| 1. |
- Elfageih, Rageia, et al.
(author)
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Cotranslational folding of alkaline phosphatase in the periplasm of Escherichia coli
- 2020
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In: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 29:10, s. 2028-2037
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Journal article (peer-reviewed)abstract
- Cotranslational protein folding studies using Force Profile Analysis, a method where the SecM translational arrest peptide is used to detect folding-induced forces acting on the nascent polypeptide, have so far been limited mainly to small domains of cytosolic proteins that fold in close proximity to the translating ribosome. In this study, we investigate the cotranslational folding of the periplasmic, disulfide bond-containing Escherichia coli protein alkaline phosphatase (PhoA) in a wild-type strain background and a strain background devoid of the periplasmic thiol: disulfide interchange protein DsbA. We find that folding-induced forces can be transmitted via the nascent chain from the periplasm to the polypeptide transferase center in the ribosome, a distance of similar to 160 angstrom, and that PhoA appears to fold cotranslationally via at least two disulfide-stabilized folding intermediates. Thus, Force Profile Analysis can be used to study cotranslational folding of proteins in an extra-cytosolic compartment, like the periplasm.
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| 2. |
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| 3. |
- Evangelou, Evangelos, et al.
(author)
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A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
- 2014
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In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 73:12, s. 2130-2136
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Journal article (peer-reviewed)abstract
- Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
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| 4. |
- Gaulton, Kyle J, et al.
(author)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Journal article (peer-reviewed)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.
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| 5. |
- Goossens, Maria E., et al.
(author)
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International pooled study on diet and bladder cancer : the bladder cancer, epidemiology and nutritional determinants (BLEND) study: design and baseline characteristics
- 2016
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In: Archives of Public Health. - : BMC. - 0778-7367 .- 2049-3258. ; 74
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Journal article (peer-reviewed)abstract
- Background: In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7th most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage. Methods/design: The BLadder cancer, Epidemiology and Nutritional Determinants (BLEND) study was set up with the purpose of collecting individual patient data from observational studies on diet and bladder cancer. In total, data from 11,261 bladder cancer cases and 675,532 non-cases from 18 case-control and 6 cohort studies from all over the world were included with the aim to investigate the association between individual food items, nutrients and dietary patterns and risk of developing bladder cancer. Discussion: The substantial number of cases included in this study will enable us to provide evidence with large statistical power, for dietary recommendations on the prevention of bladder cancer.
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| 6. |
- Grant, Marianne K O, et al.
(author)
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Human cerebrospinal fluid 6E10-immunoreactive protein species contain amyloid precursor protein fragments.
- 2019
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 14:2
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Journal article (peer-reviewed)abstract
- In a previous study, we reported that levels of two types of protein species-a type of ~55-kDa species and a type of ~15-kDa species-are elevated in the lumbar cerebrospinal fluid (CSF) of cognitively intact elderly individuals who are at risk for Alzheimer's disease (AD). These species are immunoreactive to the monoclonal antibody 6E10, which is directed against amino acids 6-10 of amyloid-β (Aβ), and their levels correlate with levels of total tau and tau phosphorylated at Thr181. In this study, we investigated the molecular composition of these AD-related proteins using immunoprecipitation (IP)/Western blotting coupled with IP/mass spectrometry. We show that canonical Aβ1-40/42 peptides, together with amyloid-β precursor protein (APP) fragments located N-terminally of Aβ, are present in the ~55-kDa, 6E10-immunoreactive species. We demonstrate that APP fragments located N-terminally of Aβ, plus the N-terminal region of Aβ, are present in the ~15-kDa, 6E10-immunoreactive species. These findings add to the catalog of AD-related Aβ/APP species found in CSF and should motivate further study to determine whether these species may serve as biomarkers of disease progression.
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| 7. |
- Grant, T. M., et al.
(author)
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Towards eco-friendly marine antifouling biocides-Nature inspired tetrasubstituted 2,5-diketopiperazines
- 2022
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In: Science of the Total Environment. - : Elsevier BV. - 0048-9697. ; 812
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Journal article (peer-reviewed)abstract
- Marine biofouling plagues all maritime industries at vast economic and environmental cost. Previous and most current methods to control biofouling have employed highly persistent toxins and heavy metals, including tin, copper, and zinc. These toxic methods are resulting in unacceptable environmental harm and are coming under immense regulatory pressure. Eco-friendly alternatives are urgently required to effectively mitigate the negative consequence of biofouling without causing collateral harm. Amphiphilic micropeptides have recently been shown to exhibit excellent broad-spectrum antifouling activity, with a non-toxic mode of action and innate biodegradability. The present work focused on incorporating the pharmacophore derived from amphiphilic micropeptides into a 2,5-diketopiperazine (DKP) scaffold. This privileged structure is present in a vast number of natural products, including marine natural product antifoulants, and provides advantages of synthetic accessibility and adaptability. A novel route to symmetrical tetrasubstituted DKPs was developed and a library of amphiphilic 2,5-DKPs were subsequently synthesised. These biodegradable compounds were demonstrated to be potent marine antifoulants displaying broad-spectrum activity in the low micromolar range against a range of common marine fouling organisms. The outcome of planned coating and field trials will dictate the future development of the lead compounds.
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| 8. |
- John, Ben Malinga, 1988-
(author)
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Union-Fertility Nexus and Fertility Variation in Sub-Saharan Africa : The Role of Marital Dissolution and Repartnering
- 2024
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Doctoral thesis (other academic/artistic)abstract
- The role of marital dissolution and repartnering in shaping fertility patterns in sub-Saharan Africa (SSA) has been largely overlooked, even though marital dissolution and repartnering are fundamental features of marriage dynamics in this region. This dissertation addresses this gap by using existing statistical and demographic techniques and developing new demographic methods to (i) examine the relationship between union dissolution and fertility at the micro level (Study I); (ii) assess the dynamics of union dissolution, including the levels of all-cause first union dissolution, the timing of first union dissolution, and the reproductive years spent outside of marriage due to union dissolution (Studies II & III); and (iii) analyze the influence of marital dissolution and repartnering on macro fertility patterns in SSA (Study IV). The analyses are mainly based on Demographic Health Survey data collected in 34 SSA countries since 1986. The findings show that marital dissolution is associated with reduced fertility at both the individual and the population level, and remarriage does not fully compensate for lost fertility at the individual level. The assessment of the dynamics of union dissolution indicates that union dissolution is common, it typically occurs at relatively early reproductive ages, and the number of reproductive years lost due to union dissolution is minimal. Furthermore, this dissertation documents that cross-country differences in union dissolution and repartnering rates account for 9.4% of cross-country fertility differences in SSA. In addition, the results show that changes in marital dissolution and repartnering rates and the fertility behaviour of women who experience these events mostly contributed to the slow pace of fertility decline in this region. For the SSA region (as a whole), fertility would have declined 1.24 times faster in the absence of such changes. These findings demonstrate that marital dissolution and repartnering are important drivers of fertility variation in SSA, and thus highlight the value of integrating these dynamics into the discourse on the union-fertility nexus and fertility variation in SSA and beyond.
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| 9. |
- Kemp, Grant, et al.
(author)
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Cotranslational folding cooperativity of contiguousdomains of α-spectrin
- 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. ; 117:25, s. 14119-14126
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Journal article (peer-reviewed)abstract
- Proteins synthesized in the cell can begin to fold during translation before the entire polypeptide has been produced, which may be particularly relevant to the folding of multidomain proteins. Here, we study the cotranslational folding of adjacent domains from the cytoskeletal protein α-spectrin using force profile analysis (FPA). Specifically, we investigate how the cotranslational folding behavior of the R15 and R16 domains are affected by their neighboring R14 and R16, and R15 and R17 domains, respectively. Our results show that the domains impact each other’s folding in distinct ways that may be important for the efficient assembly of α-spectrin, and may reduce its dependence on chaperones. Furthermore, we directly relate the experimentally observed yield of full-length protein in the FPA assay to the force exerted by the folding protein in piconewtons. By combining pulse-chase experiments to measure the rate at which the arrested protein is converted into full-length protein with a Bell model of force-induced rupture, we estimate that the R16 domain exerts a maximal force on the nascent chain of ∼15 pN during cotranslational folding.
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| 10. |
- Kemp, Grant, et al.
(author)
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Force-Profile Analysis of the Cotranslational Folding of HemK and Filamin Domains : Comparison of Biochemical and Biophysical Folding Assays
- 2019
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In: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 431:6, s. 1308-1314
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Journal article (peer-reviewed)abstract
- We have characterized the cotranslational folding of two small protein domains of different folds-the alpha-helical N-terminal domain of HemK and the beta-rich FLN5 filamin domain-by measuring the force that the folding protein exerts on the nascent chain when located in different parts of the ribosome exit tunnel (force-profile analysis, or FPA), allowing us to compare FPA to three other techniques currently used to study cotranslational folding: real-time FRET, photo induced electron transfer, and NMR. We find that FPA identifies the same cotranslational folding transitions as do the other methods, and that these techniques therefore reflect the same basic process of cotranslational folding in similar ways.
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