| 1. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 2. |
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| 3. |
- Jonsson, Lina, 1982, et al.
(författare)
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Characterisation of age and polarity at onset in bipolar disorder
- 2021
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Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
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Tidskriftsartikel (refereegranskat)abstract
- Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (beta = -0.34 years, s.e. = 0.08), major depression (beta = -0.34 years, s.e. = 0.08), schizophrenia (beta = -0.39 years, s.e. = 0.08), and educational attainment (beta = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
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| 4. |
- Tedersoo, L., et al.
(författare)
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The Global Soil Mycobiome consortium dataset for boosting fungal diversity research
- 2021
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Ingår i: Fungal Diversity. - : Springer Science and Business Media LLC. - 1560-2745 .- 1878-9129. ; 111, s. 573-588
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Tidskriftsartikel (refereegranskat)abstract
- Fungi are highly important biotic components of terrestrial ecosystems, but we still have a very limited understanding about their diversity and distribution. This data article releases a global soil fungal dataset of the Global Soil Mycobiome consortium (GSMc) to boost further research in fungal diversity, biogeography and macroecology. The dataset comprises 722,682 fungal operational taxonomic units (OTUs) derived from PacBio sequencing of full-length ITS and 18S-V9 variable regions from 3200 plots in 108 countries on all continents. The plots are supplied with geographical and edaphic metadata. The OTUs are taxonomically and functionally assigned to guilds and other functional groups. The entire dataset has been corrected by excluding chimeras, index-switch artefacts and potential contamination. The dataset is more inclusive in terms of geographical breadth and phylogenetic diversity of fungi than previously published data. The GSMc dataset is available over the PlutoF repository.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Tissot, C., et al.
(författare)
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The Association of Age-Related and Off-Target Retention with Longitudinal Quantification of 18F MK6240 Tau PET in Target Regions
- 2023
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 64:3, s. 452-459
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Tidskriftsartikel (refereegranskat)abstract
- 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F] MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stabil-ity of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off -target retention on the longitudinal quantification of [18F]MK6240 in tar-get regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzhei-mer disease spectrum with longitudinal [18F]MK6240 SUVs and SUV ratios (SUVRs) (mean +/- SD, 2.25 +/- 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [18F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 +/- 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-P-negative and tau-negative, 58.50 +/- 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associa-tions between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-P status, cross-sectionally and over time. [18F]MK6240 uptake significantly differed between CUY and CU adults in the puta-men or pallidum (affecting-75% of the region) and in the Braak II region (affecting-35%). Changes in meningeal and putamen or palli-dum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and sta-ble over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [18F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nev-ertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [18F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification.
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| 10. |
- Bethlehem, RAI, et al.
(författare)
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Brain charts for the human lifespan
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 604:7906, s. 525-
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Tidskriftsartikel (refereegranskat)abstract
- Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data (http://www.brainchart.io/). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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| 11. |
- Brevini, T, et al.
(författare)
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FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7950, s. 134-
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Tidskriftsartikel (refereegranskat)abstract
- Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Graham, N. S. N., et al.
(författare)
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Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury
- 2021
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:613
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Tidskriftsartikel (refereegranskat)abstract
- Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.
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| 17. |
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| 18. |
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| 19. |
- Bennett, S. A., et al.
(författare)
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Direct Determination of Fission-Barrier Heights Using Light-Ion Transfer in Inverse Kinematics
- 2023
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 130:20, s. 202501-
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate a new technique for obtaining fission data for nuclei away from β stability. These types of data are pertinent to the astrophysical r process, crucial to a complete understanding of the origin of the heavy elements, and for developing a predictive model of fission. These data are also important considerations for terrestrial applications related to power generation and safeguarding. Experimentally, such data are scarce due to the difficulties in producing the actinide targets of interest. The solenoidal-spectrometer technique, commonly used to study nucleon-transfer reactions in inverse kinematics, has been applied to the case of transfer-induced fission as a means to deduce the fission-barrier height, among other variables. The fission-barrier height of ^{239}U has been determined via the ^{238}U(d,pf) reaction in inverse kinematics, the results of which are consistent with existing neutron-induced fission data indicating the validity of the technique.
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| 20. |
- Graham, N., et al.
(författare)
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Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI
- 2024
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - 0022-3050. ; 95:4, s. 356-359
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundTraumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy.MethodsPlasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer's disease, with healthy controls.ResultsPlasma p-tau181 concentrations were significantly raised in patients with Alzheimer's disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates.ConclusionsPlasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration.
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| 21. |
- Ibanez, L., et al.
(författare)
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Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:7, s. 2394-2406
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Tidskriftsartikel (refereegranskat)abstract
- During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.
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| 22. |
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| 23. |
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| 24. |
- Li, L. M., et al.
(författare)
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Investigating the characteristics and correlates of systemic inflammation after traumatic brain injury: the TBI-BraINFLAMM study
- 2023
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Ingår i: Bmj Open. - 2044-6055. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionA significant environmental risk factor for neurodegenerative disease is traumatic brain injury (TBI). However, it is not clear how TBI results in ongoing chronic neurodegeneration. Animal studies show that systemic inflammation is signalled to the brain. This can result in sustained and aggressive microglial activation, which in turn is associated with widespread neurodegeneration. We aim to evaluate systemic inflammation as a mediator of ongoing neurodegeneration after TBI.Methods and analysisTBI-braINFLAMM will combine data already collected from two large prospective TBI studies. The CREACTIVE study, a broad consortium which enrolled >8000 patients with TBI to have CT scans and blood samples in the hyperacute period, has data available from 854 patients. The BIO-AX-TBI study recruited 311 patients to have acute CT scans, longitudinal blood samples and longitudinal MRI brain scans. The BIO-AX-TBI study also has data from 102 healthy and 24 non-TBI trauma controls, comprising blood samples (both control groups) and MRI scans (healthy controls only). All blood samples from BIO-AX-TBI and CREACTIVE have already been tested for neuronal injury markers (GFAP, tau and NfL), and CREACTIVE blood samples have been tested for inflammatory cytokines. We will additionally test inflammatory cytokine levels from the already collected longitudinal blood samples in the BIO-AX-TBI study, as well as matched microdialysate and blood samples taken during the acute period from a subgroup of patients with TBI (n=18).We will use this unique dataset to characterise post-TBI systemic inflammation, and its relationships with injury severity and ongoing neurodegeneration.Ethics and disseminationEthical approval for this study has been granted by the London-Camberwell St Giles Research Ethics Committee (17/LO/2066). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of larger observational and experimental medicine studies assessing the role and management of post-TBI systemic inflammation.
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| 25. |
- Merid, Simon Kebede, et al.
(författare)
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Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
- 2020
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Ingår i: Genome Medicine. - Stockholm : Karolinska Institutet, Dept of Clinical Science and Education, Södersjukhuset. - 1756-994X.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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| 26. |
- Qiu, Xia, et al.
(författare)
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Individual participant data meta-analysis to compare EPDS accuracy to detect major depression with and without the self-harm item
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Item 10 of the Edinburgh Postnatal Depression Scale (EPDS) is intended to assess thoughts of intentional self-harm but may also elicit concerns about accidental self-harm. It does not specifically address suicide ideation but, nonetheless, is sometimes used as an indicator of suicidality. The 9-item version of the EPDS (EPDS-9), which omits item 10, is sometimes used in research due to concern about positive endorsements of item 10 and necessary follow-up. We assessed the equivalence of total score correlations and screening accuracy to detect major depression using the EPDS-9 versus full EPDS among pregnant and postpartum women. We searched Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, and Web of Science from database inception to October 3, 2018 for studies that administered the EPDS and conducted diagnostic classification for major depression based on a validated semi-structured or fully structured interview among women aged 18 or older during pregnancy or within 12 months of giving birth. We conducted an individual participant data meta-analysis. We calculated Pearson correlations with 95% prediction interval (PI) between EPDS-9 and full EPDS total scores using a random effects model. Bivariate random-effects models were fitted to assess screening accuracy. Equivalence tests were done by comparing the confidence intervals (CIs) around the pooled sensitivity and specificity differences to the equivalence margin of delta = 0.05. Individual participant data were obtained from 41 eligible studies (10,906 participants, 1407 major depression cases). The correlation between EPDS-9 and full EPDS scores was 0.998 (95% PI 0.991, 0.999). For sensitivity, the EPDS-9 and full EPDS were equivalent for cut-offs 7-12 (difference range - 0.02, 0.01) and the equivalence was indeterminate for cut-offs 13-15 (all differences - 0.04). For specificity, the EPDS-9 and full EPDS were equivalent for all cut-offs (difference range 0.00, 0.01). The EPDS-9 performs similarly to the full EPDS and can be used when there are concerns about the implications of administering EPDS item 10.
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| 27. |
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| 28. |
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| 29. |
- Threlfell, S., et al.
(författare)
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Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of alpha-Synuclein and Cholesterol
- 2021
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Striatal dopamine transporters (DAT) powerfully regulate dopamine signaling, and can contribute risk to degeneration in Parkinson's disease (PD). DATs can interact with the neuronal protein alpha-synuclein, which is associated with the etiology and molecular pathology of idiopathic and familial PD. Here, we tested whether DAT function in governing dopamine (DA) uptake and release is modified in a human-alpha-synuclein-overexpressing (SNCA-OVX) transgenic mouse model of early PD. Using fast-scan cyclic voltammetry (FCV) in ex vivo acute striatal slices to detect DA release, and biochemical assays, we show that several aspects of DAT function are promoted in SNCA-OVX mice. Compared to background control alpha-synuclein-null mice (Snca-null), the SNCA-OVX mice have elevated DA uptake rates, and more pronounced effects of DAT inhibitors on evoked extracellular DA concentrations ([DA](o)) and on short-term plasticity (STP) in DA release, indicating DATs play a greater role in limiting DA release and in driving STP. We found that DAT membrane levels and radioligand binding sites correlated with alpha-synuclein level. Furthermore, DAT function in Snca-null and SNCA-OVX mice could also be promoted by applying cholesterol, and using Tof-SIMS we found genotype-differences in striatal lipids, with lower striatal cholesterol in SNCA-OVX mice. An inhibitor of cholesterol efflux transporter ABCA1 or a cholesterol chelator in SNCA-OVX mice reduced the effects of DAT-inhibitors on evoked [DA](o). Together these data indicate that human alpha-synuclein in a mouse model of PD promotes striatal DAT function, in a manner supported by extracellular cholesterol, suggesting converging biology of alpha-synuclein and cholesterol that regulates DAT function and could impact DA function and PD pathophysiology.
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| 30. |
- Xu, L. Z., et al.
(författare)
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Detection of Glial Fibrillary Acidic Protein in Patient Plasma Using On-Chip Graphene Field-Effect Biosensors, in Comparison with ELISA and Single-Molecule Array
- 2022
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Ingår i: Acs Sensors. - : American Chemical Society (ACS). - 2379-3694. ; 7:1, s. 253-262
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Tidskriftsartikel (refereegranskat)abstract
- Glial fibrillary acidic protein (GFAP) is a discriminative blood biomarker for many neurological diseases, such as traumatic brain injury. Detection of GFAP in buffer solutions using biosensors has been demonstrated, but accurate quantification of GFAP in patient samples has not been reported, yet in urgent need. Herein, we demonstrate a robust on-chip graphene field-effect transistor (GFET) biosensing method for sensitive and ultrafast detection of GFAP in patient plasma. Patients with moderate- severe traumatic brain injuries, defined by the Mayo classification, are recruited to provide plasma samples. The binding of target GFAP with the specific antibodies that are conjugated on a monolayer GFET device triggers the shift of its Dirac point, and this signal change is correlated with the GFAP concentration in the patient plasma. The limit of detection (LOD) values of 20 fg/mL (400 aM) in buffer solution and 231 fg/mL (4 fM) in patient plasma have been achieved using this approach. In parallel, for the first time, we compare our results to the state-of-the-art single-molecule array (Simoa) technology and the classic enzyme-linked immunosorbent assay (ELISA) for reference. The GFET biosensor shows competitive LOD to Simoa (1.18 pg/mL) and faster sample-to-result time (<15 min), and also it is cheaper and more user-friendly. In comparison to ELISA, GFET offers advantages of total detection time, detection sensitivity, and simplicity. This GFET biosensing platform holds high promise for the point-of-care diagnosis and monitoring of traumatic brain injury in GP surgeries and patient homes.
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| 31. |
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| 32. |
- Barbato, E, et al.
(författare)
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Renal denervation in the management of hypertension in adults. A clinical consensus statement of the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI)
- 2023
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 44:15, s. 1313-1330
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Tidskriftsartikel (refereegranskat)abstract
- Since the publication of the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines for the Management of Arterial Hypertension, several high-quality studies, including randomised, sham-controlled trials on catheter-based renal denervation (RDN) were published, confirming both the blood pressure (BP)-lowering efficacy and safety of radiofrequency and ultrasound RDN in a broad range of patients with hypertension, including resistant hypertension. A clinical consensus document by the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on RDN in the management of hypertension was considered necessary to inform clinical practice. This expert group proposes that RDN is an adjunct treatment option in uncontrolled resistant hypertension, confirmed by ambulatory BP measurements, despite best efforts at lifestyle and pharmacological interventions. RDN may also be used in patients who are unable to tolerate antihypertensive medications in the long term. A shared decision-making process is a key feature and preferably includes a patient who is well informed on the benefits and limitations of the procedure. The decision-making process should take (i) the patient’s global cardiovascular (CV) risk and/or (ii) the presence of hypertension-mediated organ damage or CV complications into account. Multidisciplinary hypertension teams involving hypertension experts and interventionalists evaluate the indication and facilitate the RDN procedure. Interventionalists require expertise in renal interventions and specific training in RDN procedures. Centres performing these procedures require the skills and resources to deal with potential complications. Future research is needed to address open questions and investigate the impact of BP-lowering with RDN on clinical outcomes and potential clinical indications beyond hypertension.
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| 33. |
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| 34. |
- Bernini, A., et al.
(författare)
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Cerebral Metabolic Dysfunction at the Acute Phase of Traumatic Brain Injury Correlates with Long-Term Tissue Loss
- 2023
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 40:5-6, s. 472-481
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Tidskriftsartikel (refereegranskat)abstract
- Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0-96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24-34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (-3.2% [-9.3 to -2.2] and -1.9% [-4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's rho = -0.68, p-value = 0.01) and low CMD glucose (rho = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI.
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| 35. |
- Ferrat, L.A., et al.
(författare)
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A combined risk score enhances prediction of type 1 diabetes among susceptible children
- 2020
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:8, s. 1247-1255
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk1. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common2,3 and is most severe in the very young4,5, in whom it can be life threatening and difficult to treat6-9. Autoantibody surveillance programs effectively prevent most ketoacidosis10-12 but require frequent evaluations whose expense limits public health adoption13. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible14 because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.
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| 36. |
- Heindl, M. W., et al.
(författare)
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Strong Induced Circular Dichroism in a Hybrid Lead-Halide Semiconductor Using Chiral Amino Acids for Crystallite Surface Functionalization
- 2022
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Ingår i: Advanced Optical Materials. - : Wiley. - 2162-7568 .- 2195-1071. ; 10:14, s. 2200204-
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Tidskriftsartikel (refereegranskat)abstract
- Chirality is a desired property in functional semiconductors for optoelectronic, catalytic, and spintronic applications. Here, introducing enantiomerically-pure 3-aminobutyric acid (3-ABA) into thin films of the 1D semiconductor dimethylammonium lead iodide (DMAPbI3) is found to result in strong circular dichroism (CD) in the optical absorption. X-ray diffraction and grazing incidence small angle X-ray scattering (GISAXS) are applied to gain molecular-scale insights into the chirality transfer mechanism, which is attributed to a chiral surface modification of DMAPbI3 crystallites. This study demonstrates that the CD signal strength can be controlled by the amino-acid content relative to the crystallite surface area. The CD intensity is tuned by the composition of the precursor solution and the spin-coating time, thereby achieving anisotropy factors (gabs) as high as 1.75 × 10–2. Grazing incidence wide angle scattering reveals strong preferential ordering that can be suppressed via tailored synthesis conditions. Different contributions to the chiroptical properties are resolved by a detailed analysis of the CD signal utilizing an approach based on the Mueller matrix model. This report of a novel class of chiral hybrid semiconductors with precise control over their optical activity presents a promising approach for the design of circularly polarized light detectors and emitters.
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| 37. |
- Kolanko, Magdalena A., et al.
(författare)
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Quantification of neurofilament light and glial fibrillary acidic protein in finger-prick blood
- 2024
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Ingår i: BRAIN COMMUNICATIONS. - 2632-1297. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- An accurate diagnosis of neurodegenerative disease and traumatic brain injury is important for prognostication and treatment. Neurofilament light and glial fibrillary acidic protein (GFAP) are leading biomarkers for neurodegeneration and glial activation that are detectable in blood. Yet, current recommendations require rapid centrifugation and ultra-low temperature storage post-venepuncture. Here, we investigated if these markers can be accurately measured in finger-prick blood using dried plasma spot cards. Fifty patients (46 with dementia; 4 with traumatic brain injury) and 19 healthy volunteers underwent finger-prick and venous sampling using dried plasma spot cards and aligned plasma sampling. Neurofilament light and GFAP were quantified using a Single molecule array assay and correlations between plasma and dried plasma spot cards assessed. Biomarker concentrations in plasma and finger-prick dried plasma spot samples were significantly positively correlated (neurofilament light rho = 0.57; GFAP rho = 0.58, P < 0.001). Finger-prick neurofilament light and GFAP were significantly elevated after acute traumatic brain injury with non-significant group-level increases in dementia (91% having Alzheimer's disease dementia). In conclusion, we present preliminary evidence that quantifying GFAP and neurofilament light using finger-prick blood collection is viable, with samples stored at room temperature using dried plasma spot cards. This has potential to expand and promote equitable testing access, including in settings where trained personnel are unavailable to perform venepuncture.
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| 38. |
- Lampousi, Anna Maria, et al.
(författare)
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Interaction between plasma phospholipid odd-chain fatty acids and GAD65 autoantibodies on the incidence of adult-onset diabetes : the EPIC-InterAct case–cohort study
- 2023
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Ingår i: Diabetologia. - : Springer Science+Business Media B.V.. - 0012-186X .- 1432-0428. ; 66:8, s. 1460-1471
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Islet autoimmunity may progress to adult-onset diabetes. We investigated whether circulating odd-chain fatty acids (OCFA) 15:0 and 17:0, which are inversely associated with type 2 diabetes, interact with autoantibodies against GAD65 (GAD65Ab) on the incidence of adult-onset diabetes. Methods: We used the European EPIC-InterAct case–cohort study including 11,124 incident adult-onset diabetes cases and a subcohort of 14,866 randomly selected individuals. Adjusted Prentice-weighted Cox regression estimated HRs and 95% CIs of diabetes in relation to 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or their main contributor, dairy intake, among GAD65Ab-negative and -positive individuals. Interactions between tertiles of OCFA and GAD65Ab status were estimated by proportion attributable to interaction (AP). Results: Low concentrations of OCFA, particularly 17:0, were associated with a higher incidence of adult-onset diabetes in both GAD65Ab-negative (HR 1.55 [95% CI 1.48, 1.64]) and GAD65Ab-positive (HR 1.69 [95% CI 1.34, 2.13]) individuals. The combination of low 17:0 and high GAD65Ab positivity vs high 17:0 and GAD65Ab negativity conferred an HR of 7.51 (95% CI 4.83, 11.69), with evidence of additive interaction (AP 0.25 [95% CI 0.05, 0.45]). Low dairy intake was not associated with diabetes incidence in either GAD65Ab-negative (HR 0.98 [95% CI 0.94, 1.02]) or GAD65Ab-positive individuals (HR 0.97 [95% CI 0.79, 1.18]). Conclusions/interpretation: Low plasma phospholipid 17:0 concentrations may promote the progression from GAD65Ab positivity to adult-onset diabetes. Graphical Abstract: [Figure not available: see fulltext.]
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| 39. |
- Laverse, Etienne, et al.
(författare)
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Plasma glial fibrillary acidic protein and neurofilament light chain, but not tau, are biomarkers of sports-related mild traumatic brain injury.
- 2020
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Ingår i: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- Mild traumatic brain injury is a relatively common event in contact sports and there is increasing interest in the long-term neurocognitive effects. The diagnosis largely relies on symptom reporting and there is a need for objective tools to aid diagnosis and prognosis. There are recent reports that blood biomarkers could potentially help triage patients with suspected injury and normal CT findings. We have measured plasma concentrations of glial and neuronal proteins and explored their potential in the assessment of mild traumatic brain injury in contact sport. We recruited a prospective cohort of active male rugby players, who had pre-season baseline plasma sampling. From this prospective cohort, we recruited 25 players diagnosed with mild traumatic brain injury. We sampled post-match rugby players without head injuries as post-match controls. We measured plasma neurofilament light chain, tau and glial fibrillary acidic protein levels using ultrasensitive single molecule array technology. The data were analysed at the group and individual player level. Plasma glial fibrillary acidic protein concentration was significantly increased 1-h post-injury in mild traumatic brain injury cases compared to the non-injured group (P=0.017). Pairwise comparison also showed that glial fibrillary acidic protein levels were higher in players after a head injury in comparison to their pre-season levels at both 1-h and 3- to 10-day post-injury time points (P=0.039 and 0.040, respectively). There was also an increase in neurofilament light chain concentration in brain injury cases compared to the pre-season levels within the same individual at both time points (P=0.023 and 0.002, respectively). Tau was elevated in both the non-injured control group and the 1-h post-injury group compared to pre-season levels (P=0.007 and 0.015, respectively). Furthermore, receiver operating characteristic analysis showed that glial fibrillary acidic protein and neurofilament light chain can separate head injury cases from control players. The highest diagnostic power was detected when biomarkers were combined in differentiating 1-h post-match control players from 1-h post-head injury players (area under curve 0.90, 95% confidence interval 0.79-1.00, P<0.0002). The brain astrocytic marker glial fibrillary acidic protein is elevated in blood 1h after mild traumatic brain injury and in combination with neurofilament light chain displayed the potential as a reliable biomarker for brain injury evaluation. Plasma total tau is elevated following competitive rugby with and without a head injury, perhaps related to peripheral nerve trauma and therefore total tau does not appear to be suitable as a blood biomarker.
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| 40. |
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| 41. |
- Löfvenborg, Josefin E., et al.
(författare)
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Interaction between gad65 antibodies and dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acids on incident adult-onset diabetes : The epic-interact study
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 44:2, s. 416-424
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acid (PUFA) concentration with the 65-kDa isoform of GAD (GAD65) antibody positivity on the risk of developing adult-onset diabetes. RESEARCH DESIGN AND METHODS: We used prospective data on 11,247 incident cases of adult-onset diabetes and 14,288 noncases from the EPIC-InterAct case-cohort study conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction [AP]) and multiplicative interactions between GAD65 antibody positivity (≥65 units/mL) and low fish/n-3 PUFA were assessed. RESULTS: The hazard of diabetes in antibody-positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52 [95% CI 1.76-3.63] and 2.48 [1.79-3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16-0.72] and 0.48 [0.24-0.72]) and multiplicative (P 5 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (≥167.5 units/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70-6.72]) and an AP of 0.46 (0.12-0.80) compared with antibody-negative individuals with high n-3 PUFAs. CONCLUSIONS: High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.
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| 42. |
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| 43. |
- Parker, Thomas D., et al.
(författare)
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Active elite rugby participation is associated with altered precentral cortical thickness
- 2023
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Ingår i: Brain Communications. - 2632-1297. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- There is growing concern that elite rugby participation may negatively influence brain health, but the underlying mechanisms are unclear. Cortical thickness is a widely applied biomarker of grey matter structure, but there is limited research into how it may be altered in active professional rugby players. Cross-sectional MRI data from 44 active elite rugby players, including 21 assessed within 1 week of head injury, and 47 healthy controls were analysed. We investigated how active elite rugby participation with and without sub-acute traumatic brain injury influenced grey matter structure using whole cortex and region of interest cortical thickness analyses. Relationships between cortical thickness and biomarkers of traumatic brain injury, including fractional anisotropy, plasma neurofilament light and glial fibrillary acidic protein, were also examined. In whole-cortex analyses, precentral cortical thickness in the right hemisphere was lower in rugby players compared with controls, which was due to reductions in non-injured players. Post hoc region of interest analyses showed non-injured rugby players had reduced cortical thickness in the inferior precentral sulcal thickness bilaterally (P = 0.005) and the left central sulcus (P = 0.037) relative to controls. In contrast, players in the sub-acute phase of mild traumatic brain injury had higher inferior precentral sulcal cortical thickness in the right hemisphere (P = 0.015). Plasma glial fibrillary acidic protein, a marker of astrocyte activation, was positively associated with right inferior precentral sulcal cortical thickness in injured rugby players (P = 0.0012). Elite rugby participation is associated with localized alterations in cortical thickness, specifically in sulcal motor regions. Sub-acute changes after mild traumatic brain injury are associated with evidence of astrocytic activation. The combination of cortical thickness and glial fibrillary acidic protein may be useful in understanding the pathophysiological relationship between sporting head injury and brain health.
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| 44. |
- Pastorino, Silvia, et al.
(författare)
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Heterogeneity of Associations between Total and Types of Fish Intake and the Incidence of Type 2 Diabetes : Federated Meta-Analysis of 28 Prospective Studies Including 956,122 Participants
- 2021
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- The association between fish consumption and new-onset type 2 diabetes is inconsistent and differs according to geographical location. We examined the association between the total and types of fish consumption and type 2 diabetes using individual participant data from 28 prospective cohort studies from the Americas (6), Europe (15), the Western Pacific (6), and the Eastern Mediterranean (1) comprising 956,122 participants and 48,084 cases of incident type 2 diabetes. Incidence rate ratios (IRRs) for associations of total fish, shellfish, fatty, lean, fried, freshwater, and saltwater fish intake and type 2 diabetes were derived for each study, adjusting for a consistent set of confounders and combined across studies using random-effects meta-analysis. We stratified all analyses by sex due to observed interaction (p = 0.002) on the association between fish and type 2 diabetes. In women, for each 100 g/week higher intake the IRRs (95% CIs) of type 2 diabetes were 1.02 (1.01–1.03, I2 = 61%) for total fish, 1.04 (1.01–1.07, I2 = 46%) for fatty fish, and 1.02 (1.00–1.04, I2 = 33%) for lean fish. In men, all associations were null. In women, we observed variation by geographical location: IRRs for total fish were 1.03 (1.02–1.04, I2 = 0%) in the Americas and null in other regions. In conclusion, we found evidence of a neutral association between total fish intake and type 2 diabetes in men, but there was a modest positive association among women with heterogeneity across studies, which was partly explained by geographical location and types of fish intake. Future research should investigate the role of cooking methods, accompanying foods and environmental pollutants, but meanwhile, existing dietary regional, national, or international guidelines should continue to guide fish consumption within overall healthy dietary patterns.
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| 45. |
- Pearce, Matthew, et al.
(författare)
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Associations of Total Legume, Pulse, and Soy Consumption with Incident Type 2 Diabetes : Federated Meta-Analysis of 27 Studies from Diverse World Regions
- 2021
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Ingår i: Journal of Nutrition. - : Elsevier. - 0022-3166 .- 1541-6100. ; 151:5, s. 1231-1240
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe consumption of legumes is promoted as part of a healthy diet in many countries but associations of total and types of legume consumption with type 2 diabetes (T2D) are not well established. Analyses across diverse populations are lacking despite the availability of unpublished legume consumption data in prospective cohort studies.ObjectiveTo examine the prospective associations of total and types of legume intake with the risk of incident T2D.MethodsMeta-analyses of associations between total legume, pulse, and soy consumption and T2D were conducted using a federated approach without physical data-pooling. Prospective cohorts were included if legume exposure and T2D outcome data were available and the cohort investigators agreed to participate. We estimated incidence rate ratios (IRRs) and CIs of associations using individual participant data including ≤42,473 incident cases among 807,785 adults without diabetes in 27 cohorts across the Americas, Eastern Mediterranean, Europe, and Western Pacific. Random-effects meta-analysis was used to combine effect estimates and estimate heterogeneity.ResultsMedian total legume intake ranged from 0–140 g/d across cohorts. We observed a weak positive association between total legume consumption and T2D (IRR = 1.02, 95% CI: 1.01 to 1.04) per 20 g/d higher intake, with moderately high heterogeneity (I2 = 74%). Analysis by region showed no evidence of associations in the Americas, Eastern Mediterranean, and Western Pacific. The positive association in Europe (IRR = 1.05, 95% CI: 1.01 to 1.10, I2 = 82%) was mainly driven by studies from Germany, UK, and Sweden. No evidence of associations was observed for the consumption of pulses or soy.ConclusionsThese findings suggest no evidence of an association of legume intakes with T2D in several world regions. The positive association observed in some European studies warrants further investigation relating to overall dietary contexts in which legumes are consumed, including accompanying foods which may be positively associated with T2D.
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| 46. |
- Rolandsson, Olov, et al.
(författare)
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Autoimmunity plays a role in the onset of diabetes after 40 years of age
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63, s. 266-277
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort.Methods: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression.Results: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors.Conclusions/interpretation: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.
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| 47. |
- Sobiecki, Jakub G., et al.
(författare)
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A nutritional biomarker score of the Mediterranean diet and incident type 2 diabetes : Integrated analysis of data from the MedLey randomised controlled trial and the EPIC-InterAct case-cohort study
- 2023
-
Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 20:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet.Methods and findings: We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22, 202 participants, of whom 9, 453 were T2D cases, with relevant biomarkers from an original case-cohort of 27, 779 participants sampled from a cohort of 340, 234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding.Conclusions: These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully.
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| 48. |
- Steur, Marinka, et al.
(författare)
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Dietary Fatty Acids, Macronutrient Substitutions, Food Sources and Incidence of Coronary Heart Disease : Findings From the EPIC-CVD Case-Cohort Study Across Nine European Countries
- 2021
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Ingår i: Journal of the American Heart Association. - : American Heart Association. - 2047-9980. ; 10:23
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain.Methods and Results: We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88-0.99]), cheese (HR, 0.98 [95% CI, 0.96-1.00]), and fish (HR, 0.87 [95% CI, 0.75-1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02-1.12]) and butter (HR, 1.02 [95% CI, 1.00-1.04]).Conclusions: This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix.
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| 49. |
- Tedersoo, Leho, et al.
(författare)
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Global patterns in endemicity and vulnerability of soil fungi.
- 2022
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Ingår i: Global change biology. - : Wiley. - 1365-2486 .- 1354-1013. ; 28:22, s. 6696-6710
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Tidskriftsartikel (refereegranskat)abstract
- Fungi are highly diverse organisms, which provide multiple ecosystem services. However, compared with charismatic animals and plants, the distribution patterns and conservation needs of fungi have been little explored. Here, we examined endemicity patterns, global change vulnerability and conservation priority areas for functional groups of soil fungi based on six global surveys using a high-resolution, long-read metabarcoding approach. We found that the endemicity of all fungi and most functional groups peaks in tropical habitats, including Amazonia, Yucatan, West-Central Africa, Sri Lanka, and New Caledonia, with a negligible island effect compared with plants and animals. We also found that fungi are predominantly vulnerable to drought, heat and land-cover change, particularly in dry tropical regions with high human population density. Fungal conservation areas of highest priority include herbaceous wetlands, tropical forests, and woodlands. We stress that more attention should be focused on the conservation of fungi, especially root symbiotic arbuscular mycorrhizal and ectomycorrhizal fungi in tropical regions as well as unicellular early-diverging groups and macrofungi in general. Given the low overlap between the endemicity of fungi and macroorganisms, but high conservation needs in both groups, detailed analyses on distribution and conservation requirements are warranted for other microorganisms and soil organisms.
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| 50. |
- Wang, Kaituo, et al.
(författare)
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Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Placental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations will support rational design of second-generation placental malaria vaccines.
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