| 1. |
- Erzurumluoglu, A. Mesut, et al.
(författare)
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
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Tidskriftsartikel (refereegranskat)abstract
- Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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| 2. |
- Needham, E. J., et al.
(författare)
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Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:11, s. 4097-4107
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible. Needham et al. reveal elevations in blood biomarkers of brain injury in patients hospitalised with COVID-19. The changes, which were severity-dependent, were associated with dysregulated immune responses including increases in pro-inflammatory cytokines and autoantibodies. Ongoing active brain injury could still be seen months after infection.
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| 3. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 4. |
- Evans, Daniel L., et al.
(författare)
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Buried solutions: How Maya urban life substantiates soil connectivity
- 2021
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Ingår i: Geoderma. - : Elsevier BV. - 0016-7061. ; 387
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Tidskriftsartikel (refereegranskat)abstract
- Soils are a pivot of sustainable development. Yet, urban planning decisions persist in compromising the usability of the urban soils resource. Urban land cover expansion to accommodate an increasing population results in soil sealing. Concealment of and physical obstructions to soils prevent urban populations from engaging with their soil dependency. The concept of soil connectivity recognises that nurturing mutually beneficial soil–society relations is an essential dimension for achieving soil security. The concentrated populations of urban environments acutely require productive soil–society relations and offer the greatest potential for enhancing soil connectivity. Soil connectivity remains notably under-researched, however, resulting in deficient evidence to substantiate exactly how soil connectivity can contribute to sustaining urban life. The entanglement of soil and urban development has been critical throughout history, but seldom recognised in soil security discourse. We review the manifestation of effective soil connectivity in Precolumbian lowland Maya tropical urbanism. Archaeological evidence reveals, first, that lowland Maya urban settlement patterns largely preserved the availability, proximity, and accessibility of soils in the subdivision and configuration of urban open space. Second, Maya urban life included practices that proactively contributed to the formation of soils by adding to the stock of soils and improving beneficial soil properties of the thin and often nutrient-poor soils resulting from the regionally dominant karstic lithology. Third, a range of Maya landscape modifications and engineering practices enabled the preservation and protection of soils within urban environments. We derive evidence-based insights on an urban tradition that endured for well over two millennia by incorporating intensive soil–society relationships to substantiate the concept of soil connectivity. Inspiring urban planning to stimulate soil connectivity through enhancing the engagement with soils in urban life would promote soil security.
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| 5. |
- Isendahl, Christian, 1965, et al.
(författare)
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Growth and decline of a sustainable city: A multitemporal perspective on blue-black-green infrastructures at the pre-Columbian Lowland Maya city of Tikal
- 2024
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Ingår i: URBAN STUDIES. - 0042-0980 .- 1360-063X.
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Tidskriftsartikel (refereegranskat)abstract
- The New Urban Agenda's call for long-term visions in urban planning fails to recognise that 'long-term' implies different longevities depending on context of assessment. Compared to other social sciences, archaeological approaches add rigour to envisioning urban sustainability over several centuries and millennia. The archaeology of the pre-Columbian Lowland Maya urban tradition is an interesting case because data have been used to support conflicting arguments about Maya urban sustainability. We suggest that these contradictions can be partly explained by: (1) sustainability being ambiguously defined, (2) subsets of the urban system being expected to indicate the behaviour of other subsets or of the entire system, and (3) processes being evaluated using different timescales. Drawing on 1500 years of urban history at Tikal, this paper examines how archaeological perspectives add depth of reflection and unfold critical assumptions of the meaning of 'long-term' and 'sustainability' concealed in self-explanatory notions. We outline the development and longevity of urban settlement at Tikal and analyse the blue-black-green (water, soil, vegetation) infrastructures that sustained urban metabolism and sponsored basic urban functions. Our analyses contribute new insights on the challenges associated with future sustainability transitions over varying temporal scales. The diversity of past and present urban systems and infrastructural initiatives cannot be fitted within a single narrative of urban sustainability, however, and much research is required to examine how blue-black-green infrastructures can support transformative change of aggregated human population zones struggling with potable water scarcity, soil degradation, and habitat and biodiversity loss.
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