| 1. |
- Fenstermacher, M.E., et al.
(author)
-
DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
-
In: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
-
Journal article (peer-reviewed)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
|
|
| 2. |
|
|
| 3. |
- Weiner, D. J., et al.
(author)
-
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
-
Journal article (peer-reviewed)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.
|
|
| 4. |
- Anney, R. J. L., et al.
(author)
-
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
-
In: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 8
-
Journal article (peer-reviewed)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.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Thorleifsson, Gudmar, et al.
(author)
-
Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma
- 2010
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:10, s. 906-909
-
Journal article (peer-reviewed)abstract
- We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[ A], odds ratio (OR) = 1.36, P = 5.0 x 10(-10)). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.
|
|
| 9. |
- Casey, Jillian P, et al.
(author)
-
A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
-
In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
-
Journal article (peer-reviewed)abstract
- Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
|
|
| 10. |
|
|
| 11. |
- Pinto, Dalila, et al.
(author)
-
Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.
- 2014
-
In: American journal of human genetics. - : Elsevier BV. - 1537-6605 .- 0002-9297. ; 94:5, s. 677-694
-
Journal article (peer-reviewed)abstract
- Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0× 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7× 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
|
|
| 12. |
- Anney, Richard, et al.
(author)
-
A genome-wide scan for common alleles affecting risk for autism.
- 2010
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
-
Journal article (peer-reviewed)abstract
- Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
|
|
| 13. |
- Ennis, G. E., et al.
(author)
-
Insulin resistance is related to cognitive decline but not change in CSF biomarkers of Alzheimer's disease in non-demented adults
- 2021
-
In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 13:1
-
Journal article (peer-reviewed)abstract
- Introduction We investigated whether insulin resistance (IR) was associated with longitudinal age-related change in cognition and biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration in middle-aged and older adults who were non-demented at baseline. Methods IR was measured with homeostatic model assessment of insulin resistance (HOMA2-IR). Core AD-related cerebrospinal fluid (CSF) biomarkers and cognition were assessed, respectively, on n = 212 (1 to 5 visits) and n = 1299 (1 to 6 visits). Linear mixed models tested whether HOMA2-IR moderated age-related change in CSF biomarkers and cognition. Linear regressions tested whether HOMA2-IR x apolipoprotein E epsilon 4 allele (APOE epsilon 4) carrier status predicted amyloid beta [A beta] chronicity (estimated duration of amyloid positron emission tomography [PET] positivity) (n = 253). Results Higher HOMA2-IR was associated with greater cognitive decline but not with changes in CSF biomarkers. HOMA2-IR x APOE4 was not related to A beta chronicity but was significantly associated with CSF phosphorylated tau (P-tau)(181)/A beta(42) level. Discussion In non-demented adults IR may not be directly associated with age-related change in AD biomarkers. Additional research is needed to determine mechanisms linking IR to cognitive decline.
|
|
| 14. |
- Panyard, D. J., et al.
(author)
-
Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease
- 2023
-
In: Alzheimers & Dementia. - 1552-5260.
-
Journal article (peer-reviewed)abstract
- INTRODUCTIONA hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODSWe conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTSWe identified 61 proteins significantly associated with the AT category (P < 5.46 x 10(-5)) and 636 significant protein-biomarker associations (P < 6.07 x 10(-6)). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSIONThese results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTSCerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing.Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins.Key glucose/carbon metabolism protein associations independently replicated.CSF proteome outperformed other omics data in predicting amyloid/tau positivity.CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.
|
|
| 15. |
|
|
| 16. |
- Pinto, Dalila, et al.
(author)
-
Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
-
Journal article (peer-reviewed)abstract
- The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
|
|
| 17. |
|
|
| 18. |
- Anney, Richard, et al.
(author)
-
Individual common variants exert weak effects on the risk for autism spectrum disorders.
- 2012
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:21, s. 4781-92
-
Journal article (peer-reviewed)abstract
- While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
|
|
| 19. |
- Berg, Frenk van den, et al.
(author)
-
How the EU project “Online Microstructure Analytics” advances inline sensing of microstructure during steel manufacturing
- 2023
-
In: Research and Review Journal of Nondestructive Testing (ReJNDT). - Lisabon : NDT.net GmbH & Co. KG. - 2941-4989. ; 1:1
-
Journal article (peer-reviewed)abstract
- Weight savings in mobility and transport are mandatory in order to reduce CO2 emissions and energy consumption. The steel industry offers weight saving solutions by a growing portfolio of Advanced High Strength Steel (AHSS) products. AHSS owe their strength to their largely refined and complex microstructures, containing multiple metallurgical phases. Optimal control of the thermo-mechanical processing of AHSS requires inline sensors for real-time monitoring of evolution and consistency of microstructure and material properties.
|
|
| 20. |
- Chiavassa, A., et al.
(author)
-
Optical interferometry and Gaia measurement uncertainties reveal the physics of asymptotic giant branch stars
- 2020
-
In: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 640
-
Journal article (peer-reviewed)abstract
- Context. Asymptotic giant branch (AGB) stars are cool luminous evolved stars that are well observable across the Galaxy and populating Gaia data. They have complex stellar surface dynamics, which amplifies the uncertainties on stellar parameters and distances.Aims. On the AGB star CL Lac, it has been shown that the convection-related variability accounts for a substantial part of the Gaia DR2 parallax error. We observed this star with the MIRC-X beam combiner installed at the CHARA interferometer to detect the presence of stellar surface inhomogeneities.Methods. We performed the reconstruction of aperture synthesis images from the interferometric observations at different wavelengths. Then, we used 3D radiative hydrodynamics (RHD) simulations of stellar convection with CO5BOLD and the post-processing radiative transfer code OPTIM3D to compute intensity maps in the spectral channels of MIRC-X observations. Then, we determined the stellar radius using the average 3D intensity profile and, finally, compared the 3D synthetic maps to the reconstructed ones focusing on matching the intensity contrast, the morphology of stellar surface structures, and the photocentre position at two different spectral channels, 1.52 and 1.70 mu m, simultaneously.Results. We measured the apparent diameter of CL Lac at two wavelengths (3.299 0.005 mas and 3.053 +/- 0.006 mas at 1.52 and 1.70 mu m, respectively) and recovered the radius (R = 307 +/- 41 and R = 284 +/- 38 R-circle dot) using a Gaia parallax. In addition to this, the reconstructed images are characterised by the presence of a brighter area that largely affects the position of the photocentre. The comparison with 3D simulation shows good agreement with the observations both in terms of contrast and surface structure morphology, meaning that our model is adequate for explaining the observed inhomogenities.Conclusions. This work confirms the presence of convection-related surface structures on an AGB star of Gaia DR2. Our result will help us to take a step forward in exploiting Gaia measurement uncertainties to extract the fundamental properties of AGB stars using appropriate RHD simulations.
|
|
| 21. |
- Erickson, Pontus, et al.
(author)
-
Prevalence and Clinical Implications of a β-Amyloid-Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease.
- 2023
-
In: JAMA neurology. - 2168-6157. ; 80:9, s. 969-979
-
Journal article (peer-reviewed)abstract
- Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile.To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications.This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023.Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240).Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET.A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile.Results suggest that the CSF A-T+ biomarker profile was found inapproximately5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.
|
|
| 22. |
- Potts, C., et al.
(author)
-
Chatbots to Support Mental Wellbeing of People Living in Rural Areas: Can User Groups Contribute to Co-design?
- 2021
-
In: Journal of Technology in Behavioral Science. - : Springer. - 2366-5963. ; 6, s. 652-665
-
Journal article (peer-reviewed)abstract
- Digital technologies such as chatbots can be used in the field of mental health. In particular, chatbots can be used to support citizens living in sparsely populated areas who face problems such as poor access to mental health services, lack of 24/7 support, barriers to engagement, lack of age appropriate support and reductions in health budgets. The aim of this study was to establish if user groups can design content for a chatbot to support the mental wellbeing of individuals in rural areas. University students and staff, mental health professionals and mental health service users (N = 78 total) were recruited to workshops across Northern Ireland, Ireland, Scotland, Finland and Sweden. The findings revealed that participants wanted a positive chatbot that was able to listen, support, inform and build a rapport with users. Gamification could be used within the chatbot to increase user engagement and retention. Content within the chatbot could include validated mental health scales and appropriate response triggers, such as signposting to external resources should the user disclose potentially harmful information or suicidal intent. Overall, the workshop participants identified user needs which can be transformed into chatbot requirements. Responsible design of mental healthcare chatbots should consider what users want or need, but also what chatbot features artificial intelligence can competently facilitate and which features mental health professionals would endorse.
|
|
| 23. |
|
|
| 24. |
- Sun, J., et al.
(author)
-
Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation
- 2009
-
In: Circulation. - 0009-7322 .- 1524-4539. ; 120:11, s. 973-982
-
Journal article (peer-reviewed)abstract
- Mast cell chymase may participate in the pathogenesis of human abdominal aortic aneurysm (AAA), yet a direct contribution of this serine protease to AAA formation remains unknown. METHODS AND RESULTS: Human AAA lesions had high numbers of chymase-immunoreactive mast cells. Serum chymase level correlated with AAA growth rate (P=0.009) in a prospective clinical study. In experimental AAA produced by aortic elastase perfusion in wild-type (WT) mice or those deficient in the chymase ortholog mouse mast cell protease-4 (mMCP-4) or deficient in mMCP-5 (Mcpt4(-/-), Mcpt5(-/-)), Mcpt4(-/-) but not Mcpt5(-/-) had reduced AAA formation 14 days after elastase perfusion. Even 8 weeks after perfusion, aortic expansion in Mcpt4(-/-) mice fell by 50% compared with that of the WT mice (P=0.0003). AAA lesions in Mcpt4(-/-) mice had fewer inflammatory cells and less apoptosis, angiogenesis, and elastin fragmentation than those of WT mice. Although Kit(W-sh/W-sh) mice had protection from AAA formation, reconstitution with mast cells from WT mice, but not those from Mcpt4(-/-) mice, partially restored the AAA phenotype. Mechanistic studies suggested that mMCP-4 regulates expression and activation of cysteine protease cathepsins, elastin degradation, angiogenesis, and vascular cell apoptosis. CONCLUSIONS: High chymase-positive mast cell content in human AAA lesions, greatly reduced AAA formation in Mcpt4(-/-) mice, and significant correlation of serum chymase levels with human AAA expansion rate suggests participation of mast cell chymase in the progression of human and mouse AAA.
|
|
