin’s lymphoma and of borderline significance for overall survival in classical Hodgkin’s lymphoma and disease-specific survival in germinal center-like and non-germinal center diffuse large B-cell lymphoma.Conclusions FOXP3+ cells represent important lymphoma/host microenvironment modulators. Assessment of FOXP3+ cell density can contribute to the prediction of outcome in diffuse large B-cell lymphoma, fallicular lymphoma and classical Hodgkin’s lymphoma.

Journal ArticleDOI
TL;DR: In this paper, the first measurements of coupled nitrogen (N) and oxygen (O) isotope fractionation of nitrate by laboratory cultures of denitrifying bacteria have been reported.
Abstract: We report the first measurements of coupled nitrogen (N) and oxygen (O) isotope fractionation of nitrate by laboratory cultures of denitrifying bacteria Two seawater strains (Pseudomonas stutzeri, Ochrobactrum sp) and three freshwater strains (Paracoccus denitrificans, Pseudomonas chlororaphis, Rhodobacter sphaeroides) were examined Among four strains of facultative anaerobic denitrifiers, N and O isotope effects were variable, ranging from 5% to 25%, with evidence for a drop in the isotope effects as nitrate concentrations approached the halfsaturation constant for nitrate transport O isotope effects were similar to their corresponding N isotope effect, such that the progressive increase in nitrate d18O, when plotted against that in d15N (where d18Osample 5 [(18 O: 16O)sample/(18 O: 16O)reference 2 1] 3 1000, and d15Nsample 5 [(15 N: 14N)sample/(15 N: 14N)reference 2 1] 3 1000), yielded slopes of 086 to 102, with a mean value of 096 R sphaeroides, a photo-heterotroph that possesses only a periplasmic (nonrespiring) dissimilatory nitrate reductase, showed less variability in nitrate N isotope effects, between 13% and 20%, with a modal value of ,15% In contrast to the respiratory denitrifiers, R sphaeroides consistently showed a distinct ratio of d 18 Ot od 15 N change of ,062 We hypothesize that heavy N and O isotope discrimination during respiratory denitrification occurs during the intracellular reduction of nitrate by the respiratory nitrate reductase, and the observed magnitude of fractionation is likely regulated by the ratio of cellular nitrate efflux relative to uptake The data for R sphaeroides are consistent with isotope discrimination directly reflecting the N and O isotope effects of the periplasmic nitrate reductase NAP, without modification by nitrate uptake and efflux

Journal ArticleDOI
22 May 2008-BMJ
TL;DR: Guideline panellists have differing opinions on whether resource use should influence decisions on individual patients as discussed by the authors, and they may find dealing with such considerations challenging, and may find it difficult to deal with such decisions.
Abstract: Guideline panellists have differing opinions on whether resource use should influence decisions on individual patients. As medical care costs rise, resource use considerations become more compelling, but panellists may find dealing with such considerations challenging

Journal ArticleDOI
TL;DR: Rigorous epidemiologic surveillance of soil-transmitted helminthiasis in the era of preventive chemotherapy is facilitated by multiple stool sampling bolstered by different diagnostic techniques.
Abstract: Background Soil-transmitted helminth infections are common throughout the tropics and subtropics and they disproportionately affect the poorest of the poor. In view of a growing global commitment to control soil-transmitted helminthiasis, there is a need to elucidate the effect of repeated stool sampling and the use of different diagnostic methods in areas targeted for preventive chemotherapy that are characterized by low-infection intensities. In this study, we focused on schoolchildren on Unguja Island, Zanzibar, an area where anthelminthic drugs have been repeatedly administered over the past decade.