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- Callaway, EM, et al.
(författare)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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- Schael, S, et al.
(författare)
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Precision electroweak measurements on the Z resonance
- 2006
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Ingår i: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 427:5-6, s. 257-454
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Forskningsöversikt (refereegranskat)abstract
- We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLID experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, m(Z) and Gamma(Z), and its couplings to fermions, for example the p parameter and the effective electroweak mixing angle for leptons, are precisely measured: m(Z) = 91.1875 +/- 0.0021 GeV, Gamma(Z) = 2.4952 +/- 0.0023 GeV, rho(l) = 1.0050 +/- 0.0010, sin(2)theta(eff)(lept) = 0.23153 +/- 0.00016. The number of light neutrino species is determined to be 2.9840 +/- 0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, m(t) = 173(+10)(+13) GeV, and the mass of the W boson, m(W) = 80.363 +/- 0.032 GeV. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of m(t) and m(W), the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than 285 GeV at 95% confidence level. (c) 2006 Elsevier B.V. All rights reserved.
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| 9. |
- Taddei, C, et al.
(författare)
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Repositioning of the global epicentre of non-optimal cholesterol
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 582:7810, s. 73-
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Tidskriftsartikel (refereegranskat)abstract
- High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.
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- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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- Guo, JP, et al.
(författare)
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Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:6, s. 773-780
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Tidskriftsartikel (refereegranskat)abstract
- The strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC.MethodsWe first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case–control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants.ResultsHLA-DQα1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10−36, OR=2.29). DRβ1:37N had an independent protective effect (p=5.81×10−16, OR=0.49). As predicted by comparative modelling, the negatively charged DQα1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRβ1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.ConclusionsWe provide the first evidence that HLA-DQα1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.
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| 19. |
- Huang, HP, et al.
(författare)
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Long latency of evoked quantal transmitter release from somata of locus coeruleus neurons in rat pontine slices
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 104:4, s. 1401-1406
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Tidskriftsartikel (refereegranskat)abstract
- The locus coeruleus (LC) harbors a compact group of noradrenergic cell bodies projecting to virtually all parts of the central nervous system. By using combined measurements of amperometry and patch-clamp, quantal vesicle release of noradrenaline (NA) was detected as amperometric spikes, after depolarization of the LC neurons. After a pulse depolarization, the average latency of amperometric spikes was 1,870 ms, whereas the latency of glutamate-mediated excitatory postsynaptic currents was 1.6 ms. A substantial fraction of the depolarization-induced amperometric spikes originated from the somata. In contrast to glutamate-mediated excitatory postsynaptic currents, NA secretion was strongly modulated by the action potential frequency (0.5–50 Hz). Somatodendritic NA release from LC upon enhanced cell activity produced autoinhibition of firing and of NA release. We conclude that, in contrast to classic synaptic transmission, quantal NA release from LC somata is characterized by a number of distinct properties, including long latency and high sensitivity to action potential frequency.
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- Shrine, N, et al.
(författare)
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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
- 2023
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 55:3, s. 410-
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Tidskriftsartikel (refereegranskat)abstract
- Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
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| 25. |
- Sieberts, SK, et al.
(författare)
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Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 12460-
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.
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| 28. |
- Tan, SY, et al.
(författare)
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Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity
- 2021
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 218:9
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Tidskriftsartikel (refereegranskat)abstract
- The maturation and functional competence of natural killer (NK) cells is a tightly controlled process that relies on transcription factors (TFs). Here, we identify transcriptional repressor zinc fingers and homeoboxes 2 (Zhx2) as a novel regulator that restricts NK cell maturation and function. Mice with Zhx2 conditional deletion in NK cells (Zhx2Δ/Δ) showed accumulation of matured NK cells. Loss of Zhx2 enhanced NK cell survival and NK cell response to IL-15. Transcriptomic analysis revealed Zeb2, a key TF in NK cell terminal maturation, as a direct downstream target of Zhx2. Therapeutically, transfer of Zhx2-deficient NK cells resulted in inhibition of tumor growth and metastasis in different murine models. Our findings collectively unmask a previously unrecognized role of Zhx2 as a novel negative regulator in NK cell maturation and highlight its therapeutic potential as a promising strategy to enhance NK cell–mediated tumor surveillance.
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- Zhe, XW, et al.
(författare)
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Hypertriglyceridemic waist is associated with increased carotid atherosclerosis in chronic kidney disease patients
- 2012
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Ingår i: Nephron. Clinical practice. - : S. Karger AG. - 1660-2110. ; 122:3-4, s. 146-152
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Patients with chronic kidney disease (CKD) have an unacceptably high risk of death, primarily as a result of cardiovascular disease (CVD). The ‘hypertriglyceridemic waist' phenotype has been proposed as a simple and strong predictor of CVD risk. Therefore, we investigated the relationship between the hypertriglyceridemic waist phenotype and carotid atherosclerosis in CKD patients. <b><i>Methods:</i></b> In a cross-sectional study, we enrolled 785 prevalent CKD patients [416 males, aged 44.6 years (21.7-69.4), glomerular filtration rate 52.5 ml/min/1.73 m<sup>2</sup> (5.3-119.4)]. We divided the patients into three groups: group 1: waist circumference >90 cm in men or >85 cm in women and triglycerides ≥2 mmol/l (n = 109); group 3: waist circumference ≤90 cm in men or ≤85 cm in women and triglycerides <2 mmol/l (n = 379), and group 2: the remaining patients (n = 297). Routine biochemical parameters and carotid artery intima-media thickness (IMT) were measured. <b><i>Results:</i></b> The prevalence of the hypertriglyceridemic waist phenotypes was 13.8% in the CKD patients. Triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol concentrations in group 1 were significantly higher than those in group 3. Carotid artery IMT of the hypertriglyceridemic waist group was the highest. <b><i>Conclusion:</i></b> The hypertriglyceridemic waist phenotype was associated with worse carotid atherosclerosis in CKD patients. This suggests that the hypertriglyceridemic waist phenotype may be useful for predicting CVD risk in CKD patients.
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| 34. |
- Chen, Y, et al.
(författare)
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Immunological Classification of Pancreatic Carcinomas to Identify Immune Index and Provide a Strategy for Patient Stratification
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12, s. 719105-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer immunotherapy has produced significant positive clinical effects in a variety of tumor types. However, pancreatic ductal adenocarcinoma (PDAC) is widely considered to be a “cold” cancer with poor immunogenicity. Our aim is to determine the detailed immune features of PDAC to seek new treatment strategies.MethodsThe immune cell abundance of PDAC patients was evaluated with the single-sample gene set enrichment analysis (ssGSEA) using 119 immune gene signatures. Based on these data, patients were classified into different immune subtypes (ISs) according to immune gene signatures. We analyzed their response patterns to immunotherapy in the datasets, then established an immune index to reflect the different degrees of immune infiltration through linear discriminant analysis (LDA). Finally, potential prognostic markers associated with the immune index were identified based on weighted correlation network analysis (WGCNA) that was functionally validated in vitro.ResultsThree ISs were identified in PDAC, of which IS3 had the best prognosis across all three cohorts. The different expressions of immune profiles among the three ISs indicated a distinct responsiveness to immunotherapies in PDAC subtypes. By calculating the immune index, we found that the IS3 represented higher immune infiltration, while IS1 represented lower immune infiltration. Among the investigated signatures, we identified ZNF185, FANCG, and CSTF2 as risk factors associated with immune index that could potentially facilitate diagnosis and could be therapeutic target markers in PDAC patients.ConclusionsOur findings identified immunologic subtypes of PDAC with distinct prognostic implications, which allowed us to establish an immune index to represent the immune infiltration in each subtype. These results show the importance of continuing investigation of immunotherapy and will allow clinical workers to personalized treatment more effectively in PDAC patients.
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| 39. |
- Kobiela, A, et al.
(författare)
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Exposure of Keratinocytes to Candida Albicans in the Context of Atopic Milieu Induces Changes in the Surface Glycosylation Pattern of Small Extracellular Vesicles to Enhance Their Propensity to Interact With Inhibitory Siglec Receptors
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13, s. 884530-
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Tidskriftsartikel (refereegranskat)abstract
- Candida albicans (C. albicans) infection is a potential complication in the individuals with atopic dermatitis (AD) and can affect clinical course of the disease. Here, using primary keratinocytes we determined that atopic milieu promotes changes in the interaction of small extracellular vesicles (sEVs) with dendritic cells and that this is further enhanced by the presence of C. albicans. sEV uptake is largely dependent on the expression of glycans on their surface; modelling of the protein interactions indicated that recognition of this pathogen through C. albicans-relevant pattern recognition receptors (PRRs) is linked to several glycosylation enzymes which may in turn affect the expression of sEV glycans. Here, significant changes in the surface glycosylation pattern, as determined by lectin array, could be observed in sEVs upon a combined exposure of keratinocytes to AD cytokines and C. albicans. This included enhanced expression of multiple types of glycans, for which several dendritic cell receptors could be proposed as binding partners. Blocking experiments showed predominant involvement of the inhibitory Siglec-7 and -9 receptors in the sEV-cell interaction and the engagement of sialic acid-containing carbohydrate moieties on the surface of sEVs. This pointed on ST6 β-Galactoside α-2,6-Sialyltransferase 1 (ST6GAL1) and Core 1 β,3-Galactosyltransferase 1 (C1GALT1) as potential enzymes involved in the process of remodelling of the sEV surface glycans upon C. albicans exposure. Our results suggest that, in combination with atopic dermatitis milieu, C. albicans promotes alterations in the glycosylation pattern of keratinocyte-derived sEVs to interact with inhibitory Siglecs on antigen presenting cells. Hence, a strategy aiming at this pathway to enhance antifungal responses and restrict pathogen spread could offer novel therapeutic options for skin candidiasis in AD.
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| 46. |
- Liu, Qing, et al.
(författare)
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Roquinimex inhibits dextran sodium sulfate-induced murine colitis
- 2003
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 52:2, s. 64-68
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Roquinimex is a modulator of the immune system and has been shown to attenuate induction of several inflammatory and autoimmune diseases. The objective of the present study was to determine the efficacy of roquinimex in a model of murine colitis. Materials and methods: For this purpose, Balb/c mice were exposed to 5% dextran sodium sulfate (DSS) in the drinking water for five to six days. Roquinimex (300 mg kg(-1) day(-1)) was administered by subcutaneous (s.c.) injection 3 days prior to and throughout the treatment period with DSS. In separate experiments, 300 mg kg(-1) day(-1) of roquinimex was given therapeutically after initiation of DSS challenge. Results: DSS provoked clinical signs of colitis, reduced crypt height (CH) and increased mucosal damage score (MDS) as analyzed by histology. In addition, challenge with DSS increased the colonic content of myeloperoxidase (MPO). Prophylactic administration of DSS-treated mice with roquinimex significantly reduced clinical signs of colitis, MDS and the CH-reduction. Moreover, in roquinimex treated animals, the MPO activity was significantly reduced by more than 50% compared to DSS control mice. Notably, therapeutic administration of roquinimex in DSS-treated mice also significantly inhibited the MDS, CH-reduction and MPO activity. Conclusions: These findings suggest that roquinimex strongly inhibits murine colitis and may provide a novel pharmacological approach to treat inflammatory bowel disease.
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