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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Eijsbouts, C., et al.
(author)
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Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
- 2021
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53:11, s. 1543-1552
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Journal article (peer-reviewed)abstract
- Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS. © 2021, The Author(s).
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| 6. |
- Elsik, Christine G., et al.
(author)
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The Genome Sequence of Taurine Cattle : A Window to Ruminant Biology and Evolution
- 2009
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 324:5926, s. 522-528
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Journal article (peer-reviewed)abstract
- To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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| 7. |
- Wain, Louise V., et al.
(author)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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In: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Journal article (peer-reviewed)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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| 8. |
- Wightman, D. P., et al.
(author)
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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
- 2021
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:9, s. 1276-1282
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Journal article (peer-reviewed)abstract
- Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.
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| 9. |
- Evangelou, Evangelos, et al.
(author)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Journal article (peer-reviewed)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 10. |
- Estrada, Karol, et al.
(author)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Journal article (peer-reviewed)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 11. |
- Abbafati, Cristiana, et al.
(author)
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- 2020
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Journal article (peer-reviewed)
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| 12. |
- Oei, Ling, et al.
(author)
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A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
- 2014
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In: Journal of Medical Genetics. - : BMJ Publishing Group. - 0022-2593 .- 1468-6244. ; 51:2, s. 122-131
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Journal article (peer-reviewed)abstract
- BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.AIM: To identify CNVs associated with osteoporotic bone fracture risk.METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
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| 13. |
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| 14. |
- Ninan, Neethu, et al.
(author)
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Plasma assisted design of biocompatible 3D printed PCL/silver nanoparticle scaffolds : in vitro and in vivo analyses
- 2021
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In: Materials Advances. - : Royal Society of Chemistry (RSC). - 2633-5409. ; 2:20, s. 6620-6630
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Journal article (peer-reviewed)abstract
- 3D printing provides numerous opportunities for designing tissue engineering constructs with intricate porosity, geometry and favourable mechanical properties and has the potential to revolutionize medical treatments. However, an often-encountered restriction is the selection of materials suitable for utilization in 3D printing, not all of which have appropriate biocompatibility properties. In this work, fused deposition modeling was employed to fabricate 3D PCL constructs without the use of any solvent. Plasma deposition was used to modify the surface of the scaffolds, followed by immobilization of silver nanoparticles. The physico-chemical and mechanical analyses demonstrated that the scaffolds retained their porosity and mechanical integrity. The mechanical properties evaluated by the nanoindentation technique demonstrated an increase in reduced modulus to 1.87 +/- 0.012 GPa for PCL scaffolds functionalized with silver nanoparticles for 24 hours. We also showed complete prevention of colonization by medically relevant pathogens. The modified scaffolds had good biocompatibility. The immune response studies in the culture of macrophages confirmed a reduction in the level of expression of pro-inflammatory cytokines which is a key requirement for successful wound healing. The in vivo studies on Sprague Dawley rats indicated enhanced angiogenesis and the absence of foreign body reaction for scaffolds functionalized with silver nanoparticles for 6 hours. The 3D printing approach presented in this study provides new sustainable opportunities that can be adopted for designing biomaterial constructs with enhanced biological properties.
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| 15. |
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| 16. |
- Tuncel, J., et al.
(author)
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Animal Models of Rheumatoid Arthritis (I) : Pristane-Induced Arthritis in the Rat
- 2016
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
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Journal article (peer-reviewed)abstract
- BACKGROUND: To facilitate the development of therapies for rheumatoid arthritis (RA), the Innovative Medicines Initiative BTCure has combined the experience from several laboratories worldwide to establish a series of protocols for different animal models of arthritis that reflect the pathogenesis of RA. Here, we describe chronic pristane-induced arthritis (PIA) model in DA rats, and provide detailed instructions to set up and evaluate the model and for reporting data. METHODS: We optimized dose of pristane and immunization procedures and determined the effect of age, gender, and housing conditions. We further assessed cage-effects, reproducibility, and frequency of chronic arthritis, disease markers, and efficacy of standard and novel therapies. RESULTS: Out of 271 rats, 99.6% developed arthritis after pristane-administration. Mean values for day of onset, day of maximum arthritis severity and maximum clinical scores were 11.8+/-2.0 days, 20.3+/-5.1 days and 34.2+/-11 points on a 60-point scale, respectively. The mean frequency of chronic arthritis was 86% but approached 100% in long-term experiments over 110 days. Pristane was arthritogenic even at 5 microliters dose but needed to be administrated intradermally to induce robust disease with minimal variation. The development of arthritis was age-dependent but independent of gender and whether the rats were housed in conventional or barrier facilities. PIA correlated well with weight loss and acute phase reactants, and was ameliorated by etanercept, dexamethasone, cyclosporine A and fingolimod treatment. CONCLUSIONS: PIA has high incidence and excellent reproducibility. The chronic relapsing-remitting disease and limited systemic manifestations make it more suitable than adjuvant arthritis for long-term studies of joint-inflammation and screening and validation of new therapeutics.
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| 17. |
- Agrawal, Ritvija, et al.
(author)
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The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor
- 2022
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In: eLife. - 2050-084X. ; 11
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Journal article (peer-reviewed)abstract
- Dynein harnesses ATP hydrolysis to move cargo on microtubules in multiple biological contexts. Dynein meets a unique challenge in meiosis by moving chromosomes tethered to the nuclear envelope to facilitate homolog pairing essential for gametogenesis. Though processive dynein motility requires binding to an activating adaptor, the identity of the activating adaptor required for dynein to move meiotic chromosomes is unknown. We show that the meiosis-specific nuclear-envelope protein KASH5 is a dynein activating adaptor: KASH5 directly binds dynein using a mechanism conserved among activating adaptors and converts dynein into a processive motor. We map the dynein-binding surface of KASH5, identifying mutations that abrogate dynein binding in vitro and disrupt recruitment of the dynein machinery to the nuclear envelope in cultured cells and mouse spermatocytes in vivo. Our study identifies KASH5 as the first transmembrane dynein activating adaptor and provides molecular insights into how it activates dynein during meiosis.
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| 18. |
- Amirahmadi, S. F., et al.
(author)
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Arthritogenic anti-type II collagen antibodies are pathogenic for cartilage-derived chondrocytes independent of inflammatory cells
- 2005
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In: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 52:6, s. 1897-1906
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Some monoclonal antibodies (mAb) to type II collagen (CII) are arthritogenic upon passive transfer to mice. We undertook this study to investigate whether such mAb are pathogenic in the absence of mediators of inflammation. METHODS: The arthritogenic mAb CIIC1 and M2139, and the nonarthritogenic mAb CIIF4, each reactive with a distinct and well-defined conformational epitope on CII, were compared with control mAb GAD6. Bovine chondrocytes were cultured with one of the mAb, and on days 3, 6, and 9, antibody binding by chondrocytes and newly synthesized extracellular matrix (ECM) was examined by immunofluorescence, morphologic effects were studied by electron microscopy, and synthesis of matrix components was determined by metabolic labeling with (3)H-proline for collagen and (35)S-sulfate for proteoglycans. RESULTS: All 3 mAb to CII bound to the matrix. CIIC1 and M2139 adversely affected the cultures, whereas CIIF4 did not. CIIC1 caused disorganization of CII fibrils in the ECM without affecting chondrocyte morphology, and increased matrix synthesis. M2139 caused thickening and aggregation of CII fibrils in the ECM and abnormal chondrocyte morphology but matrix synthesis was unaffected. CONCLUSION: The unique arthritogenic capacity of particular anti-CII mAb upon passive transfer could be explained by their adverse, albeit differing, effects in primary cultures of chondrocytes. Such effects occur independent of inflammation mediators and are related to the epitope specificity of the mAb. Interference with the structural integrity of CII could precede, and even initiate, the inflammatory expression of disease.
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| 19. |
- Backlund, J., et al.
(author)
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C57BL/6 mice need MHC class II Aq to develop collagen-induced arthritis dependent on autoreactive T cells
- 2013
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 72:7, s. 1225-1232
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Collagen-induced arthritis (CIA) has traditionally been performed in MHC class II A(q)-expressing mice, whereas most genetically modified mice are on the C57BL/6 background (expressing the b haplotype of the major histocompatibility complex (MHC) class II region). However, C57BL/6 mice develop arthritis after immunisation with chicken-derived collagen type II (CII), but arthritis susceptibility has been variable, and the immune specificity has not been clarified. OBJECTIVE: To establish a CIA model on the C57BL/6 background with a more predictable and defined immune response to CII. RESULTS: Both chicken and rat CII were arthritogenic in C57BL/6 mice provided they were introduced with high doses of Mycobacterium tuberculosis adjuvant. However, contaminating pepsin was strongly immunogenic and was essential for arthritis development. H-2(b)-restricted T cell epitopes on chicken or rat CII could not be identified, but expression of A(q) on the C57BL/6 background induced T cell response to the CII260-270 epitope, and also prolonged the arthritis to be more chronic. CONCLUSIONS: The putative (auto)antigen and its arthritogenic determinants in C57BL/6 mice remains undisclosed, questioning the value of the model for addressing T cell-driven pathological pathways in arthritis. To circumvent this impediment, we recommend MHC class II congenic C57BL/6N.Q mice, expressing A(q), with which T cell determinants have been thoroughly characterised.
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| 20. |
- Bao, Erik L, et al.
(author)
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Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 586:7831, s. 769-775
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Journal article (peer-reviewed)abstract
- Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers1. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10-8), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states-collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.
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| 21. |
- Batavia, B., et al.
(author)
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Export stagnation and budget deficits in the peripheral EU nations with EMU membership
- 2013
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In: Journal of Economic Asymmetries. - : Elsevier BV. - 1703-4949. ; 10:2, s. 94-100
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Journal article (peer-reviewed)abstract
- This paper presents a theoretical model of the economic and financial implications of EMU entry for the peripheral nations of the Euro area, the so-called PIGS nations. The model derived shows that EMU membership initiates huge capital inflows into the PIGS nations, driving up prices and wage costs. The rise in prices reduces international trade competitiveness, reducing net exports, while the rise in wage costs leads to greater government budget outlays, deteriorating the government budget. Without exchange rate adjustments, export stagnation, further exacerbated by the economic downturn in the Euro area as a whole, has been the price paid by the peripheral Euro nations. Examining the data for the recent decade suggests that the arguments against laying the blame for the economic and financial crises in the PIGS nations squarely on bad domestic policy-making and practices need to be taken seriously.
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| 22. |
- Bowden, John A., et al.
(author)
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Harmonizing lipidomics : NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma
- 2017
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In: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 58:12, s. 2275-2288
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Journal article (peer-reviewed)abstract
- As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra-and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium.jlr While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.
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| 23. |
- Crombie, D. E., et al.
(author)
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Destructive effects of murine arthritogenic antibodies to type II collagen on cartilage explants in vitro
- 2005
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In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7:5
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Journal article (peer-reviewed)abstract
- Certain monoclonal antibodies (mAbs) to type II collagen (CII) induce arthritis in vivo after passive transfer and have adverse effects on chondrocyte cultures and inhibit self assembly of collagen fibrils in vitro. We have examined whether such mAbs have detrimental effects on pre-existing cartilage. Bovine cartilage explants were cultured over 21 days in the presence of two arthritogenic mAbs to CII (CIIC1 or M2139), a non-arthritogenic mAb to CII (CIIF4) or a control mAb (GAD6). Penetration of cartilage by mAb was determined by immunofluorescence on frozen sections and correlated with changes to the extracellular matrix and chondrocytes by morphometric analysis of sections stained with toluidine blue. The effects of mAbs on matrix components were examined by Fourier transform infrared microspectroscopy (FTIRM). A possible role of Fc-binding was investigated using F(ab)2 from CIIC1. All three mAbs to CII penetrated the cartilage explants and CIIC1 and M2139, but not CIIF4, had adverse effects that included proteoglycan loss correlating with mAb penetration, the later development in cultures of an abnormal superficial cellular layer, and an increased proportion of empty chondrons. FTIRM showed depletion and denaturation of CII at the explant surface in the presence of CIIC1 or M2139, which paralleled proteoglycan loss. The effects of F(ab)2 were greater than those of intact CIIC1. Our results indicate that mAbs to CII can adversely affect preformed cartilage, and that the specific epitope on CII recognised by the mAb determines both arthritogenicity in vivo and adverse effects in vitro. We conclude that antibodies to CII can have pathogenic effects that are independent of inflammatory mediators or Fc-binding.
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| 24. |
- Fransen, M. F., et al.
(author)
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A Restricted Role for FcgammaR in the Regulation of Adaptive Immunity
- 2018
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In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 200:8, s. 2615-2626
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Journal article (peer-reviewed)abstract
- By their interaction with IgG immune complexes, FcgammaR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcgammaR-knockout mice, it has been concluded that FcgammaRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcgammaRs (FcgammaRI/II/III/IV(-/-) mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcgammaRIIb-deficient mice, FcgammaRI/II/III/IV(-/-) mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcgammaRs in the modulation of the adaptive immune response in vivo. We conclude that FcgammaRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.
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| 25. |
- Johannesson, Martina, et al.
(author)
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Identification of epistasis through a partial advanced intercross reveals three arthritis loci within the Cia5 QTL in mice
- 2005
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In: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 6:3, s. 175-185
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Journal article (peer-reviewed)abstract
- Identification of genes controlling complex diseases has proven to be difficult; however, animal models may pave the way to determine how low penetrant genes interact to promote disease development. We have dissected the Cia5/Eae3 susceptibility locus on mouse chromosome 3 previously identified to control disease in experimental models of multiple sclerosis and rheumatoid arthritis. Congenic strains showed significant but small effects on severity of both diseases. To improve the penetrance, we have now used a new strategy that defines the genetic interactions. The QTL interacted with another locus on chromosome 15 and a partial advanced intercross breeding of the two congenic strains for eight generations accumulated enough statistical power to identify interactions with several loci on chromosome 15. Thereby, three separate loci within the original QTL could be identified; Cia5 affected the onset of arthritis by an additive interaction with Cia31 on chromosome 15, whereas the Cia21 and Cia22 affected severity during the chronic phase of the disease through an epistatic interaction with Cia32 on chromosome 15. The definition of genetic interactions was a prerequisite to dissect the Cia5 QTL and we suggest the partial advanced intercross strategy to be helpful also for dissecting other QTL controlling complex phenotypes.
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| 26. |
- Jose, Jiya, et al.
(author)
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Fabrication and functionalization of 3D-printed soft and hard scaffolds with growth factors for enhanced bioactivity
- 2020
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In: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 10:62, s. 37928-37937
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Journal article (peer-reviewed)abstract
- Strategies to improve the acceptance of scaffolds by the body is crucial in tissue engineering (TE) which requires tailoring of the pore structure, mechanical properties and surface characteristics of the scaffolds. In the current study we used a 3-dimensional (3D) printing technique to tailor the pore structure and mechanical properties of (i) nanocellulose based hydrogel scaffolds for soft tissue engineering and (ii) poly lactic acid (PLA) based scaffolds for hard tissue engineering in combination with surface treatment by protein conjugation for tuning the scaffold bioactivity. Dopamine coating of the scaffolds enhanced the hydrophilicity and their capability to bind bioactive molecules such as fibroblast growth factor (FGF-18) for soft TE scaffolds and arginyl glycyl aspartic acid (RGD) peptide for hard TE scaffolds, which was confirmed using MALDI-TOFs. This functionalization approach enhanced the performance of the scaffolds and provided antimicrobial activity indicating that these scaffolds can be used for cartilage or bone regeneration applications. Blood compatibility studies revealed that both the materials were compatible with human red blood cells. Significant enhancement of cell attachment and proliferation confirmed the bioactivity of growth factor functionalized 3D printed soft and hard tissues. This approach of combining 3D printing with biological tuning of the interface is expected to significantly advance the development of biomedical materials related to soft and hard tissue engineering.
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| 27. |
- Kessel, C., et al.
(author)
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A single functional group substitution in c5a breaks B cell and T cell tolerance and protects against experimental arthritis
- 2014
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In: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 66:3, s. 610-621
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Journal article (peer-reviewed)abstract
- OBJECTIVE: A deficiency in C5 protects against arthritis development. However, there is currently no approach successfully translating these findings into arthritis therapy, as by targeting the key component, C5a. The aim of this study was to develop a vaccination strategy targeting C5a as therapy for patients with rheumatoid arthritis. METHODS: An anti-C5a vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (4NPA) into selected sites in the murine C5a molecule. C5a-4NPA variants were screened for their immunogenicity in mice on different arthritis-susceptible class II major histocompatibility complex (MHC) backgrounds. A candidate vaccine was tested for its impact on disease in a murine model of collagen-induced arthritis (CIA). Immunity toward endogenous C5a as well as type II collagen was monitored and characterized. RESULTS: Replacing a single tyrosine residue in position 35 (Y(35) ) with 4NPA allowed the generation of an anti-C5a vaccine, which partly protected mice against the development of CIA while strongly ameliorating the severity of clinical disease. Although differing in just 3 atoms from wild-type C5a (wtC5a), C5aY(35) 4NPA induced loss of T cell and B cell tolerance toward the endogenous protein in mice expressing class II MHC H-2(q) molecules. Despite differential B cell epitope recognition, antibodies induced by both wtC5a and C5aY(35) 4NPA neutralized C5a. Thus, anti-wtC5a IgG titers during arthritis priming were potentially of critical importance for disease protection, because high titers of C5a-neutralizing antibodies after disease onset were unable to reverse the course of arthritis. CONCLUSION: The results of this study suggest that the most effective anti-C5a treatment in arthritis can be accomplished using a preventive vaccination strategy, and that treatment using conventional biologic or small molecule strategies targeting the C5a/C5aR axis may miss the optimal window for therapeutic intervention during the subclinical priming phase of the disease.
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| 28. |
- Kulkarni, Kishore G, et al.
(author)
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Avoiding the Middle Income Trap : Evidence and Examination of Few Countries
- 2022
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In: Saudi Journal of Economics and Finance. - : Scholars Middle East Publisher. - 2523-9414 .- 2523-6563. ; 6:1, s. 29-36
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Research review (peer-reviewed)abstract
- The middle income trap is a spectre looming up in front of countries who have performed well to rise up to middle income level from the lower income level, and are hoping for a quick admission to upper income echelons. Unfortunately, the trap seems unavoidable for many middle income nations, as seen poignantly in the case of Argentina and even Brazil. This paper tries to pinpoint the performance parameters that distinguish countries such as Malaysia and Chile who have been successful in avoiding getting mired in the trap – and may be now even viewing it nonchalantly as just a mirage appearing during the development process. The parameters identified as probable positive forces include the pillars of the Global Competitive Index, in addition to the usual suspects appearing in economic growth theory and estimations. Estimation of coefficients was carried by cross-country regressions using a sample of seventy upper and lower income nations. ICT adaptation, innovative capabilities, health standards, and openness as represented by FDI and export ratios to GDP were identified as parameters identified as important in closing the per capita income gap towards high income nations.
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| 29. |
- Kulkarni, Kishore G., et al.
(author)
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The Impact of Covid-19 on the Macro Economy with Special Reference to the USA
- 2021
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In: ANVESHAK- International Journal of Management. - : SCES's Indira Institute of Management. - 2278-8913 .- 2350-0794. ; 10:2, s. 132-161
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Journal article (peer-reviewed)abstract
- In this paper we investigate impacts of the pandemic on the US economy in the aggregate, and on various sectors and types of businesses and groups. Noting the theoretical premises that imply varying responses across country types, the developments in a number of some other countries are also touched upon. It is seen that while the “K” type recovery dominates in almost all countries, this similarity hides some differences. A general fiscal expansion is seen not to provide a lifeline out of them crisis as the recession is a mix of the demand and supply type, and different in a number of aspects from the financial crisis of 2007-09 as well as the oil price shock scenarios of the 1970s. Fiscal policies will have to be tailor-made, and can vary according to country needs, depending on the fiscal health of the country. Monetary expansion seems possible, given the low inflation risk. US monetary expansion can come as a boon to other countries opting for monetary expansion, since the risk for depreciation against the dollar is removed. Policies to help small businesses and disadvantaged groups can also help in boosting aggregate demand, but may not be continued indefinitely into the future as the behaviour patterns of economic agents may be then changed permanently.
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| 30. |
- Lahore, G. F., et al.
(author)
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Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases
- 2020
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:40, s. 24986-24997
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Journal article (peer-reviewed)abstract
- It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.
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| 31. |
- Lahore, GF, et al.
(author)
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Polymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 5565-
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Journal article (peer-reviewed)abstract
- Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors probably controls the sex discrepancy in the immune response, but the underlying mechanisms are unclear. Here we positionally identify a polymorphic estrogen receptor binding site that regulates Cd2 expression, leading to female-specific differences in T cell-dependent mouse models of autoimmunity. Female mice with reduced Cd2 expression have impaired autoreactive T cell responses. T cells lacking Cd2 costimulation upregulate inhibitory Lag-3. These findings help explain sexual dimorphism in human autoimmunity, as we find that CD2 polymorphisms are associated with rheumatoid arthritis and 17-β-estradiol-regulation of CD2 is conserved in human T cells. Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice. These results demonstrate the relevance of sex-genotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.
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| 32. |
- Nandakumar, M. P., et al.
(author)
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Integrated flow-injection processing for on-line quantification of plasmid DNA during cultivation of E. coli
- 2001
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In: Biotechnology and Bioengineering. - : Wiley. - 0006-3592 .- 1097-0290. ; 73:5, s. 406-411
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Journal article (peer-reviewed)abstract
- An integrated flow-injection processing (FIP) system for the quantification of plasmids during cultivation is described. The system performs on-line sampling, cell lysis, and quantification of plasmids in an integrated manner during cultivation of E. coli. The system was operated by using a miniaturized expanded-bed column which can be used for handling samples containing cells and cell debris without interfering with the binding analysis. Two types of detectors (one measuring UV absorbance at 254 nm and a fluorometer) are used for on-line plasmid detection. The system was developed using standard solutions and it was successfully applied in monitoring plasmid contents during a cultivation of E. coli.
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| 33. |
- Nandakumar, Madayi P., et al.
(author)
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Superporous agarose monoliths as mini-reactors in flow injection systems
- 2000
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In: Bioseparation. - 1573-8272. ; 9:4, s. 193-202
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Journal article (peer-reviewed)abstract
- A new type of agarose material, superporous agarose, was used as a support material in an analytical system designed for monitoring of bioprocesses with respect to metabolites and intracellular enzymes. The superporous agarose was used in the form of miniaturised gel plug columns (15×5.0 mM I.D. monolithic gel bed). The gel plugs were designed to have one set of very large pores (about 50 μm in diameter) through which cells, cell debris and other particulate contaminants from the bioreactor could easily pass. The material also had normal diffusion pores (300 Å) characteristic of all agarose materials, providing ample surface for covalent attachment of antibodies and enzymes used in the analytical sequence. The superporous agarose gel plug columns were characterised with respect to flow properties and handling of heavy cell loads as well as dispersion of injected samples (a Bodenstein number of about 40 was observed with acetone tracer at a flow rate of 1 ml min−1). To evaluate the practical performance of the superporous gel plug columns, two applications were studied: (1) on-line determination of glucose in cultivation broth (gel plug with immobilized glucose oxidase) and (2) immunochemical quantification of intracellular β-galactosidase in E. coli (gel plug with lysozyme to achieve cell lysis and gel plug with antibodies against β-galactosidase).
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| 34. |
- Nandakumar, M. P., et al.
(author)
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Variations in plasmid content during Escherichia coli cultivations detected by on-line flow injection processing
- 2001
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In: Biotechnology Letters. - 0141-5492. ; 23:14, s. 1135-1140
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Journal article (peer-reviewed)abstract
- An integrated flow injection process for analysis of intracellular components of microbes has been used to monitor plasmid content in Escherichia coli cultivations inoculated with cells subcultured in the presence or absence of ampicillin. The system allows sampling, sample handling, cell disruption, separation of intracellular components, and analysis in a semi-on-line mode of operation. The time scale for the assay is in the range 15 min (plasmid peak) to 25 min (complete assay cycle). As expected, lower initial plasmid content was found using an inoculum subcultured in the absence of ampicillin. More importantly, significant decrease in plasmid content was detected in the later stages of the cultivations (grown in ampicillin containing medium) even when using inoculum subcultured in the presence of ampicillin. This illustrates the versatility of the system, which allows monitoring of plasmid content as the cultivation proceeds.
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| 35. |
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| 36. |
- Pålsson, Eva, et al.
(author)
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Miniaturised expanded-bed column with low dispersion suitable for fast flow-ELISA analyses
- 2000
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In: Biotechnology Letters. - 0141-5492. ; 22, s. 245-250
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Journal article (peer-reviewed)abstract
- Flow-ELISA measurements of the monoclonal antibody concentration in cultivation broth containing murine hybriboma cells were carried out using a small expanded-bed column (0.5×2.5 cm) charged with protein A. A new specialised pellicular agarose/stainless steel matrix designed for high flow rates with fast mass transport properties was used. Special care was taken to get an efficient flow distribution. The axial dispersion coefficient was very low (2×10−6 m2 s−1 for latex particles at a linear velocity of 10 cm min−1). Breakthrough curves for polyclonal IgG on the protein A-derivatised support (at 2–11 cm min−1) further emphasised its advantageous properties. No significant change in dynamic capacity was found over the entire speed range.
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| 37. |
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| 38. |
- Schultheis, M., et al.
(author)
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Baade's window and APOGEE Metallicities, ages, and chemical abundances
- 2017
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 600
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Journal article (peer-reviewed)abstract
- Context. Baade's window (BW) is one of the most observed Galactic bulge fields in terms of chemical abundances. Owing to its low and homogeneous interstellar absorption it is considered the perfect calibration field for Galactic bulge studies. Aims. In the era of large spectroscopic surveys, calibration fields such as BW are necessary for cross calibrating the stellar parameters and individual abundances of the APOGEE survey. Methods. We use the APOGEE BW stars to derive the metallicity distribution function (MDF) and individual abundances for alpha- and iron-peak elements of the APOGEE ASPCAP pipeline (DR13), as well as the age distribution for stars in BW. Results. We determine the MDF of APOGEE stars in BW and find a remarkable agreement with that of the Gaia-ESO survey (GES). Both exhibit a clear bimodal distribution. We also find that the Mg-metallicity planes of the two surveys agree well, except for the metal-rich part ([Fe/H] > 0.1), where APOGEE finds systematically higher Mg abundances with respect to the GES. The ages based on the [C/N] ratio reveal a bimodal age distribution, with a major old population at similar to 10 Gyr, with a decreasing tail towards younger stars. A comparison of stellar parameters determined by APOGEE and those determined by other sources reveals detectable systematic offsets, in particular for spectroscopic surface gravity estimates. In general, we find a good agreement between individual abundances of O,Na, Mg, Al, Si, K, Ca, Cr, Mn, Co, and Ni from APOGEE with that of literature values. Conclusions. We have shown that in general APOGEE data show a good agreement in terms of MDF and individual chemical abundances with respect to literature works. Using the [C/N] ratio we found a significant fraction of young stars in BW.
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| 39. |
- Styriakova, I, et al.
(author)
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Bacterial destruction of mica during bioleaching of kaolin and quartz sand by Bacillus cereus
- 2003
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In: World Journal of Microbiology & Biotechnology. - 0959-3993. ; 19:6, s. 583-590
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Journal article (peer-reviewed)abstract
- Growth and metabolic activities of Bacillus cereus were found to cause the extraction of iron atoms from the octahedral position in mica in the kaolin sample (49%) and in the quartz sands sample (17%) after 3 months of bioleaching, while aluminium removal was only 5%. Mica destruction was detected in kaolin and quartz sands samples by X-ray diffraction analysis and also by i.r. adsorption spectroscopy in quartz sands samples. The structural changes obtained were confirmed by scanning electron microscopy (SEM) analysis. The SEM pictures show a different morphology in the boundary region of mica grains before and after bioleaching. Bacterial destruction effects were feeble in the interlayer sites and were specially directed to split planes, which are occupied by a number of bacterial cells. The biological destruction of mica with phengite composition after iron removal led to development of illite, which was detected by energy-dispersion microanalysis (EDS). Illite development caused also the enrichment of the kaolin sample by fine-grained fraction.
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| 40. |
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| 41. |
- Wagué, Cheick, et al.
(author)
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The Contrasting Nature of Global Value Chains in high Income Countries and Developing Nations
- 2021
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In: International Journal of Business, Economics and Laws. - 2289-1552. ; 25:1, s. 51-57
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Journal article (peer-reviewed)abstract
- Global value chain linkages exhibited by high income nations, emerging market nations and the African countries are examined.It is noted that the upper income countries have more global supply chain linkages, which tend to be more of the backward linkagetype, being more active in the downstream part of the production processes. African nations have lower total and backward globalvalue chain linkages, and they are more upstream in production processes, exporting intermediate goods that are used for exportsproduction by trading partners. Examining the regional aspects of global supply chain linkages, it is noted that the EuropeanUnion countries have more global value chain linkages within themselves, thus substantiating the rationale for forming a unionamong themselves. The East and Southeast Asian group of countries have greatest global value chain linkages within the group,while African nations have low global value chain linkages among themselves. This observation raises the question whether theattempts to form monetary unions in Africa have followed the customary sequence of trade liberalization and expansion prior tomonetary integration.
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| 42. |
- Wagué, Cheick, et al.
(author)
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The Nordic model : a promise of prosperity for all?
- 2017
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Book (other academic/artistic)abstract
- The Nordic countries top every survey on overall well-being and expressed happiness and satisfaction with living conditions and the environment, and, moreover, emerge on top even in measures of global competitiveness. This book unravels the unique economic and social processes by which these countries have achieved such universally acclaimed success. The authors note that the Nordic success has not been a sudden surge forward, and provide substance to the argument that conditions going back to feudal times, and unique societal relations and a social consensus allowing low power distances and smooth decentralization have played key roles in the Nordic transition into full-fledged knowledge economies. Indeed, as they note, “if there is a Valhalla for Nordic politicians, policy-makers and organization leaders, it will surely provide them an idyllic island under a mellow sun for holding amiable discussions, lowering their guards in a give-and-take spirit, on issues pertaining to the well-being of that Nordic paradise.”
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| 43. |
- Wigerblad, G., et al.
(author)
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Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism
- 2016
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 75:4, s. 730-738
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Journal article (peer-reviewed)abstract
- OBJECTIVE: An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. METHODS: Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. RESULTS: Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. CONCLUSIONS: The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.
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| 44. |
- Zhang, Jingjing, 1986, et al.
(author)
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The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells.
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Breast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR). In meiosis, BRCA2 binds to MEILB2 to localize to DNA double-strand breaks (DSBs). Here, we identify BRCA2 and MEILB2-associating protein 1 (BRME1), which functions as a stabilizer of MEILB2 by binding to an α-helical N-terminus of MEILB2 and preventing MEILB2 self-association. BRCA2 binds to the C-terminus of MEILB2, resulting in the formation of the BRCA2-MEILB2-BRME1 ternary complex. In Brme1 knockout (Brme1-/-) mice, the BRCA2-MEILB2 complex is destabilized, leading to defects in DSB repair, homolog synapsis, and crossover formation. Persistent DSBs in Brme1-/- reactivate the somatic-like DNA-damage response, which repairs DSBs but cannot complement the crossover formation defects. Further, MEILB2-BRME1 is activated in many human cancers, and somatically expressed MEILB2-BRME1 impairs mitotic HR. Thus, the meiotic BRCA2 complex is central in meiotic HR, and its misregulation is implicated in cancer development.
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