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| 2. |
- Anney, R. J. L., et al.
(författare)
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Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia
- 2017
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Ingår i: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) < 1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P= 9 x10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental- related genes such as EXT1, ASTN2, MACROD2, and HDAC4.
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| 3. |
- Weiner, D. J., et al.
(författare)
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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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| 4. |
- Block, Keith I., et al.
(författare)
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Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
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Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
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Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
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- Journeau, C., et al.
(författare)
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Safest roadmap for corium experimental research in Europe
- 2018
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Ingår i: ASCE-ASME J of Risk & Uncertainty in Engineering Systems Part B. - : ASME Press. - 2332-9017 .- 2332-9025. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- Severe accident facilities for European safety targets (SAFEST) is a European project networking the European experimental laboratories focused on the investigation of a nuclear power plant (NPP) severe accident (SA) with reactor core melting and formation of hazardous material system known as corium. The main objective of the project is to establish coordinated activities, enabling the development of a common vision and severe accident research roadmaps for the next years, and of the management structure to achieve these goals. In this frame, a European roadmap on severe accident experimental research has been developed to define research challenges to contribute to further reinforcement of Gen II and III NPP safety. The roadmap takes into account different SA phenomena and issues identified and prioritized in the analyses of severe accidents at commercial NPPs and in the results of the recent European stress tests carried out after the Fukushima accident. Nineteen relevant issues related to reactor core meltdown accidents have been selected during these efforts. These issues have been compared to a survey of the European SA research experimental facilities and corium analysis laboratories. Finally, the coherence between European infrastructures and R&D needs has been assessed and a table linking issues and infrastructures has been derived. The comparison shows certain important lacks in SA research infrastructures in Europe, especially in the domains of core late reflooding impact on source term, reactor pressure vessel failure and molten core release modes, spent fuel pool (SFP) accidents, as well as the need for a large-scale experimental facility operating with up to 500 kg of chemically prototypic corium melt.
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| 6. |
- Kortekaas Krohn, I., et al.
(författare)
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Emerging roles of innate lymphoid cells in inflammatory diseases : Clinical implications
- 2018
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Ingår i: Allergy: European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 73:4, s. 837-850
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Forskningsöversikt (refereegranskat)abstract
- Innate lymphoid cells (ILC) represent a group of lymphocytes that lack specific antigen receptors and are relatively rare as compared to adaptive lymphocytes. ILCs play important roles in allergic and nonallergic inflammatory diseases due to their location at barrier surfaces within the airways, gut, and skin, and they respond to cytokines produced by activated cells in their local environment. Innate lymphoid cells contribute to the immune response by the release of cytokines and other mediators, forming a link between innate and adaptive immunity. In recent years, these cells have been extensively characterized and their role in animal models of disease has been investigated. Data to translate the relevance of ILCs in human pathology, and the potential role of ILCs in diagnosis, as biomarkers and/or as future treatment targets are also emerging. This review, produced by a task force of the Immunology Section of the European Academy of Allergy and Clinical Immunology (EAACI), encompassing clinicians and researchers, highlights the role of ILCs in human allergic and nonallergic diseases in the airways, gastrointestinal tract, and skin, with a focus on new insights into clinical implications, therapeutic options, and future research opportunities.
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| 8. |
- Basu Bal, Abhinayan, 1980, et al.
(författare)
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International Single Window Environment: Prospects and Challenges.
- 2017
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Ingår i: ADBI Working Papers.
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Konferensbidrag (refereegranskat)abstract
- Efforts of various international institutions have supported implementation of national/regional single windows and the next logical step would be to internationalize and make them interoperable to allow for greater collaborative information sharing. The purpose of this paper is to review the legal framework necessary for implementing international single window environment (ISWE) and, in that context, examine particular economic and financial aspects of the current developments. The discussion shows that ISWE is desirable as it may contribute towards creating a level playing field for SMEs participating in global supply chains. The paper discusses ASEAN Single Window to identify prospects and challenges, and highlight the legal and economic viability of interoperability. ASW is examined from transaction cost and information asymmetry theory perspectives to provide a methodology for conducting empirical analysis at country-level. Based on the findings the paper argues that full potential of ISWE can be realised through integration of transport and commercial requirements thereby improving G2G, B2G and B2B information flows. Nevertheless, such integration would require the ability to capture the complex relationships between various transport actors from legal and technical standpoints. To illustrate this legal complexity from transport and e-commerce law angle, the disadvantageous position of SMEs vis-à-vis use of electronic bills of lading and access to supply chain finance is examined. A critical analysis of selected legal texts is made through the lens of recent developments such as distributed ledger and cloud technologies to suggest solutions for SMEs. The conclusion highlights that transport and commercial requirements in the ISWE has to be incorporated through laws made for e-commerce and not through a piecemeal approach that replicate the functions of paper documents in an electronic environment.
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