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  • 1
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 99, No. 5 ( 2016-05-01), p. 749-760
    Abstract: The cytokine IL-6 is part of a regulatory signaling network that controls immune responses. IL-6 binds either to the membrane-bound IL-6 receptor-α (classic signaling) or to the soluble IL-6 receptor-α (trans-signaling) to initiate signal transduction via gp130 activation. Because classic and trans-signaling of IL-6 fulfill different tasks during immune responses, controlled shedding of the membrane-bound IL-6 receptor-α from the surface of immune cells can be considered a central regulator of IL-6 function. The results from cell culture-based experiments have implicated both a disintegrin and metalloprotease 10 and a disintegrin and metalloprotease 17 in IL-6 receptor-α shedding. However, the nature of the protease mediating IL-6 receptor-α release in vivo is not yet known. We used hypomorphic a disintegrin and metalloprotease 17 mice and conditional a disintegrin and metalloprotease 10 knock-out mice to identify the natural protease of the murine IL-6 receptor-α. Circulating homeostatic soluble IL-6 receptor-α levels are not dependent on a disintegrin and metalloprotease 10 or 17 activity. However, during Listeria monocytogenes infection, IL-6 receptor-α cleavage by the α-secretase a disintegrin and metalloprotease 17 is rapidly induced from the surface of different leukocyte populations. In contrast, CD4-Cre-driven a disintegrin and metalloprotease 10 deletion in T cells did not influence IL-6 receptor-α shedding from these cells after L. monocytogenes infection. A disintegrin and metalloprotease 17 was also required for IL-6 receptor-α ectodomain cleavage and release during endotoxemia. These results demonstrate a novel physiologic role for a disintegrin and metalloprotease 17 in regulating murine IL-6 signals during inflammatory processes.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 2026833-6
    SSG: 12
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  • 2
    In: Genetics, Oxford University Press (OUP), Vol. 196, No. 4 ( 2014-04-01), p. 985-999
    Abstract: DNA damage by ultraviolet (UV) light poses a risk for mutagenesis and a potential hindrance for cell cycle progression. Cells cope with UV-induced DNA damage through two general strategies to repair the damaged nucleotides and to promote cell cycle progression in the presence of UV-damaged DNA. Defining the genetic pathways and understanding how they function together to enable effective tolerance to UV remains an important area of research. The structural maintenance of chromosomes (SMC) proteins form distinct complexes that maintain genome stability during chromosome segregation, homologous recombination, and DNA replication. Using a forward genetic screen, we identified two alleles of smc-5 that exacerbate UV sensitivity in Caenorhabditis elegans. Germ cells of smc-5-defective animals show reduced proliferation, sensitivity to perturbed replication, chromatin bridge formation, and accumulation of RAD-51 foci that indicate the activation of homologous recombination at DNA double-strand breaks. Mutations in the translesion synthesis polymerase polh-1 act synergistically with smc-5 mutations in provoking genome instability after UV-induced DNA damage. In contrast, the DNA damage accumulation and sensitivity of smc-5 mutant strains to replication impediments are suppressed by mutations in the C. elegans BRCA1/BARD1 homologs, brc-1 and brd-1. We propose that SMC-5/6 promotes replication fork stability and facilitates recombination-dependent repair when the BRC-1/BRD-1 complex initiates homologous recombination at stalled replication forks. Our data suggest that BRC-1/BRD-1 can both promote and antagonize genome stability depending on whether homologous recombination is initiated during DNA double-strand break repair or during replication stalling.
    Type of Medium: Online Resource
    ISSN: 1943-2631
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2014
    detail.hit.zdb_id: 1477228-0
    SSG: 12
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  • 3
    In: JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 111, No. 2 ( 2019-02-01), p. 146-157
    Abstract: Previous genome-wide association studies (GWAS) have identified 42 loci (P 〈 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P 〈 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P 〈 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
    Type of Medium: Online Resource
    ISSN: 0027-8874 , 1460-2105
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2992-0
    detail.hit.zdb_id: 1465951-7
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  • 4
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 119, No. 3 ( 2023-05-02), p. 857-866
    Abstract: The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. Methods and results We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10−08) and was replicated in an independent case–control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10−16), GATA4 (P = 1.61 × 10−09), and TEX41 (P = 7.68 × 10−04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Conclusion Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.
    Type of Medium: Online Resource
    ISSN: 0008-6363 , 1755-3245
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1499917-1
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  • 5
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 25, No. 15 ( 2016-08-01), p. 3383-3394
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2020
    In:  Brain Communications Vol. 2, No. 2 ( 2020-07-01)
    In: Brain Communications, Oxford University Press (OUP), Vol. 2, No. 2 ( 2020-07-01)
    Abstract: The ability to communicate, functionally, after stroke or other types of acquired brain injury is crucial for the person involved and the people around them. Accordingly, assessment of functional communication is increasingly used in large-scale randomized controlled trials as the primary outcome measure. Despite the importance of functional communication abilities to everyday life and their centrality to the measured efficacy of aphasia interventions, there is little knowledge about how commonly used measures of functional communication relate to each other, whether they capture and grade the full range of patients’ remaining communication skills and how these abilities relate to the patients’ verbal and non-verbal impairments as well as the underpinning lesions. Going beyond language-only factors is essential given that non-verbal abilities can play a crucial role in an individual’s ability to communicate effectively. This study, based on a large sample of patients covering the full range and types of post-stroke aphasia, addressed these important, open questions. The investigation combined data from three established measures of functional communication with a thorough assessment of verbal and non-verbal cognition as well as structural neuroimaging. The key findings included: (i) due to floor or ceiling effects, the full range of patients’ functional communication abilities was not captured by a single assessment alone, limiting the utility of adopting individual tests as outcome measures in randomized controlled trials; (ii) phonological abilities were most strongly related to all measures of functional communication and (iii) non-verbal cognition was particularly crucial when language production was relatively impaired and other modes of communication were allowed, when patients rated their own communication abilities, and when carers rated patients’ basic communication abilities. Finally, in addition to lesion load being significantly related to all measures of functional communication, lesion analyses showed partially overlapping clusters in language regions for the functional communication tests. Moreover, mirroring the findings from the regression analyses, additional regions previously associated with non-verbal cognition emerged for the Scenario Test and for the Patient Communication Outcome after Stroke rating scale. In conclusion, our findings elucidated the cognitive and neural bases of functional communication abilities, which may inform future clinical practice regarding assessments and therapy. In particular, it is necessary to use more than one measure to capture the full range and multifaceted nature of patients’ functional communication abilities and a therapeutic focus on non-verbal cognition might have positive effects on this important aspect of activity and participation.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 3020013-1
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  • 7
    In: Biology of Reproduction, Oxford University Press (OUP), Vol. 94, No. 5 ( 2016-05-01)
    Type of Medium: Online Resource
    ISSN: 0006-3363 , 1529-7268
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 1469812-2
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2023
    In:  Journal of Public Health ( 2023-11-20)
    In: Journal of Public Health, Oxford University Press (OUP), ( 2023-11-20)
    Abstract: Governments around the world used mobile vaccination units (MVUs) to increase COVID-19 vaccine uptake, but the causal effect of MVUs has not yet been evaluated. Methods In a randomized controlled trial (RCT) with 20 Swiss communities (10 treatment, 10 control) in August 2021, MVUs were sent to treatment communities for 4 hours on a single day. The experimental sample comprises 20 414 adults who were unvaccinated against COVID-19 at this point. The researchers designed the RCT and the government introduced the idea to test the effectiveness of MVUs and was responsible for administering the vaccines. Results The vaccination rate in the sample of the treatment group surpassed the rate in the control group by a factor of 3.4 (+9.0 percentage points) over 3 weeks. The increase was present and highly statistically significant for women, men and for all age groups. We found no evidence of cannibalization of vaccinations at other service locations. Conclusions The offer of MVUs is highly effective in raising vaccination rates, even at a later point in the vaccination campaign. The absence of cannibalization effects suggests that MVUs reach more people overall, not just faster.
    Type of Medium: Online Resource
    ISSN: 1741-3842 , 1741-3850
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1497445-9
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