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| 3. |
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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- Bastard, P, et al.
(författare)
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Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs
- 2022
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Ingår i: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 78:7490, s. eabp8966-
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Tidskriftsartikel (refereegranskat)abstract
- Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.
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| 8. |
- 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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| 9. |
- 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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| 10. |
- Nguyen, Thanh N, et al.
(författare)
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Global Impact of the COVID-19 Pandemic on Stroke Volumes and Cerebrovascular Events: A 1-Year Follow-up.
- 2023
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Ingår i: Neurology. - 1526-632X. ; 100:4
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Tidskriftsartikel (refereegranskat)abstract
- Declines in stroke admission, IV thrombolysis (IVT), and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the effect of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), IVT, and mechanical thrombectomy over a 1-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020).We conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, IVT treatments, and mechanical thrombectomy procedures. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.There were 148,895 stroke admissions in the 1 year immediately before compared with 138,453 admissions during the 1-year pandemic, representing a 7% decline (95% CI [95% CI 7.1-6.9]; p < 0.0001). ICH volumes declined from 29,585 to 28,156 (4.8% [5.1-4.6]; p < 0.0001) and IVT volume from 24,584 to 23,077 (6.1% [6.4-5.8]; p < 0.0001). Larger declines were observed at high-volume compared with low-volume centers (all p < 0.0001). There was no significant change in mechanical thrombectomy volumes (0.7% [0.6-0.9]; p = 0.49). Stroke was diagnosed in 1.3% [1.31-1.38] of 406,792 COVID-19 hospitalizations. SARS-CoV-2 infection was present in 2.9% ([2.82-2.97], 5,656/195,539) of all stroke hospitalizations.There was a global decline and shift to lower-volume centers of stroke admission volumes, ICH volumes, and IVT volumes during the 1st year of the COVID-19 pandemic compared with the prior year. Mechanical thrombectomy volumes were preserved. These results suggest preservation in the stroke care of higher severity of disease through the first pandemic year.This study is registered under NCT04934020.
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| 11. |
- Van Dorsselaere, J. -P, et al.
(författare)
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Status of the SARNET network on severe accidents
- 2010
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Ingår i: International Congress on Advances in Nuclear Power Plants 2010, ICAPP 2010. - 9781617386435 ; , s. 1029-1043
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Konferensbidrag (refereegranskat)abstract
- After four and a half years of operation in the frame of the 6th Framework Programme (FP6) of the European Commission, SARNET (Severe Accidents Research NETwork of excellence) continues in the FP7 (project named SARNET2) from April 2009 for 4 years. Forty-one organisations from 21 countries network their capacities of research in order to resolve the most important remaining uncertainties and safety issues on severe accidents (SA) in existing and future water-cooled nuclear power plants (NPPs). It includes a large majority of the Europeanactors involved in SA research plus a few non-European important ones. The objective is to perform the common research programmes that have been defined in the network first phase and to continue to improve the common computer tools and methodologies for NPP safety assessment. It will consolidate the sustainable integration of the European SA research capacities. These research programmes concern essentially the six highest priority safety issues that were identified after ranking in the first phase of the network: in-vessel core coolability, molten-corium-concrete-interaction, fuel-coolant interaction, hydrogen mixing and combustion in containment, impact of oxidising conditions on source term, and iodine chemistry. The Joint Programme of Activities includes the following main tasks: Performing new experiments on the above mentioned issues andjointly analysing their results in order to elaborate a common understanding of the concerned physical phenomena; Continuing the development and assessment of the ASTEC integral computer code (jointly developed by IRSN and GRS to predict the NPP behaviour during a postulated SA), which capitalizes in terms of models the knowledge produced in the network. In particular efforts are being extended to its applicability to BWR and CANDU NPP types; Continuing the storage of the SA experimental results in a scientific database, based on the STRESA JRC tool; Promoting educational and training courses, ERMSAR (European Review Meeting on Severe Accident Research) international conferences (to be held once a year) and mobility of young researchers or students between the various European organisations. Some R&D results obtained in the first year of the project are presented, in particular: the VULCANO experiment done in CEA mid-2009 on molten-core-corium-interaction, and the release of the first version of the new ASTEC V2 series.
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| 12. |
- Albiol, T., et al.
(författare)
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SARNET : Severe accident research network of excellence
- 2010
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Ingår i: PROG NUCL ENERGY. - : Elsevier BV. ; , s. 2-10
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Konferensbidrag (refereegranskat)abstract
- Fifty-one organisations network in SARNET (Severe Accident Research NETwork of Excellence) their research capacities in order to resolve the most important pending issues for enhancing, with regard to Severe Accidents (SA). the safety of existing and future Nuclear Power Plants (NPPs). This project. co-funded by the European Commission (EC) under the 6th Framework Programme, has been defined in order to optimise the use of the available means and to constitute sustainable research groups in the European Union. SARNET tackles the fragmentation that may exist between the different national R&D programmes, in defining common research programmes and developing common computer tools and methodologies for safety assessment. SARNET comprises most of the organisations involved in SA research in Europe, plus Canada. To reach these objectives, all the organisations networked in SARNET contributed to a joint Programme of Activities, which consisted of: Implementation of an advanced communication tool for accessing all project information, fostering exchange of information, and managing documents: Harmonization and re-orientation of the research programmes, and definition of new ones; Analysis of the experimental results provided by research programmes in order to elaborate a common understanding of relevant phenomena; Development of the ASTEC code (integral computer code used to predict the NPP behaviour during a postulated SA), which capitalizes in terms of physical models the knowledge produced within SARNET; Development of Scientific Databases in which all the results of research programmes are stored in a common format (DATANET); Development of a common methodology for Probabilistic Safety Assessment of NPPs; Development of short courses and writing a textbook on Severe Accidents for students and researchers; Promotion of personnel mobility amongst various European organisations. This paper presents the major achievements after four and a half years of operation of the network, in terms of knowledge gained, of improvement of the ASTEC reference code, of dissemination of results and of integration of the research programmes conducted by the various partners. After this first period (2004-2008), co-funded by the EC, a further contract SARNET2 with the EC for the next four years started in April 2009 as part of the 7th Framework Programme. During this period, the networking activities will focus mainly on the remaining pending issues as determined during the first period, experimental activities will be directly included in the common work and the network will evolve toward complete self-sustainability. The bases for such an evolution are presented in the last part of the paper.
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| 13. |
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| 14. |
- 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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| 15. |
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| 16. |
- Forsby, A, et al.
(författare)
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Neuronal in vitro models for the estimation of acute systemic toxicity.
- 2009
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Ingår i: Toxicology in vitro : an international journal published in association with BIBRA. - : Elsevier BV. - 1879-3177. ; 23:8, s. 1564-1569
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Tidskriftsartikel (refereegranskat)abstract
- The objective of the EU funded integrated project "ACuteTox" is to develop a strategy in which general cytotoxicity, together with organ-specific endpoints and biokinetic features, are taken into consideration in the in vitro prediction of oral acute systemic toxicity. With regard to the nervous system, the effects of 23 reference chemicals were tested with approximately 50 endpoints, using a neuronal cell line, primary neuronal cell cultures, brain slices and aggregated brain cell cultures. Comparison of the in vitro neurotoxicity data with general cytotoxicity data generated in a non-neuronal cell line and with in vivo data such as acute human lethal blood concentration, revealed that GABA(A) receptor function, acetylcholine esterase activity, cell membrane potential, glucose uptake, total RNA expression and altered gene expression of NF-H, GFAP, MBP, HSP32 and caspase-3 were the best endpoints to use for further testing with 36 additional chemicals. The results of the second analysis showed that no single neuronal endpoint could give a perfect improvement in the in vitro-in vivo correlation, indicating that several specific endpoints need to be analysed and combined with biokinetic data to obtain the best correlation with in vivo acute toxicity.
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| 17. |
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| 18. |
- Nayak, Arun Kumar, et al.
(författare)
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A numerical and experimental study of water ingression phenomena in melt pool coolability
- 2009
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Ingår i: Nuclear Engineering and Design. - : Elsevier BV. - 0029-5493 .- 1872-759X. ; 239:7, s. 1285-1293
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Tidskriftsartikel (refereegranskat)abstract
- During a postulated severe accident, the core can melt and the melt can fail the reactor vessel. Subsequently, the molten corium can be relocated in the containment cavity forming a melt pool. The melt pool can be flooded with water at the top for quenching it. However, the question that arises is to what extent the water can ingress in the corium melt pool to cool and quench it. To reveal that, a numerical study has been carried out using the computer code MELCOOL The code considers the heat transfer behaviour in axial and radial directions from the molten pool to the overlaying water, crust generation and growth, thermal stresses built-in the crust, disintegration of crust into debris, natural convection heat transfer in debris and water ingression into the debris bed. To validate the computer code, experiments were conducted in a facility named as core melt coolability (COMECO). The facility consists of a test section (200 mm x 200 mm square cross-section) and with a height of 300 mm. About 14 L of melt comprising of 30% CaO + 70% B2O3 (by wt.) was poured into the test section. The melt was heated by four heaters from outside the test section to simulate the decay heat of corium. The melt was water flooded from the top, and the depth of water pool was kept constant at around 700 mm throughout the experiment. The transient temperature behaviour in the melt pool at different axial and radial locations was measured with 24 K-type thermocouples and the steam flow rate was measured using a vortex flow meter. The melt temperature measurements indicated that water could ingress only up to a certain depth into the melt pool. The MELCOOL predictions were compared with the test data for the temperature distribution inside the molten pool. The code was found to simulate the quenching behaviour and depth of water ingression quite well.
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| 19. |
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| 20. |
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| 21. |
- Van Dorsselaere, J. -P, et al.
(författare)
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Sustainable integration of EU research in severe accident phenomenology and management
- 2011
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Ingår i: Nuclear Engineering and Design. - : Elsevier BV. - 0029-5493. ; 241:9, s. 3451-3460
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Tidskriftsartikel (refereegranskat)abstract
- In order to optimise the use of the available means and to constitute sustainable research groups in the European Union, the Severe Accident Research NETwork of Excellence (SARNET) has gathered, between 2004 and 2008, 51 organizations representing most of the actors involved in severe accident (SA) research in Europe plus Canada. This project was co-funded by the European Commission (EC) under the 6th Euratom Framework Programme. Its objective was to resolve the most important pending issues for enhancing, in regard of SA, the safety of existing and future nuclear power plants (NPPs). SARNET tackled the fragmentation that existed between the national R&D programmes, in defining common research programmes and developing common computer codes and methodologies for safety assessment. The Joint Programme of Activities consisted in:Implementing an advanced communication tool for accessing all project information, fostering exchange of information, and managing documents;Harmonizing and re-orienting the research programmes, and defining new ones;Analyzing the experimental results provided by research programmes in order to elaborate a common understanding of relevant phenomena;Developing the ASTEC code (integral computer code used to predict the NPP behaviour during a postulated SA) by capitalizing in terms of physical models the knowledge produced within SARNET;Developing scientific databases, in which the results of research experimental programmes are stored in a common format;Developing a common methodology for probabilistic safety assessment of NPPs;Developing short courses and writing a text book on severe accidents for students and researchers;Promoting personnel mobility amongst various European organizations. This paper presents the major achievements after four and a half years of operation of the network, in terms of knowledge gained, of improvements of the ASTEC reference code, of dissemination of results and of integration of the research programmes conducted by the various partners. Most initial objectives were reached but the continuation of the SARNET network, co-funded by EC in the 7th Framework Programme (SARNET2 project that started in April 2009 for 4 years), will consolidate the first assets and focus mainly on the highest priority pending issues as determined during the first period. The objective will be also to make the network evolve towards a complete self-sustainability.
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