| 1. |
- Fazey, Ioan, et al.
(författare)
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Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
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Ingår i: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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| 2. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 3. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 4. |
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| 5. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 6. |
- Krämer, Martina, et al.
(författare)
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A microphysics guide to cirrus – Part 2 : Climatologies of clouds and humidity from observations
- 2020
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 20:21, s. 12569-12608
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Tidskriftsartikel (refereegranskat)abstract
- This study presents airborne in situ and satellite remote sensing climatologies of cirrus clouds and humidity. The climatologies serve as a guide to the properties of cirrus clouds, with the new in situ database providing detailed insights into boreal midlatitudes and the tropics, while the satellite-borne data set offers a global overview.To this end, an extensive, quality-checked data archive, the Cirrus Guide II in situ database, is created from airborne in situ measurements during 150 flights in 24 campaigns. The archive contains meteorological parameters, ice water content (IWC), ice crystal number concentration (Nice), ice crystal mean mass radius (Rice), relative humidity with respect to ice (RHice), and water vapor mixing ratio (H2O) for each of the flights. Depending on the parameter, the database has been extended by about a factor of 5–10 compared to earlier studies.As one result of our investigation, we show that the medians of Nice, Rice, and RHice have distinct patterns in the IWC–T parameter space. Lookup tables of these variables as functions of IWC and T can be used to improve global model cirrus representation and remote sensing retrieval methods. Another outcome of our investigation is that across all latitudes, the thicker liquid-origin cirrus predominate at lower altitudes, while at higher altitudes the thinner in situ-origin cirrus prevail. Further, examination of the radiative characteristics of in situ-origin and liquid-origin cirrus shows that the in situ-origin cirrus only slightly warm the atmosphere, while liquid-origin cirrus have a strong cooling effect.An important step in completing the Cirrus Guide II is the provision of the global cirrus Nice climatology, derived by means of the retrieval algorithm DARDAR-Nice from 10 years of cirrus remote sensing observations from satellite. The in situ measurement database has been used to evaluate and improve the satellite observations. We found that the global median Nice from satellite observations is almost 2 times higher than the in situ median and increases slightly with decreasing temperature. Nice medians of the most frequently occurring cirrus sorted by geographical regions are highest in the tropics, followed by austral and boreal midlatitudes, Antarctica, and the Arctic. Since the satellite climatologies enclose the entire spatial and temporal Nice occurrence, we could deduce that half of the cirrus are located in the lowest, warmest (224–242 K) cirrus layer and contain a significant amount of liquid-origin cirrus.A specific highlight of the study is the in situ observations of cirrus and humidity in the Asian monsoon anticyclone and the comparison to the surrounding tropics. In the convectively very active Asian monsoon, peak values of Nice and IWC of 30 cm−3 and 1000 ppmv are detected around the cold point tropopause (CPT). Above the CPT, ice particles that are convectively injected can locally add a significant amount of water available for exchange with the stratosphere. We found IWCs of up to 8 ppmv in the Asian monsoon in comparison to only 2 ppmv in the surrounding tropics. Also, the highest RHice values (120 %–150 %) inside of clouds and in clear sky are observed around and above the CPT. We attribute this to the high H2O mixing ratios (typically 3–5 ppmv) observed in the Asian monsoon compared to 1.5 to 3 ppmv found in the tropics. Above the CPT, supersaturations of 10 %–20 % are observed in regions of weak convective activity and up to about 50 % in the Asian monsoon. This implies that the water available for transport into the stratosphere might be higher than the expected saturation value.
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| 7. |
- McNabb, Sarah, et al.
(författare)
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Meta-analysis of 16 studies of the association of alcohol with colorectal cancer
- 2020
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 146:3, s. 861-873
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (<= 1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.
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| 8. |
- Middleton, Steven J, et al.
(författare)
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Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 145:10, s. 3637-3653
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Tidskriftsartikel (refereegranskat)abstract
- Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial EMG (n = 3 CIP participants and n = 8 healthy controls) we have found that these patients also have abnormalities in the encoding of affective touch which is mediated by the specialised afferents; C-low threshold mechanoreceptors (C-LTMRs). In the mouse we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.
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| 9. |
- Papadimitriou, Nikos, et al.
(författare)
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Physical activity and risks of breast and colorectal cancer : a Mendelian randomisation analysis
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value=0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value=0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers. Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
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| 10. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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