| 1. |
- Ge, Changrong, et al.
(author)
-
Key interactions in the trimolecular complex consisting of the rheumatoid arthritis-associated DRB1*04:01 molecule, the major glycosylated collagen II peptide and the T-cell receptor
- 2022
-
In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 81:4, s. 480-489
-
Journal article (peer-reviewed)abstract
- Objectives Rheumatoid arthritis (RA) is an autoimmune disease strongly associated with the major histocompatibility complex (MHC) class II allele DRB1*04:01, which encodes a protein that binds self-peptides for presentation to T cells. This study characterises the autoantigen-presenting function of DRB1*04:01 (HLA-DRA*01:01/HLA-DRB1*04:01) at a molecular level for prototypic T-cell determinants, focusing on a post-translationally modified collagen type II (Col2)-derived peptide.Methods The crystal structures of DRB1*04:01 molecules in complex with the peptides HSP70(289-306), citrullinated CILP982-996 and galactosylated Col2(259-273) were determined on cocrystallisation. T cells specific for Col2(259-273) were investigated in peripheral blood mononuclear cells from patients with DRB1*04:01-positive RA by cytofluorometric detection of the activation marker CD154 on peptide stimulation and binding of fluorescent DRB1*0401/Col2(259-273) tetramer complexes. The cDNAs encoding the T-cell receptor (TCR) alpha-chains and beta-chains were cloned from single-cell sorted tetramer-positive T cells and transferred via a lentiviral vector into TCR-deficient Jurkat 76 cells.Results The crystal structures identified peptide binding to DRB1*04:01 and potential side chain exposure to T cells. The main TCR recognition sites in Col2(259-273) were lysine residues that can be galactosylated. RA T-cell responses to DRB1*04:01-presented Col2(259-273) were dependent on peptide galactosylation at lysine 264. Dynamic molecular modelling of a functionally characterised Col2(259-273)-specific TCR complexed with DRB1*04:01/Col2(259-273) provided evidence for differential allosteric T-cell recognition of glycosylated lysine 264.Conclusions The MHC-peptide-TCR interactions elucidated in our study provide new molecular insights into recognition of a post-translationally modified RA T-cell determinant with a known dominant role in arthritogenic and tolerogenic responses in murine Col2-induced arthritis.
|
|
| 2. |
- Bertl, Kristina, et al.
(author)
-
A survey on oral health-related standard of care for head and neck cancer patients in the EU
- 2023
-
In: Oral Diseases. - : John Wiley & Sons. - 1354-523X .- 1601-0825.
-
Journal article (peer-reviewed)abstract
- Objective: To map oral health-related standard of care in the context of head and neck cancer (HNC) treatment across the European Union (EU).Materials and Methods: Six hundred and ninety centers across the European Union were contacted. The questionnaire contained questions focusing on the team/department structure, HNC treatment planning routines, and assessment and handling of dental treatment needs prior to cancer treatment.Results: Eighty-seven centers across the EU responded. Department structure and number of HNC patients treated per year varied widely and dental professionals are included as part of the team in about 25% of the centers. Standard of care, in terms of dental assessment and preventive dentistry routines, such as recording an orthopantomogram, offering dental treatment, and providing a radiation protection splint and splint for fluoride application, differed significantly among the European regions. Independent of the region, these aspects are positively affected if dental professionals are part of the interdisciplinary treatment team and if dental treatment is offered within the center.Conclusion: Dental professionals are still only to a very limited extent included in interdisciplinary treatment planning teams of HNC patients. However, their inclusion and/or offering dental treatment within the same hospital/center appears to improve oral health-related standard of care.Clinical Relevance: Inclusion of dental professionals in treatment planning teams of HNC patients appears to improve oral health-related standard of care within HNC treatment.
|
|
| 3. |
- Furthner, Dieter, et al.
(author)
-
Single Point Insulin Sensitivity Estimator in Pediatric Non-Alcoholic Fatty Liver Disease
- 2022
-
In: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 13
-
Journal article (peer-reviewed)abstract
- BackgroundAttenuated insulin-sensitivity (IS) is a central feature of pediatric non-alcoholic fatty liver disease (NAFLD). We recently developed a new index, single point insulin sensitivity estimator (SPISE), based on triglycerides, high-density-lipoprotein and body-mass-index (BMI), and validated by euglycemic-hyperinsulinemic clamp-test (EHCT) in adolescents. This study aims to assess the performance of SPISE as an estimation of hepatic insulin (in-)sensitivity. Our results introduce SPISE as a novel and inexpensive index of hepatic insulin resistance, superior to established indices in children and adolescents with obesity. Materials and MethodsNinety-nine pubertal subjects with obesity (13.5 +/- 2.0 years, 59.6% males, overall mean BMI-SDS + 2.8 +/- 0.6) were stratified by MRI (magnetic resonance imaging) into a NAFLD (>5% liver-fat-content; male n=41, female n=16) and non-NAFLD (<= 5%; male n=18, female n=24) group. Obesity was defined according to WHO criteria (> 2 BMI-SDS). EHCT were used to determine IS in a subgroup (n=17). Receiver-operating-characteristic (ROC)-curve was performed for diagnostic ability of SPISE, HOMA-IR (homeostatic model assessment for insulin resistance), and HIRI (hepatic insulin resistance index), assuming null hypothesis of no difference in area-under-the-curve (AUC) at 0.5. ResultsSPISE was lower in NAFLD (male: 4.8 +/- 1.2, female: 4.5 +/- 1.1) than in non-NAFLD group (male 6.0 +/- 1.6, female 5.6 +/- 1.5; P< 0.05 {95% confidence interval [CI]: male NAFLD 4.5, 5.2; male non-NAFLD 5.2, 6.8; female NAFLD 4.0, 5.1, female non-NAFLD 5.0, 6.2}). In males, ROC-AUC was 0.71 for SPISE (P=0.006, 95% CI: 0.54, 0.87), 0.68 for HOMA-IR (P=0.038, 95% CI: 0.48, 0.88), and 0.50 for HIRI (P=0.543, 95% CI: 0.27, 0.74). In females, ROC-AUC was 0.74 for SPISE (P=0.006), 0.59 for HOMA-IR (P=0.214), and 0.68 for HIRI (P=0.072). The optimal cutoff-level for SPISE between NAFLD and non-NAFLD patients was 5.18 overall (Youden-index: 0.35; sensitivity 0.68%, specificity 0.67%). ConclusionSPISE is significantly lower in juvenile patients with obesity-associated NAFLD. Our results suggest that SPISE indicates hepatic IR in pediatric NAFLD patients with sensitivity and specificity superior to established indices of hepatic IR.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Jansen, Iris E, et al.
(author)
-
Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
-
In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
-
Journal article (peer-reviewed)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
|
|
| 7. |
- Johansen, Johanna, et al.
(author)
-
A multidisciplinary definition of privacy labels
- 2022
-
In: Information and Computer Security. - : Emerald Group Publishing Limited. - 2056-4961. ; 30:3, s. 452-469
-
Journal article (peer-reviewed)abstract
- Purpose This paper aims to present arguments about how a complex concept of privacy labeling can be a solution to the current state of privacy. Design/methodology/approach The authors give a precise definition of Privacy Labeling (PL), painting a panoptic portrait from seven different perspectives: Business, Legal, Regulatory, Usability and Human Factors, Educative, Technological and Multidisciplinary. They describe a common vision, proposing several important "traits of character" of PL as well as identifying "undeveloped potentialities", i.e. open problems on which the community can focus. Findings This position paper identifies the stakeholders of the PL and their needs with regard to privacy, describing how PL should be and look like to address these needs. Main aspects considered are the PL's educational power to change people's knowledge of privacy, tools useful for constructing PL and the possible visual appearances of PL. They also identify how the present landscape of privacy certifications could be improved by PL. Originality/value The authors adopt a multidisciplinary approach to defining PL as well as give guidelines in the form of goals, characteristics, open problems, starting points and a roadmap for creating the ideal PL.
|
|
| 8. |
- Kattge, Jens, et al.
(author)
-
TRY plant trait database - enhanced coverage and open access
- 2020
-
In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
-
Journal article (peer-reviewed)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
|
|
| 9. |
- Mueller, Stefanie H., et al.
(author)
-
Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
-
In: Genome Medicine. - : BioMed Central (BMC). - 1756-994X .- 1756-994X. ; 15
-
Journal article (peer-reviewed)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
|
|
| 10. |
|
|
