| 1. |
- Ding, Li, et al.
(författare)
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Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
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Tidskriftsartikel (refereegranskat)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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| 2. |
- Power, M. J., et al.
(författare)
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Changes in fire regimes since the Last Glacial Maximum : an assessment based on a global synthesis and analysis of charcoal data
- 2008
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Ingår i: Climate Dynamics. - : Springer Science and Business Media LLC. - 0930-7575 .- 1432-0894. ; 30:7-8, s. 887-907
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Tidskriftsartikel (refereegranskat)abstract
- Fire activity has varied globally and continuously since the last glacial maximum (LGM) in response to long-term changes in global climate and shorter-term regional changes in climate, vegetation, and human land use. We have synthesized sedimentary charcoal records of biomass burning since the LGM and present global maps showing changes in fire activity for time slices during the past 21,000 years (as differences in charcoal accumulation values compared to pre-industrial). There is strong broad-scale coherence in fire activity after the LGM, but spatial heterogeneity in the signals increases thereafter. In North America, Europe and southern South America, charcoal records indicate less-than-present fire activity during the deglacial period, from 21,000 to ∼11,000 cal yr BP. In contrast, the tropical latitudes of South America and Africa show greater-than-present fire activity from ∼19,000 to ∼17,000 cal yr BP and most sites from Indochina and Australia show greater-than-present fire activity from 16,000 to ∼13,000 cal yr BP. Many sites indicate greater-than-present or near-present activity during the Holocene with the exception of eastern North America and eastern Asia from 8,000 to ∼3,000 cal yr BP, Indonesia and Australia from 11,000 to 4,000 cal yr BP, and southern South America from 6,000 to 3,000 cal yr BP where fire activity was less than present. Regional coherence in the patterns of change in fire activity was evident throughout the post-glacial period. These complex patterns can largely be explained in terms of large-scale climate controls modulated by local changes in vegetation and fuel load.
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| 3. |
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| 4. |
- Terracciano, A, et al.
(författare)
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National character does not reflect mean personality trait levels in 49 cultures
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 310:5745, s. 96-100
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Tidskriftsartikel (refereegranskat)abstract
- Most people hold beliefs about personality characteristics typical of members of their own and others' cultures. These perceptions of national character may be generalizations from personal experience, stereotypes with a "kernel of truth," or inaccurate stereotypes. We obtained national character ratings of 3989 people from 49 cultures and compared them with the average personality scores of culture members assessed by observer ratings and self-reports. National character ratings were reliable but did not converge with assessed traits. Perceptions of national character thus appear to be unfounded stereotypes that may serve the function of maintaining a national identity.
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| 5. |
- Beer, Nicola L., et al.
(författare)
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The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:21, s. 4081-4088
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified a number of signals for both Type 2 Diabetes and related quantitative traits. For the majority of loci, the transition from association signal to mutational mechanism has been difficult to establish. Glucokinase (GCK) regulates glucose storage and disposal in the liver where its activity is regulated by glucokinase regulatory protein (GKRP; gene name GCKR). Fructose-6 and fructose-1 phosphate (F6P and F1P) enhance or reduce GKRP-mediated inhibition, respectively. A common GCKR variant (P446L) is reproducibly associated with triglyceride and fasting plasma glucose levels in the general population. The aim of this study was to determine the mutational mechanism responsible for this genetic association. Recombinant human GCK and both human wild-type (WT) and P446L-GKRP proteins were generated. GCK kinetic activity was observed spectrophotometrically using an NADP(+)-coupled assay. WT and P446L-GKRP-mediated inhibition of GCK activity and subsequent regulation by phosphate esters were determined. Assays matched for GKRP activity demonstrated no difference in dose-dependent inhibition of GCK activity or F1P-mediated regulation. However, the response to physiologically relevant F6P levels was significantly attenuated with P446L-GKRP (n = 18; P < 0.03). Experiments using equimolar concentrations of both regulatory proteins confirmed these findings (n = 9; P < 0.001). In conclusion, P446L-GKRP has reduced regulation by physiological concentrations of F6P, resulting indirectly in increased GCK activity. Altered GCK regulation in liver is predicted to enhance glycolytic flux, promoting hepatic glucose metabolism and elevating concentrations of malonyl-CoA, a substrate for de novo lipogenesis, providing a mutational mechanism for the reported association of this variant with raised triglycerides and lower glucose levels.
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| 6. |
- Bennett, N. S., et al.
(författare)
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Enhanced n-type dopant solubility in tensile-strained Si
- 2008
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Ingår i: Thin Solid Films. - : Elsevier BV. - 0040-6090 .- 1879-2731. ; 517:1, s. 331-333
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Tidskriftsartikel (refereegranskat)abstract
- The creation of highly conductive ultrashallow-doped regions in strained Si is a key requirement for future Si based devices. It is shown that in the presence of tensile strain, Sb becomes a contender to replace As in strain-engineered CMOS devices due to advantages in sheet resistance. While strain reduces resistance for both As and Sb; a result of enhanced electron mobility, the reduction is significantly larger for Sb due to an increase in donor activation. Differential Hall measurements suggest this is a consequence of a strain-induced Sb solubility enhancement following solid-phase epitaxial regrowth, increasing Sb solubility in Si to levels approaching 10(21) cm(-3). Experiments highlight the importance of maintaining substrate strain during thermal annealing to maintain this high Sb activation.
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| 7. |
- Eisenstat, R. A., et al.
(författare)
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The uncompromising leader
- 2008
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Ingår i: Harvard Business Review. - 0017-8012. ; 86:7-8, s. 50-
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Tidskriftsartikel (refereegranskat)abstract
- Managing the tension between performance and people is at the heart of the CEO's job. But CEOs under fierce pressure from capital markets often focus solely on the shareholder, which can lead to employee disenchantment. Others put so much stock in their firms' heritage that they don't notice as their organizations slide into complacency. Some leaders, though, manage to avoid those traps and create high-commitment, high-performance (HCHP) companies. The authors' in-depth research of HCHP CEOs reveals several shared traits: These CEOs earn the trust of their organizations through their openness to the unvarnished truth. They are deeply engaged with their people, and their exchanges are direct and personal. They mobilize employees around a focused agenda, concentrating on only one or two initiatives. And they work to build collective leadership capabilities. These leaders also forge an emotionally resonant shared purpose across their companies. That consists of a three-part promise: The company will help employees build a better world and deliver performance they can be proud of, and will provide an environment in which they can grow. HCHP CEOs approach finding a firm's moral and strategic center in a competitive market as a calling, not an engineering problem. They drive their firms to be strongly market focused while at the same time reinforcing their firms' core values. They are committed to short-term performance while also investing in long-term leadership and organizational capabilities. By refusing to compromise on any of these terms, they build great companies.
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| 8. |
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| 9. |
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| 10. |
- Muscheler, R, et al.
(författare)
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The cosmic ray clock during the Younger Dryas cold period clues about climate forcing and the timing of climate change : clues about climate forcing and the timing of climate change
- 2009
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Konferensbidrag (refereegranskat)abstract
- The last cold spell of the last deglaciation, the Younger Dryas period, serves as the prime example for rapid climate change induced by ocean circulation changes. However, the detailed processes behind this cold event are far from being satisfactorily understood. Although, the oceanic involvement in this climate deterioration is not disputed, there are various speculations about mechanisms that could have triggered and terminated it. Here we present 10Be data from the GRIP ice core around the transition from the Bölling/Alleröd warm period into the Younger Dryas cold period. The data provide a high-resolution cosmic ray signal that can be used to synchronize different radionuclide records and the connected climate reconstructions. This approach can lead to robust results about synchronous and non-synchronous climate changes at different locations, insights into the possible processes behind the changes and also the prospect of an improved 14C calibration beyond the Holocene period.
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