Showing papers by "University of Münster published in 2011"
TL;DR: It is shown by an extensive benchmark on molecular energy data that the mathematical form of the damping function in DFT‐D methods has only a minor impact on the quality of the results and BJ‐damping seems to provide a physically correct short‐range behavior of correlation/dispersion even with unmodified standard functionals.
Abstract: It is shown by an extensive benchmark on molecular energy data that the mathematical form of the damping function in DFT-D methods has only a minor impact on the quality of the results. For 12 different functionals, a standard "zero-damping" formula and rational damping to finite values for small interatomic distances according to Becke and Johnson (BJ-damping) has been tested. The same (DFT-D3) scheme for the computation of the dispersion coefficients is used. The BJ-damping requires one fit parameter more for each functional (three instead of two) but has the advantage of avoiding repulsive interatomic forces at shorter distances. With BJ-damping better results for nonbonded distances and more clear effects of intramolecular dispersion in four representative molecular structures are found. For the noncovalently-bonded structures in the S22 set, both schemes lead to very similar intermolecular distances. For noncovalent interaction energies BJ-damping performs slightly better but both variants can be recommended in general. The exception to this is Hartree-Fock that can be recommended only in the BJ-variant and which is then close to the accuracy of corrected GGAs for non-covalent interactions. According to the thermodynamic benchmarks BJ-damping is more accurate especially for medium-range electron correlation problems and only small and practically insignificant double-counting effects are observed. It seems to provide a physically correct short-range behavior of correlation/dispersion even with unmodified standard functionals. In any case, the differences between the two methods are much smaller than the overall dispersion effect and often also smaller than the influence of the underlying density functional.
14,151 citations
TL;DR: This critical review summarizes and discusses endeavours towards the development of mild C-H activation methods and wishes to trigger more research towards this goal.
Abstract: Functionalizing traditionally inert carbon–hydrogen bonds represents a powerful transformation in organic synthesis, providing new entries to valuable structural motifs and improving the overall synthetic efficiency. C–H bond activation, however, often necessitates harsh reaction conditions that result in functional group incompatibilities and limited substrate scope. An understanding of the reaction mechanism and rational design of experimental conditions have led to significant improvement in both selectivity and applicability. This critical review summarizes and discusses endeavours towards the development of mild C–H activation methods and wishes to trigger more research towards this goal. In addition, we examine select examples in complex natural product synthesis to demonstrate the synthetic utility of mild C–H functionalization (84 references).
2,137 citations
TL;DR: In this paper, dispersion corrections to standard Kohn-Sham density functional theory (DFT) are reviewed, focusing on computationally efficient methods for large systems that do not depend on virtual orbitals or rely on separated fragments.
Abstract: Dispersion corrections to standard Kohn–Sham density functional theory (DFT) are reviewed. The focus is on computationally efficient methods for large systems that do not depend on virtual orbitals or rely on separated fragments. The recommended approaches (van der Waals density functional and DFT-D) are asymptotically correct and can be used in combination with standard or slightly modified (short-range) exchange–correlation functionals. The importance of the dispersion energy in intramolecular cases (conformational problems and thermochemistry) is highlighted. © 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 211-228 DOI: 10.1002/wcms.30
2,057 citations
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
1,829 citations
University of Miami1, University of Texas Southwestern Medical Center2, University of Alabama at Birmingham3, Harvard University4, Veterans Health Administration5, University of Illinois at Chicago6, Wake Forest University7, Tulane University8, University of California, San Francisco9, University of Pennsylvania10, University of Michigan11, Temple University12, University of Münster13, National Institutes of Health14
TL;DR: It is reported that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort and suggested that chronically elevated F GF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
Abstract: Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor–dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF–receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
1,709 citations
Heribert Schunkert1, Inke R. König1, Sekar Kathiresan2, Muredach P. Reilly3 +163 more•Institutions (59)
TL;DR: This paper performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals.
Abstract: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
1,705 citations
TL;DR: There is no statistical correlation between a functional's accuracy for atomization energies and the performance for chemically more relevant reaction energies, and it is shown that double-hybrids in general outperform those.
Abstract: A thorough energy benchmark study of various density functionals (DFs) is carried out with the new GMTKN30 database for general main group thermochemistry, kinetics and noncovalent interactions [Goerigk and Grimme, J. Chem. Theor. Comput., 2010, 6, 107; Goerigk and Grimme, J. Chem. Theor. Comput., 2011, 7, 291]. In total, 47 DFs are investigated: two LDAs, 14 GGAs, three meta-GGAs, 23 hybrids and five double-hybrids. Besides the double-hybrids, also other modern approaches, i.e., the M05 and M06 classes of functionals and range-separated hybrids, are tested. For almost all functionals, the new DFT-D3 correction is applied in order to consistently test the performance also for important noncovalent interactions; the parameters are taken from previous works or determined for the present study. Basis set and quadrature grid issues are also considered. The general aim of the study is to work out which functionals are generally well applicable and robust to describe the energies of molecules. In summary, we recommend on the GGA level the B97-D3 and revPBE-D3 functionals. The best meta-GGA is oTPSS-D3 although meta-GGAs represent in general no clear improvement compared to numerically simpler GGAs. Notably, the widely used B3LYP functional performs worse than the average of all tested hybrids and is also very sensitive to the application of dispersion corrections. We discourage its usage as a standard method without closer inspection of the results, as it still seems to be often done nowadays. Surprisingly, long-range corrected exchange functionals do in general not perform better than the corresponding standard hybrids. However, the ωB97X-D functional seems to be a promising method. The most robust hybrid is Zhao and Truhlar's PW6B95 functional in combination with DFT-D3. If higher accuracy is required, double-hybrids should be applied. The corresponding DSD-BLYP-D3 and PWPB95-D3 variants are the most accurate and robust functionals of the entire study. Additional calculations with MP2 and and its spin-scaled variants SCS-MP2, S2-MP2 and SOS-MP2 revealed that double-hybrids in general outperform those. Only SCS-MP2 can be recommended, particularly for reaction energies. We suggest its usage when a large self-interaction error is expected that prohibits usage of double-hybrids. Perdews' metaphoric picture of Jacob's Ladder for the classification of density functionals' performance could unbiasedly be confirmed with GMTKN30. We also show that there is no statistical correlation between a functional's accuracy for atomization energies and the performance for chemically more relevant reaction energies.
1,578 citations
Mayo Clinic1, New York University2, University of Hamburg3, Children's National Medical Center4, University of Girona5, Johns Hopkins University6, St George's, University of London7, Harvard University8, University of Ottawa9, University of Toronto10, University of Miami11, University of Paris12, University College London13, University of Münster14, University of Sydney15, Cincinnati Children's Hospital Medical Center16, University of Oxford17, University of Amsterdam18, Indiana University19
TL;DR: This dissertation aims to provide a history of modern medicine and some of the techniques and practices used in modern medicine, as well as some new approaches, that were introduced in the field of medicine more than 40 years ago.
1,254 citations
TL;DR: An extended and improved version of the recently published database for general main group thermochemistry, kinetics, and noncovalent interactions is presented, and the PWPB95-D3 functional is recommended in general chemistry applications as the least basis set dependent and the best functional at the triple-ζ level.
Abstract: We present an extended and improved version of our recently published database for general main group thermochemistry, kinetics, and noncovalent interactions [J. Chem. Theory Comput. 2010, 6, 107], which is dubbed GMTKN30. Furthermore, we suggest and investigate two new double-hybrid-meta-GGA density functionals called PTPSS-D3 and PWPB95-D3. PTPSS-D3 is based on reparameterized TPSS exchange and correlation contributions; PWPB95-D3 contains reparameterized PW exchange and B95 parts. Both functionals contain fixed amounts of 50% Fock-exchange. Furthermore, they include a spin-opposite scaled perturbative contribution and are combined with our latest atom-pairwise London-dispersion correction [J. Chem. Phys. 2010, 132, 154104]. When evaluated with the help of the Laplace transformation algorithm, both methods scale as N(4) with system size. The functionals are compared with the double hybrids B2PLYP-D3, B2GPPLYP-D3, DSD-BLYP-D3, and XYG3 for GMTKN30 with a quadruple-ζ basis set. PWPB95-D3 and DSD-BLYP-D3 are the best functionals in our study and turned out to be more robust than B2PLYP-D3 and XYG3. Furthermore, PWPB95-D3 is the least basis set dependent and the best functional at the triple-ζ level. For the example of transition metal carbonyls, it is shown that, mainly due to the lower amount of Fock-exchange, PWPB95-D3 and PTPSS-D3 are better applicable than the other double hybrids. Finally, we discuss in some detail the XYG3 functional [Proc. Nat. Acad. Sci. U.S.A. 2009, 106, 4963], which makes use of B3LYP orbitals and electron densities. We show that it is basically a highly nonlocal variant of B2PLYP and that its partially good performance is mainly due to a larger effective amount of perturbative correlation compared to other double hybrids. We finally recommend the PWPB95-D3 functional in general chemistry applications.
999 citations
TL;DR: Analysis of changes in the mean levels and rank order of the Big Five personality traits in a heterogeneous sample of 14,718 Germans across all of adulthood shows that personality changes throughout the life span, but with more pronounced changes in young and old ages, and that this change is partly attributable to social demands and experiences.
Abstract: Does personality change across the entire life course, and are those changes due to intrinsic maturation or major life experiences? This longitudinal study investigated changes in the mean levels and rank order of the Big Five personality traits in a heterogeneous sample of 14,718 Germans across all of adulthood. Latent change and latent moderated regression models provided 4 main findings: First, age had a complex curvilinear influence on mean levels of personality. Second, the rank-order stability of Emotional Stability, Extraversion, Openness, and Agreeableness all followed an inverted U-shaped function, reaching a peak between the ages of 40 and 60 and decreasing afterward, whereas Conscientiousness showed a continuously increasing rank-order stability across adulthood. Third, personality predicted the occurrence of several objective major life events (selection effects) and changed in reaction to experiencing these events (socialization effects), suggesting that personality can change due to factors other than intrinsic maturation. Fourth, when events were clustered according to their valence, as is commonly done, effects of the environment on changes in personality were either overlooked or overgeneralized. In sum, our analyses show that personality changes throughout the life span, but with more pronounced changes in young and old ages, and that this change is partly attributable to social demands and experiences.
956 citations
Posted Content•
01 Jan 2011TL;DR: In this paper, the authors investigated changes in the mean levels and rank order of the Big Five personality traits in a heterogeneous sample of 14,718 Germans across all of adulthood.
Abstract: Does personality change across the entire life course, and are those changes due to intrinsic maturation or major life experiences? This longitudinal study investigated changes in the mean levels and rank order of the Big Five personality traits in a heterogeneous sample of 14,718 Germans across all of adulthood. Latent change and latent moderated regression models provided four main findings: First, age had a complex curvilinear influence on mean levels of personality. Second, the rank-order stability of Emotional Stability, Extraversion, Openness, and Agreeableness all followed an inverted U-shaped function, reaching a peak between the ages of 40 and 60, and decreasing afterwards, whereas Conscientiousness showed a continuously increasing rank-order stability across adulthood. Third, personality predicted the occurrence of several objective major life events (selection effects) and changed in reaction to experiencing these events (socialization effects), suggesting that personality can change due to factors other than intrinsic maturation.. - Fourth, when events were clustered according to their valence, as is commonly done,. - effects of the environment on changes in personality were either overlooked or. - overgeneralized. In sum, our analyses show that personality changes throughout the life. - span, but with more pronounced changes in young and old ages, and that this change is. - partly attributable to social demands and experiences.
TL;DR: This review bridges functional and evolutionary aspects of plastid chromosome architecture in land plants and their putative ancestors and suggests that the slow mode at which the plastome typically evolves is likely to be influenced by a combination of different molecular mechanisms.
Abstract: This review bridges functional and evolutionary aspects of plastid chromosome architecture in land plants and their putative ancestors. We provide an overview on the structure and composition of the plastid genome of land plants as well as the functions of its genes in an explicit phylogenetic and evolutionary context. We will discuss the architecture of land plant plastid chromosomes, including gene content and synteny across land plants. Moreover, we will explore the functions and roles of plastid encoded genes in metabolism and their evolutionary importance regarding gene retention and conservation. We suggest that the slow mode at which the plastome typically evolves is likely to be influenced by a combination of different molecular mechanisms. These include the organization of plastid genes in operons, the usually uniparental mode of plastid inheritance, the activity of highly effective repair mechanisms as well as the rarity of plastid fusion. Nevertheless, structurally rearranged plastomes can be found in several unrelated lineages (e.g. ferns, Pinaceae, multiple angiosperm families). Rearrangements and gene losses seem to correlate with an unusual mode of plastid transmission, abundance of repeats, or a heterotrophic lifestyle (parasites or myco-heterotrophs). While only a few functional gene gains and more frequent gene losses have been inferred for land plants, the plastid Ndh complex is one example of multiple independent gene losses and will be discussed in detail. Patterns of ndh-gene loss and functional analyses indicate that these losses are usually found in plant groups with a certain degree of heterotrophy, might rendering plastid encoded Ndh1 subunits dispensable.
TL;DR: The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocyTomas implicate BRAFV600E mutation as a valuable diagnostic marker for these rare tumor entities.
Abstract: Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAFV600E mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAFV600E mutation was strongly associated with extra-cerebellar location (p = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAFV600E mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAFV600E mutant brain tumor patients will benefit from BRAFV600E-directed targeted therapies.
TL;DR: The remarkable advances made during the last decade in organic synthesis, catalysis, and biotechnology using plant oils and the basic oleochemicals derived from them will be reported, including, for example, ω-functionalization of fatty acids containing internal double bonds, application of the olefin metathesis reaction, and de novo synthesis of fatty fatty acids from abundantly available renewable carbon sources.
Abstract: Oils and fats of vegetable and animal origin have been the most important renewable feedstock of the chemical industry in the past and in the present. A tremendous geographical and feedstock shift of oleochemical production has taken place from North America and Europe to southeast Asia and from tallow to palm oil. It will be important to introduce and to cultivate more and new oil plants containing fatty acids with interesting and desired properties for chemical utilization while simultaneously increasing the agricultural biodiversity. The problem of the industrial utilization of food plant oils has become more urgent with the development of the global biodiesel production. The remarkable advances made during the last decade in organic synthesis, catalysis, and biotechnology using plant oils and the basic oleochemicals derived from them will be reported, including, for example, ω-functionalization of fatty acids containing internal double bonds, application of the olefin metathesis reaction, and de novo synthesis of fatty acids from abundantly available renewable carbon sources.
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University of Milano-Bicocca1, University of Brescia2, University of Bologna3, University Hospital of Lausanne4, Queen Mary University of London5, Ghent University6, University of Barcelona7, University of Glasgow8, Istanbul University9, Katholieke Universiteit Leuven10, Hannover Medical School11, Manchester Royal Infirmary12, Gdańsk Medical University13, University of Münster14, University of Valencia15, Complutense University of Madrid16, University of Amsterdam17, University of Milan18
TL;DR: This article estimated glomerular filtration rate of the human glomerus and showed that the estimated rate can be improved by using the enzyme GFR-BPBP-DBPDBPdiastolic blood pressure
Abstract: ACEangiotensin-converting enzymeBPblood pressureDBPdiastolic blood pressureeGFRestimated glomerular filtration rateESCEuropean Society of CardiologyESHEuropean Society of HypertensionETendothelinIM...
TL;DR: The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug.
Abstract: Summary Background Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m 2 dose and twice per week schedule in patients with relapsed multiple myeloma. Methods This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1·3 mg/m 2 , on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. Findings 222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference −0·4%, 95% CI −14·3 to 13·5), showing non-inferiority (p=0·002). After a median follow-up of 11·8 months (IQR 7·9–16·8) in the subcutaneous group and 12·0 months (8·1–15·6) in the intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% CI 8·5–11·7, vs 9·4 months, 7·6–10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1–80·0, vs 76·7%, 64·1–85·4; p=0·504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. Interpretation Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile. Funding Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals.
Columbia University1, University of California, Los Angeles2, University of Zurich3, University of Münster4, University of Coimbra5, University of Nantes6, Weizmann Institute of Science7, University of Mainz8, Shanghai Jiao Tong University9, Max Planck Society10, Rice University11, University of Bologna12
TL;DR: The XENON100 detector, installed underground at the Laboratori Nazionali del Gran Sasso of INFN, Italy, finds no evidence for dark matter, leading to the most stringent limit on dark matter interactions today.
Abstract: We present results from the direct search for dark matter with the XENON100 detector, installed underground at the Laboratori Nazionali del Gran Sasso of INFN, Italy. XENON100 is a two-phase time-projection chamber with a 62 kg liquid xenon target. Interaction vertex reconstruction in three dimensions with millimeter precision allows the selection of only the innermost 48 kg as the ultralow background fiducial target. In 100.9 live days of data, acquired between January and June 2010, no evidence for dark matter is found. Three candidate events were observed in the signal region with an expected background of (1.8{+-}0.6) events. This leads to the most stringent limit on dark matter interactions today, excluding spin-independent elastic weakly interacting massive particle (WIMP) nucleon scattering cross sections above 7.0x10{sup -45} cm{sup 2} for a WIMP mass of 50 GeV/c{sup 2} at 90% confidence level.
TL;DR: Augmented adherence of the strain to intestinal epithelium might facilitate systemic absorption of Shiga toxin and could explain the high progression to haemolytic uraemic syndrome.
Abstract: Summary Background In an ongoing outbreak of haemolytic uraemic syndrome and bloody diarrhoea caused by a virulent Escherichia coli strain O104:H4 in Germany (with some cases elsewhere in Europe and North America), 810 cases of the syndrome and 39 deaths have occurred since the beginning of May, 2011. We analysed virulence profiles and relevant phenotypes of outbreak isolates recovered in our laboratory. Methods We analysed stool samples from 80 patients that had been submitted to the National Consulting Laboratory for Haemolytic Uraemic Syndrome in Munster, Germany, between May 23 and June 2, 2011. Isolates were screened with standard PCR for virulence genes of Shiga-toxin-producing E coli and a newly developed multiplex PCR for characteristic features of the outbreak strain ( rfb O104 , fliC H4 , stx 2 , and terD ). Virulence profiles of the isolates were determined with PCR targeting typical virulence genes of Shiga-toxin-producing E coli and of other intestinal pathogenic E coli . We sequenced stx with Sanger sequencing and measured Shiga-toxin production, adherence to epithelial cells, and determined phylogeny and antimicrobial susceptibility. Findings All isolates were of the HUSEC041 clone (sequence type 678). All shared virulence profiles combining typical Shiga-toxin-producing E coli ( stx 2 , iha, lpf O26 , lpf O113 ) and enteroaggregative E coli ( aggA, aggR, set1, pic, aap ) loci and expressed phenotypes that define Shiga-toxin-producing E coli and enteroaggregative E coli , including production of Shiga toxing 2 and aggregative adherence to epithelial cells. Isolates additionally displayed an extended-spectrum β-lactamase phenotype absent in HUSEC041. Interpretation Augmented adherence of the strain to intestinal epithelium might facilitate systemic absorption of Shiga toxin and could explain the high progression to haemolytic uraemic syndrome. This outbreak demonstrates that blended virulence profiles in enteric pathogens, introduced into susceptible populations, can have extreme consequences for infected people. Funding German Federal Ministry of Education and Research, Network Zoonoses.
TL;DR: An efficient Rh(III)-catalyzed oxidative olefination by directed C-H bond activation of N-methoxybenzamides is reported, which results in the selective formation of valuable tetrahydroisoquinolinone products.
Abstract: An efficient Rh(III)-catalyzed oxidative olefination by directed C-H bond activation of N-methoxybenzamides is reported. In this mild, practical, selective, and high-yielding process, the N-O bond acts as an internal oxidant. In addition, simply changing the substituent of the directing/oxidizing group results in the selective formation of valuable tetrahydroisoquinolinone products.
TL;DR: An efficient intermolecular Stetter reaction is developed for the formation of α-amino acid derivatives, with broad aldehyde scope and high enantiomeric excess, and tailor-made thiazolylidene catalysts allowed the unprecedented use of nonactivated olefins and alkynes as aldehydes coupling partners.
Abstract: Transition metal catalysis is a powerful means of effecting organic reactions, but it has some inherent drawbacks, such as the cost of the catalyst and the toxicity of the metals. Organocatalysis represents an attractive alternative and, in some cases, offers transformations unparalleled in metal catalysis. Unique transformations are a particular hallmark of N-heterocyclic carbene (NHC) organocatalysis, a versatile method for which a number of modes of action are known. The NHC-catalyzed umpolung (that is, the inversion of polarity) of electrophilic aldehydes, through formation of the nucleophilic Breslow intermediate, is probably the most important mode of action. In this Account, we discuss the reaction of Breslow intermediates with unconventional reaction partners.In two traditional umpolung reactions, the benzoin condensation and the Stetter reaction, some selectivity issues represent significant challenges, especially in intermolecular variants of these reactions. In intermolecular cross-benzoin reac...
Indiana University – Purdue University Indianapolis1, University of Pittsburgh2, Harvard University3, University of California, San Francisco4, University of Münster5, Peter MacCallum Cancer Centre6, Royal Brisbane and Women's Hospital7, University of Nottingham8, University of Porto9, Singapore General Hospital10, The Chinese University of Hong Kong11, Cancer Research UK12, The Breast Cancer Research Foundation13
TL;DR: The purpose of this article was to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.
TL;DR: Spin selectivity at room temperature was extremely high as compared with other known spin filters, and the spin filtration efficiency depended on the length of the DNA in the monolayer and its organization.
Abstract: In electron-transfer processes, spin effects normally are seen either in magnetic materials or in systems containing heavy atoms that facilitate spin-orbit coupling. We report spin-selective transmission of electrons through self-assembled monolayers of double-stranded DNA on gold. By directly measuring the spin of the transmitted electrons with a Mott polarimeter, we found spin polarizations exceeding 60% at room temperature. The spin-polarized photoelectrons were observed even when the photoelectrons were generated with unpolarized light. The observed spin selectivity at room temperature was extremely high as compared with other known spin filters. The spin filtration efficiency depended on the length of the DNA in the monolayer and its organization.
K. Aamodt1, A. Abrahantes Quintana, Dagmar Adamová2, Andrew Marshall Adare3 +938 more•Institutions (80)
TL;DR: In this paper, the centrality dependence of the chargedparticle multiplicity density at midrapidity in Pb-Pb collisions at root s(NN) = 2: 76 TeV is presented.
Abstract: The centrality dependence of the charged-particle multiplicity density at midrapidity in Pb-Pb collisions at root s(NN) = 2: 76 TeV is presented. The charged-particle density normalized per participating nucleon pair increases by about a factor of 2 from peripheral (70%-80%) to central (0%-5%) collisions. The centrality dependence is found to be similar to that observed at lower collision energies. The data are compared with models based on different mechanisms for particle production in nuclear collisions.
TL;DR: Alkoxyamines derived from nitroxides are shown to be highly useful precursors of C-centered radicals in synthesis and also in polymer chemistry, and new developments in the synthesis of complex polymer architectures are highlighted.
Abstract: This Review describes the application of nitroxides to synthesis and polymer chemistry. The synthesis and physical properties of nitroxides are discussed first. The largest section focuses on their application as stoichiometric and catalytic oxidants in organic synthesis. The oxidation of alcohols and carbanions, as well as oxidative C-C bond-forming reactions are presented along with other typical oxidative transformations. A section is also dedicated to the extensive use of nitroxides as trapping reagents for C-centered radicals in radical chemistry. Alkoxyamines derived from nitroxides are shown to be highly useful precursors of C-centered radicals in synthesis and also in polymer chemistry. The last section discusses the basics of nitroxide-mediated radical polymerization (NMP) and also highlights new developments in the synthesis of complex polymer architectures.
UCL Institute of Neurology1, French Institute of Health and Medical Research2, Leiden University3, University of British Columbia4, University of London5, University of Ulm6, University of Iowa7, University of Oxford8, Central Manchester University Hospitals NHS Foundation Trust9, University of Münster10, Monash University11
TL;DR: The Track-HD study as discussed by the authors examined disease progression in premanifest individuals carrying the mutant HTT gene and those with early stage disease and reported 12-month longitudinal changes, building on baseline findings.
Abstract: Summary Background TRACK-HD is a prospective observational study of Huntington's disease (HD) that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with early stage disease. We report 12-month longitudinal changes, building on baseline findings. Methods We did a 12-month follow-up of patients recruited from the four TRACK-HD study sites in Canada, France, the Netherlands, and the UK. Participants were premanifest individuals (preHD) carrying the mutant HTT gene, patients with early HD, and controls matched by age and sex with the combined preHD and early HD groups. Data were collected by use of 3T MRI and clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Statistical analysis assessed annualised change with the use of linear regression models to estimate differences between groups. Findings 116 preHD individuals, 114 early HD patients, and 115 people in the control group completed follow-up. Four preHD individuals, nine early HD patients, and eight people in the control group did not complete the follow-up. A further nine participants, who completed follow-up assessments, were unable to undergo MRI. After adjustment for demographics, annualised rates of generalised and regional brain atrophy were higher in preHD and early HD groups than in controls. Whole-brain atrophy rates were 0·20% (95% CI 0·05–0·34; p=0·0071) per year higher in preHD participants and 0·60% (0·44–0·76; p Interpretation Quantitative imaging showed the greatest differentiation across the spectrum of disease and functional measures of decline were sensitive in early HD, with cognitive and quantitative motor impairment also detectable in preHD. We show longitudinal change over 12 months in generalised and regional brain volume, cognition, and quantitative motor tasks in individuals many years from predicted disease onset and show the feasibility of obtaining quantifiable endpoints for future trials. Funding CHDI/HighQ Foundation Inc.
K. Aamodt1, A. Abrahantes Quintana, Dagmar Adamová2, Andrew Marshall Adare3 +909 more•Institutions (76)
TL;DR: In this article, the authors measured the transverse momentum spectra of primary charged particles in Pb-Pb collisions at root s(NN) = 2.76 TeV at the ALICE Collaboration at the LHC.
11 Jul 2011
TL;DR: The first measurement of the triangular v3, quadrangular v4, and pentagonal v5 charged particle flow in Pb-Pb collisions is reported, and a double peaked structure in the two-particle azimuthal correlations is observed, which can be naturally explained from the measured anisotropic flow Fourier coefficients.
Abstract: We report on the first measurement of the triangular nu(3), quadrangular nu(4), and pentagonal nu(5) charged particle flow in Pb-Pb collisions at root s(NN) = 2.76 TeV measured with the ALICE detector at the CERN Large Hadron Collider. We show that the triangular flow can be described in terms of the initial spatial anisotropy and its fluctuations, which provides strong constraints on its origin. In the most central events, where the elliptic flow nu(2) and nu(3) have similar magnitude, a double peaked structure in the two-particle azimuthal correlations is observed, which is often interpreted as a Mach cone response to fast partons. We show that this structure can be naturally explained from the measured anisotropic flow Fourier coefficients.
TL;DR: The systematic literature further emphasis the heterogeneity of existing multimorbidity indices, however, one important similarity is that the focus is on diseases with a high prevalence and a severe impact on affected individuals.
Abstract: Multimorbidity, defined as the coexistence of 2 or more chronic diseases, is a common phenomenon especially in older people. Numerous efforts to establish a standardized instrument to assess the level of multimorbidity have failed until now, and indices are primarily characterized by their high heterogeneity. Thus, the objective is to provide a comprehensive overview on existing instruments on the basis of a systematic literature review.
TL;DR: The recent developments of the new generation of the Sensor Web Enablement specification framework are illustrated and related to other emerging concepts such as the Web of Things and point out challenges and resulting future work topics for research on Sensor Web enablement.
Abstract: Many sensor networks have been deployed to monitor Earth’s environment, and more will follow in the future. Environmental sensors have improved continuously by becoming smaller, cheaper, and more intelligent. Due to the large number of sensor manufacturers and differing accompanying protocols, integrating diverse sensors into observation systems is not straightforward. A coherent infrastructure is needed to treat sensors in an interoperable, platform-independent and uniform way. The concept of the Sensor Web reflects such a kind of infrastructure for sharing, finding, and accessing sensors and their data across different applications. It hides the heterogeneous sensor hardware and communication protocols from the applications built on top of it. The Sensor Web Enablement initiative of the Open Geospatial Consortium standardizes web service interfaces and data encodings which can be used as building blocks for a Sensor Web. This article illustrates and analyzes the recent developments of the new generation of the Sensor Web Enablement specification framework. Further, we relate the Sensor Web to other emerging concepts such as the Web of Things and point out challenges and resulting future work topics for research on Sensor Web Enablement.
TL;DR: Using in vitro metabolomic profiling techniques, paraoxonase-1 (PON1) is identified as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation.
Abstract: Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.