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101.
A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis 总被引:1,自引:0,他引:1
Khor CC Chapman SJ Vannberg FO Dunne A Murphy C Ling EY Frodsham AJ Walley AJ Kyrieleis O Khan A Aucan C Segal S Moore CE Knox K Campbell SJ Lienhardt C Scott A Aaby P Sow OY Grignani RT Sillah J Sirugo G Peshu N Williams TN Maitland K Davies RJ Kwiatkowski DP Day NP Yala D Crook DW Marsh K Berkley JA O'Neill LA Hill AV 《Nature genetics》2007,39(4):523-528
Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction. 相似文献
102.
Clee SM Yandell BS Schueler KM Rabaglia ME Richards OC Raines SM Kabara EA Klass DM Mui ET Stapleton DS Gray-Keller MP Young MB Stoehr JP Lan H Boronenkov I Raess PW Flowers MT Attie AD 《Nature genetics》2006,38(6):688-693
We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus. 相似文献
103.
Solvent Extraction Developments in Southern Africa 总被引:1,自引:0,他引:1
Peter M. Cole Kathryn C. Sole Angus M. Feather 《清华大学学报》2006,11(2):153-159
Introduction Solvent extraction (SX) has been an integral part of the hydrometallurgist’s arsenal in Southern Africa for many decades[1]. In the early 1970s, several SX plants were built to recover uranium, commonly occurring with the gold-bearing minera… 相似文献
104.
Lemaire SA McDonald ML Guo DC Russell L Miller CC Johnson RJ Bekheirnia MR Franco LM Nguyen M Pyeritz RE Bavaria JE Devereux R Maslen C Holmes KW Eagle K Body SC Seidman C Seidman JG Isselbacher EM Bray M Coselli JS Estrera AL Safi HJ Belmont JW Leal SM Milewicz DM 《Nature genetics》2011,43(10):996-1000
Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10(-5) in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD. 相似文献
105.
106.
Richards A van den Maagdenberg AM Jen JC Kavanagh D Bertram P Spitzer D Liszewski MK Barilla-Labarca ML Terwindt GM Kasai Y McLellan M Grand MG Vanmolkot KR de Vries B Wan J Kane MJ Mamsa H Schäfer R Stam AH Haan J de Jong PT Storimans CW van Schooneveld MJ Oosterhuis JA Gschwendter A Dichgans M Kotschet KE Hodgkinson S Hardy TA Delatycki MB Hajj-Ali RA Kothari PH Nelson SF Frants RR Baloh RW Ferrari MD Atkinson JP 《Nature genetics》2007,39(9):1068-1070
Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias. 相似文献
107.
The term ‘Sustainable Development’ is brandished by modern businesses as a marketing ploy used to suggest evidence of ethical conduct, innovative thinking and moral superiority. However, when analysing an organisations’ adoption of sustainable practices, it is often clear—within the UK—that there are few activities that have been undertaken as an ethical stance instead of legal obligation (McCormick in Environmental politics and policy in industrialized countries, MIT, London, 2002). Our hypothesis is that most methodologies and practices for environmental management do not adopt a holistic perspective, causing significant problems in implementation from inadequate structures and communication channels (Espinosa et al. in Eur J Oper Res, 187:636–651, 2008). In particular we consider that most organisations are currently stifled with management hierarchies that prevent informal/social networking, which may be one of the most powerful natural forms for self-organisation. It is proposed that sustainable development requires more efficient communication channels that foster self-organisation and self-regulation as a method for more productive change processes. In this paper, we explain the reasons why meta-systemic principles of self-organisation and distributed network management offer clear criteria to design an environmental management system that operates on the basis of self-controlled individuals and communities. 相似文献
108.
STING is a direct innate immune sensor of cyclic di-GMP 总被引:1,自引:0,他引:1
Burdette DL Monroe KM Sotelo-Troha K Iwig JS Eckert B Hyodo M Hayakawa Y Vance RE 《Nature》2011,478(7370):515-518
109.
The concept of interactional expertise – characterized by sociologists Harry Collins and Robert Evans as the ability to speak the language of a discipline without the corresponding ability to practice – can serve as a powerful way of breaking down expert/non-expert dichotomies and providing a role for new voices in specialist communities. However, in spite of the vast uptake of this concept and its potential to fruitfully address many important issues related to scientific expertise, there has been surprisingly little critical analysis of it. We seek to remedy this situation by considering potential benefits of interactional expertise and the ways in which the current conception can – and cannot – realize those benefits. In particular, we argue that interactional expertise hasn't reached its full potential for addressing who ought to be involved in scientific research and decision-making, largely owing to an unnecessarily restrictive way of operationalizing the concept. In its place, we offer a broader, more pluralistic account of interactional expertise – one that is in line with the original spirit of the concept, but also captures the diversity that we see as being an important aspect of interactional experts and the value they can bring to the table. 相似文献
110.
In many areas of the Rocky Mountains, elk ( Cervus elaphus ) migrate from low-elevation mountain valleys during spring to high-elevation subalpine and alpine areas for the summer. Research has focused on the impacts of elk herbivory on winter-range plant communities, particularly on woody species such as willow and aspen; however, little information is available on the effects of elk herbivory on alpine willows. In the Sangre de Cristo Mountains of south central Colorado, select alpine areas appear to receive high levels of summer elk herbivory, while other areas are nearly unbrowsed. In 2005 and 2008, we measured willow height, cover, and utilization on sites that appeared to be used heavily by elk, as well as on sites that appeared to be used lightly, to determine differences between these communities over time. We found less willow cover and shorter willows at sites that received higher levels of browsing compared to those that had lower levels of browsing. Human recreational use was greater at lightly browsed sites than at highly browsed sites. From 2005 to 2008, willow utilization declined, and willow cover and height increased at sites with heavy browsing, likely owing to ownership change of adjacent valley land which led to (1) removal of grazing competition from cattle at valley locations and (2) increased human use in alpine areas, which displaced elk. We discuss the implications of increased human use and climate change on elk use of these alpine habitats. En muchas áreas de las Montañas Rocosas, el ciervo rojo ( Cervus elaphus ) migra durante la primavera de valles montañosos de baja elevación a áreas altas subalpinas y alpinas para el verano. Hasta ahora la investigación se ha enfocado en el impacto de la herbivoría del ciervo rojo sobre las comunidades de plantas en el invierno, particularmente en las especies leñosas como el sauce y el álamo; sin embargo, existe poca información disponible sobre el efecto de la herbivoría del ciervo rojo en los sauces alpinos. En la cordillera Sangre de Cristo al centro-sur de Colorado, ciertas áreas alpinas parecen tener altos niveles de herbivoría de verano por el ciervo rojo, en tanto que otras áreas quedan casi sin ramoneo. En 2005 y 2008 medimos la altura, cobertura y uso de los sauces en sitios en los que parecía haber sido abundante el ramoneo y los comparamos con sitios donde parecía haber sido más ligero, a fin de determinar las diferencias entre estas comunidades en el tiempo. Encontramos menos cobertura y altura de sauces en los sitios que recibían niveles más altos de ramoneo en comparación a los que tenían menos evidencia de ello. El uso humano recreativo era mayor en los sitios de ramoneo ligero que en donde era abundante. De 2005 a 2008, disminuyó el uso y aumentó la cobertura y la altura en sitios de ramoneo abundante, probablemente debido a que un valle adyacente cambió de propietario, lo cual provocó (1) la eliminación de la competencia por el pastoreo en ganado en el valle; y (2) un aumento del uso humano en áreas alpinas, desplazando al ciervo rojo. Discutimos las implicaciones del aumento del uso humano y el cambio climático en el uso por el ciervo rojo de estos hábitats alpinos. 相似文献