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| 8. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 9. |
- Park, J, et al.
(author)
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Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?
- 2021
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In: Cancers. - : MDPI AG. - 2072-6694. ; 13:10
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Journal article (peer-reviewed)abstract
- In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
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| 16. |
- Chung, SH, et al.
(author)
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Risk factors for mortality in diabetic peritoneal dialysis patients
- 2010
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In: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 25:11, s. 3742-3748
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Journal article (peer-reviewed)
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| 17. |
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| 18. |
- Kang, JS, et al.
(author)
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Risk prediction for malignant intraductal papillary mucinous neoplasm of the pancreas: logistic regression versus machine learning
- 2020
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 20140-
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Journal article (peer-reviewed)abstract
- Most models for predicting malignant pancreatic intraductal papillary mucinous neoplasms were developed based on logistic regression (LR) analysis. Our study aimed to develop risk prediction models using machine learning (ML) and LR techniques and compare their performances. This was a multinational, multi-institutional, retrospective study. Clinical variables including age, sex, main duct diameter, cyst size, mural nodule, and tumour location were factors considered for model development (MD). After the division into a MD set and a test set (2:1), the best ML and LR models were developed by training with the MD set using a tenfold cross validation. The test area under the receiver operating curves (AUCs) of the two models were calculated using an independent test set. A total of 3,708 patients were included. The stacked ensemble algorithm in the ML model and variable combinations containing all variables in the LR model were the most chosen during 200 repetitions. After 200 repetitions, the mean AUCs of the ML and LR models were comparable (0.725 vs. 0.725). The performances of the ML and LR models were comparable. The LR model was more practical than ML counterpart, because of its convenience in clinical use and simple interpretability.
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| 21. |
- Zhu, RJ, et al.
(author)
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Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms
- 2021
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In: Cell research. - : Springer Science and Business Media LLC. - 1748-7838 .- 1001-0602. ; 31:12, s. 1244-1262
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Journal article (peer-reviewed)abstract
- The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors — CX3CR1 and L-selectin — were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.
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| 22. |
- Aad, G, et al.
(author)
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- 2015
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swepub:Mat__t
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| 23. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 24. |
- Abel, I, et al.
(author)
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Overview of the JET results with the ITER-like wall
- 2013
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In: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10, s. 104002-
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Journal article (peer-reviewed)abstract
- Following the completion in May 2011 of the shutdown for the installation of the beryllium wall and the tungsten divertor, the first set of JET campaigns have addressed the investigation of the retention properties and the development of operational scenarios with the new plasma-facing materials. The large reduction in the carbon content (more than a factor ten) led to a much lower Z(eff) (1.2-1.4) during L- and H-mode plasmas, and radiation during the burn-through phase of the plasma initiation with the consequence that breakdown failures are almost absent. Gas balance experiments have shown that the fuel retention rate with the new wall is substantially reduced with respect to the C wall. The re-establishment of the baseline H-mode and hybrid scenarios compatible with the new wall has required an optimization of the control of metallic impurity sources and heat loads. Stable type-I ELMy H-mode regimes with H-98,H-y2 close to 1 and beta(N) similar to 1.6 have been achieved using gas injection. ELM frequency is a key factor for the control of the metallic impurity accumulation. Pedestal temperatures tend to be lower with the new wall, leading to reduced confinement, but nitrogen seeding restores high pedestal temperatures and confinement. Compared with the carbon wall, major disruptions with the new wall show a lower radiated power and a slower current quench. The higher heat loads on Be wall plasma-facing components due to lower radiation made the routine use of massive gas injection for disruption mitigation essential.
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| 28. |
- Chen, DS, et al.
(author)
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Single cell atlas for 11 non-model mammals, reptiles and birds
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 7083-
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Journal article (peer-reviewed)abstract
- The availability of viral entry factors is a prerequisite for the cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Large-scale single-cell screening of animal cells could reveal the expression patterns of viral entry genes in different hosts. However, such exploration for SARS-CoV-2 remains limited. Here, we perform single-nucleus RNA sequencing for 11 non-model species, including pets (cat, dog, hamster, and lizard), livestock (goat and rabbit), poultry (duck and pigeon), and wildlife (pangolin, tiger, and deer), and investigated the co-expression of ACE2 and TMPRSS2. Furthermore, cross-species analysis of the lung cell atlas of the studied mammals, reptiles, and birds reveals core developmental programs, critical connectomes, and conserved regulatory circuits among these evolutionarily distant species. Overall, our work provides a compendium of gene expression profiles for non-model animals, which could be employed to identify potential SARS-CoV-2 target cells and putative zoonotic reservoirs.
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| 29. |
- Chung, SH, et al.
(author)
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Impact of incremental risk factors on peritoneal dialysis patient survival: proposal of a simplified clinical mortality risk score
- 2009
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In: Blood purification. - : S. Karger AG. - 1421-9735 .- 0253-5068. ; 27:2, s. 165-171
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Journal article (peer-reviewed)abstract
- <i>Background/Aim:</i> Peritoneal dialysis (PD) patient survival is influenced by many factors and there is no consensus on the relative importance of these predictors, independently or combined. This study was designed to evaluate how these independent factors, alone or in various combinations, may influence PD patient survival. <i>Methods:</i> A peritoneal equilibration test, subjective global assessment (SGA), and comorbid diseases (CMD) were assessed. <i>Results:</i> On multivariate analysis, age (>60 years), CMD, malnutrition, and low RRF (≤2 ml/min) were independent predictors of mortality. Three-year patient survival was 100, 95, 75, 49, and 0%, and the risk ratio for mortality was 1.0, 6.6, 21.9, and 85.9 in patients with none, one, two, three, and four of these risk factors, respectively. <i>Conclusions:</i> The combination of independent predictors of mortality in PD patients leads to a markedly increasing risk for mortality. Evaluation of a single risk factor underestimates the true impact of risk factors.
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| 38. |
- Han, W, et al.
(author)
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Trends in live births in the past 20 years in Zhengzhou, China
- 2011
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In: ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA. - 0001-6349. ; 90:4, s. 332-337
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Journal article (peer-reviewed)abstract
- Abstract: Objective. To evaluate changing trends in neonatal births and deaths in a provincial women's and children's hospital over the past 20 years. Design: Retrospective longitudinal study. Setting. Henan Provincial Women's and Children's Hospital, China. Population. Live births in Henan Provincial Women's and Children's Hospital from January 1987 to December 2006. Methods: Data was stratified by sex, birth weight, delivery type, maternal age, gestational age, and single or multiple births. The incidence of low Apgar scores and neonatal death was calculated for each fiscal year. Main outcome measures: Trends in the fundamental status of hospital-born live births and risk factors for neonatal death. Results. 26 760 hospital live births were included. The ratio of males to females was 1.16:1. The mean gestational age decreased from 39.5 +/- 1.4 weeks to 38.4 +/- 2.5 weeks (p<0.001) and multiple births increased from 1.5 to 7.3% (p<0.001). The proportion of preterm births increased from 4.7 to 18.9% (p<0.001), maternal age increased from 25.9 +/- 3.7 years to 29.0 +/- 4.4 years (p<0.001), and cesarean deliveries increased from 23.7 to 65.5% (p<0.001). The incidence of low Apgar scores decreased from 12.9 to 1.1% (p<0.001). The incidence of neonatal death was 8.5/1 000 live births, with preterm births and low Apgar scores accounting for 72.8 and 16.2% of all neonatal deaths, respectively. Conclusion. Preterm births, multiple births, and cesarean deliveries increased dramatically. Preterm birth is the leading cause of neonatal death.
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| 40. |
- Kim, DI, et al.
(author)
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PRMT3 regulates hepatic lipogenesis through direct interaction with LXRα
- 2015
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 64:1, s. 60-71
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Journal article (peer-reviewed)abstract
- Arginine methylation is responsible for diverse biological functions and is mediated by protein arginine methyltransferases (PRMTs). Nonalcoholic fatty liver disease (NAFLD) is accompanied by excessive hepatic lipogenesis via liver X receptor α (LXRα). Thus we examined the pathophysiological role of PRMTs in NAFLD and their relationship with LXRα. In this study, palmitic acid (PA) treatment increased PRMT3, which is correlated with the elevation of hepatic lipogenic proteins. The expression of lipogenic proteins was increased by PRMT3 overexpression, but decreased by PRMT3 silencing and use of the PRMT3 knockout (KO) mouse embryonic fibroblast cell line. PRMT3 also increased the transcriptional activity of LXRα by directly binding with LXRα in a methylation-independent manner. In addition, PA treatment translocated PRMT3 to the nucleus. In animal models, a high-fat diet increased the LXRα and PRMT3 expressions and binding, which was not observed in LXRα KO mice. Furthermore, increased PRMT3 expression and its binding with LXRα were observed in NAFLD patients. Taken together, LXRα and PRMT3 expression was increased in cellular and mouse models of NAFLD and human patients, and PRMT3 translocated into the nucleus bound with LXRα as a transcriptional cofactor, which induced lipogenesis. In conclusion, PRMT3 translocation by PA is coupled to the binding of LXRα, which is responsible for the onset of fatty liver.
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| 46. |
- Ogishi, M, et al.
(author)
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Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency
- 2022
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:10
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Journal article (peer-reviewed)abstract
- Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
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| 47. |
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| 48. |
- Pulit, SL, et al.
(author)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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In: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Journal article (peer-reviewed)abstract
- The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 49. |
- Romanelli, F, et al.
(author)
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Overview of the JET results
- 2011
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In: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 51:9
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Journal article (peer-reviewed)abstract
- Since the last IAEA Conference JET has been in operation for one year with a programmatic focus on the qualification of ITER operating scenarios, the consolidation of ITER design choices and preparation for plasma operation with the ITER-like wall presently being installed in JET. Good progress has been achieved, including stationary ELMy H-mode operation at 4.5 MA. The high confinement hybrid scenario has been extended to high triangularity, lower ρ*and to pulse lengths comparable to the resistive time. The steady-state scenario has also been extended to lower ρ*and ν*and optimized to simultaneously achieve, under stationary conditions, ITER-like values of all other relevant normalized parameters. A dedicated helium campaign has allowed key aspects of plasma control and H-mode operation for the ITER non-activated phase to be evaluated. Effective sawtooth control by fast ions has been demonstrated with3He minority ICRH, a scenario with negligible minority current drive. Edge localized mode (ELM) control studies using external n = 1 and n = 2 perturbation fields have found a resonance effect in ELM frequency for specific q95values. Complete ELM suppression has, however, not been observed, even with an edge Chirikov parameter larger than 1. Pellet ELM pacing has been demonstrated and the minimum pellet size needed to trigger an ELM has been estimated. For both natural and mitigated ELMs a broadening of the divertor ELM-wetted area with increasing ELM size has been found. In disruption studies with massive gas injection up to 50% of the thermal energy could be radiated before, and 20% during, the thermal quench. Halo currents could be reduced by 60% and, using argon/deuterium and neon/deuterium gas mixtures, runaway electron generation could be avoided. Most objectives of the ITER-like ICRH antenna have been demonstrated; matching with closely packed straps, ELM resilience, scattering matrix arc detection and operation at high power density (6.2 MW m-2) and antenna strap voltages (42 kV). Coupling measurements are in very good agreement with TOPICA modelling. © 2011 IAEA, Vienna.
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| 50. |
- Sia, WR, et al.
(author)
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Exploring the Role of Innate Lymphocytes in the Immune System of Bats and Virus-Host Interactions
- 2022
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In: Viruses. - : MDPI AG. - 1999-4915. ; 14:1
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Journal article (peer-reviewed)abstract
- Bats are reservoirs of a large number of viruses of global public health significance, including the ancestral virus for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the causative agent of coronavirus disease 2019 (COVID-19). Although bats are natural carriers of multiple pathogenic viruses, they rarely display signs of disease. Recent insights suggest that bats have a more balanced host defense and tolerance system to viral infections that may be linked to the evolutionary adaptation to powered flight. Therefore, a deeper understanding of bat immune system may provide intervention strategies to prevent zoonotic disease transmission and to identify new therapeutic targets. Similar to other eutherian mammals, bats have both innate and adaptive immune systems that have evolved to detect and respond to invading pathogens. Bridging these two systems are innate lymphocytes, which are highly abundant within circulation and barrier tissues. These cells share the characteristics of both innate and adaptive immune cells and are poised to mount rapid effector responses. They are ideally suited as the first line of defense against early stages of viral infections. Here, we will focus on the current knowledge of innate lymphocytes in bats, their function, and their potential role in host–pathogen interactions. Moreover, given that studies into bat immune systems are often hindered by a lack of bat-specific research tools, we will discuss strategies that may aid future research in bat immunity, including the potential use of organoid models to delineate the interplay between innate lymphocytes, bat viruses, and host tolerance.
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