| 1. |
- Gaulton, Kyle J, et al.
(författare)
-
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
-
Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
|
|
| 2. |
- Locke, Adam E, et al.
(författare)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
|
|
| 3. |
- Söderlund, Karin, et al.
(författare)
-
Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer
- 2013
-
Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 190:8, s. 4420-4430
-
Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro-and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell-derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities. The Journal of Immunology, 2013, 190: 4420-4430.
|
|
| 4. |
- Justice, Anne E., et al.
(författare)
-
Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
-
Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
|
|
| 5. |
- Lewandowski, Jörg, et al.
(författare)
-
Is the Hyporheic Zone Relevant beyond the Scientific Community?
- 2019
-
Ingår i: Water. - : MDPI AG. - 2073-4441. ; 11:11
-
Tidskriftsartikel (refereegranskat)abstract
- Rivers are important ecosystems under continuous anthropogenic stresses. The hyporheic zone is a ubiquitous, reactive interface between the main channel and its surrounding sediments along the river network. We elaborate on the main physical, biological, and biogeochemical drivers and processes within the hyporheic zone that have been studied by multiple scientific disciplines for almost half a century. These previous efforts have shown that the hyporheic zone is a modulator for most metabolic stream processes and serves as a refuge and habitat for a diverse range of aquatic organisms. It also exerts a major control on river water quality by increasing the contact time with reactive environments, which in turn results in retention and transformation of nutrients, trace organic compounds, fine suspended particles, and microplastics, among others. The paper showcases the critical importance of hyporheic zones, both from a scientific and an applied perspective, and their role in ecosystem services to answer the question of the manuscript title. It identifies major research gaps in our understanding of hyporheic processes. In conclusion, we highlight the potential of hyporheic restoration to efficiently manage and reactivate ecosystem functions and services in river corridors.
|
|
| 6. |
- Lorant, Tomas, 1975-, et al.
(författare)
-
Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients
- 2018
-
Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 18:11, s. 2752-2762
-
Tidskriftsartikel (refereegranskat)abstract
- Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS [imlifidase]) were assessed in a single-center, open-label ascending-dose study in highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 [n = 3]; 0.25 mg/kg ×1 [n = 3], or 0.25 mg/kg ×2 [n = 2]). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti-HLA was abolished. IdeS also cleaved the IgG-type B cell receptor on CD19+ memory B cells. Anti-IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA-B7), detected by complement-dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA-incompatible donor (HLA-B7+) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.
|
|
| 7. |
- Ovchinnikova, Olga, et al.
(författare)
-
T-Cell Activation Leads to Reduced Collagen Maturation in Atherosclerotic Plaques of Apoe−/− Mice
- 2009
-
Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 174:2, s. 693-700
-
Tidskriftsartikel (refereegranskat)abstract
- Rupture of the collagenous, fibrous cap of an atherosclerotic plaque commonly causes thrombosis. Activated immune cells can secrete mediators that jeopardize the integrity of the fibrous cap. This study aimed to determine the relationship between T-cell-mediated inflammation and collagen turnover in a mouse model of experimental atherosclerosis. Both Apoe(-/-) x CD4dnT beta RII mice with defective transforming growth factor-beta receptors in T cells (and hence released from tonic suppression of T-cell activation) and lesion size-matched Apoe(-/-) mice were used. Picrosirius red staining showed a lower content of thick mature collagen fibers in lesions of Apoe(-/-) x CD4dnT beta RII mice, although both groups had similar levels of procollagen type I or M mRNA and total collagen content in lesions. Analysis of both gene expression and protein content showed a significant decrease of lysyl oxidase, the extracellular enzyme needed for collagen cross-linking, in aortas of Apoe(-/-) - CD4dnT beta RII mice. T-cell-driven inflammation provoked a selective and limited increase in the expression of proteinases that catabolize the extracellular matrix. Atheromata of Apoe(-/-) - CD4dnT beta RII mice had increased levels of matrix metalloproteinase-13 and cathepsin S mRNAs and of the active form of cathepsin S protein but no increase was detected in collagen fragmentation. our results suggest that exaggerated T-cell-driven inflammation limits collagen maturation in the atherosclerotic plaque while having little effect on collagen degradation.
|
|
| 8. |
- Rao, Komal Umashankar, et al.
(författare)
-
A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy
- 2021
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.
|
|
| 9. |
- Robertson, Anna-Karin L
(författare)
-
T cells in atherogenesis
- 2004
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The work of this thesis aims to answer the following questions: (1) Which role do CD4+ cells play in atherosclerosis? (2) Is the expression of CD4 essential for the athero-protective effect mediated by immunization with oxidized LDL by adjuvant? (3) How does the antigenspecific T cell response to oxidized LDL influence lesion development? (4) Is there a general shift to Th2 responses in severe hypercholesterolemia? and finally (5) Which role does transforming growth factor-B (TGF-B)-signaling in T cells play in atherogenesis? ApoE-/-CD4-/- mice were used to study the effect of CD4 deficiency in atherosclerosis. The development of atherosclerosis was decreased with attenuated inflammation in apoE-/- mice lacking CD4+ cells compared to immunocompetent apoE-/-. Immunization with oxidized LDL protected against atherosclerosis in the absence of CD4+ T cells but adjuvant-induced protection against atherosclerosis was extinguished in CD4/apoE double knockout mice. Thus, CD4+ cells play a significant role in the development of atherosclerosis and our findings further indicate that the adjuvant-induced atheroprotection is CD4-dependent. In contrast, immunization with oxLDL may confer disease protection through mechanisms operating also in CD4 deficient mice. To study the importance of T cell specificity in atherogenesis, we transferred CD4+ T cells from mice immunized with oxidized LDL or with the unrelated antigen keyhole limpet hemocyanine (KLH) to apoE-/-scid/scid mice. The mice receiving T cells from mice immunized with oxidized LDL developed more atherosclerosis than the mice receiving cells from KLH-immunized mice. There was a more substantial T cell infiltrate in lesions from the former group, suggesting homing to the lesions by antigen-specific T cells. These results indicate an antigen-specific immune activation by CD4+ cells specific for oxidized LDL. ApoE-/- mice with different levels of hypercholesterolemia were immunized with KLH. Immune responses in mice with severe hypercholesterolemia were skewed to Th2 as shown by decreased titers of KLH antibodies of the IgG2a subclass and increased IgE antibodies, increased production of interleukin-4 (IL-4) and IL-10 and decreased production of IFN-y. Lipid metabolites may therefore affect T cell function, which could be of relevance in local environments with high lipid levels, for example in the inflamed arterial intima. Finally, we crossed the atherosclerosis-prone apolipoprotein E knockout (apoE-/-) mice with mice carrying dominant negative receptors for TGF-B on T cells, thus rendering the T cells insensitive to the dampening effect of TGF-B The formation of atherosclerotic lesions was dramatically increased in the mice with abrogated TGF-B signaling in T cells, with lesions of a vulnerable phenotype. Therefore, TGF-B exerts important anti-atherosclerotic effects by acting on T cells. In conclusion, we have studied T cells in atherosclerosis and severe hypercholesterolemia. CD4+ T cells play a major role in the proatherogenic inflammatory process, and cell-mediated immunity to oxLDL promotes atherogenesis. In addition, T cells play differential roles in diseaseprotecting immunization strategies and regulated by lipid components in their environment as well as by anti-inflammatory cytokines, with TGF-B probably playing major role as an antiatherosclerotic mediator.
|
|
