| 191. |
- Delgado-Vega, Angelica M., et al.
(author)
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Replication of the TNFSF4 (OX40L) promoter region association with systemic lupus erythematosus
- 2009
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In: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 10:3, s. 248-253
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Journal article (peer-reviewed)abstract
- The tumor necrosis factor ligand superfamily member 4 gene (TNFSF4) encodes the OX40 ligand (OX40L), a costimulatory molecule involved in T-cell activation. A recent study demonstrated the association of TNFSF4 haplotypes located in the upstream region with risk for or protection from systemic lupus erythematosus (SLE). To replicate this association, five single nucleotide polymorphisms (SNPs) tagging the previously associated haplotypes and passing the proper quality-control filters were tested in 1312 cases and 1801 controls from Germany, Italy, Spain and Argentina. The association of TNFSF4 with SLE was replicated in all the sets except Spain. There was a unique risk haplotype tagged by the minor alleles of the SNPs rs1234317 (pooled odds ratio (OR)=1.39, P=0.0009) and rs12039904 (pooled OR=1.38, P=0.0012). We did not observe association to a single protective marker (rs844644) or haplotype as the first study reported; instead, we observed different protective haplotypes, all carrying the major alleles of both SNPs rs1234317 and rs12039904. Association analysis conditioning on the haplotypic background confirmed that these two SNPs explain the entire haplotype effect. This first replication study confirms the association of genetic variation in the upstream region of TNFSF4 with susceptibility to SLE.
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| 192. |
- Ebarasi, Lwaki, et al.
(author)
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Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome
- 2015
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:1, s. 153-161
-
Journal article (peer-reviewed)abstract
- Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.
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| 193. |
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| 194. |
- Espaillat, Akbar, master, 1988-, et al.
(author)
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A distinctive family of L,D-transpeptidases catalyzing L-Ala-mDAP crosslinks in Alpha- and Betaproteobacteria
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- The bacterial cell-wall peptidoglycan is made of glycan strands crosslinked by short peptide stems. Crosslinks are catalyzed by DD-transpeptidases (4,3-crosslinks) and LD-transpeptidases (3,3-crosslinks). However, recent research on non-model species has revealed novel crosslink types, suggesting the existence of uncharacterized enzymes. Here, we identify an LD-transpeptidase, LDTGo, that generates 1,3-crosslinks in the acetic-acid bacterium Gluconobacter oxydans. LDTGo-like proteins are found in Alpha- and Betaproteobacteria lacking LD3,3-transpeptidases. In contrast with the strict specificity of typical LD- and DD-transpeptidases, LDTGo can use non-terminal amino acid moieties for crosslinking. A high-resolution crystal structure of LDTGo reveals unique features when compared to LD3,3-transpeptidases, including a proline-rich region that appears to limit substrate access, and a cavity accommodating both glycan chain and peptide stem from donor muropeptides. Finally, we show that DD-crosslink turnover is involved in supplying the necessary substrate for LD1,3-transpeptidation. This phenomenon underscores the interplay between distinct crosslinking mechanisms in maintaining cell wall integrity in G. oxydans.
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| 195. |
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| 196. |
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| 197. |
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| 198. |
- Huynh-Le, MP, et al.
(author)
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Polygenic hazard score is associated with prostate cancer in multi-ethnic populations
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 1236-
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Journal article (peer-reviewed)abstract
- Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10−180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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| 199. |
- Jiménez-Ruano, A., et al.
(author)
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Assessing human-caused wildfire ignition likelihood across Europe
- 2023
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In: Int. Conf. Smart Sustain. Technol., SpliTech. - : Institute of Electrical and Electronics Engineers Inc.. - 9789532901283
-
Conference paper (peer-reviewed)abstract
- Fire ignition probability is an essential component of most fire risk assessment frameworks. This study, framed within the H2020 project FirEUrisk, features a cohesive modelling approach in a set of representative regions (pilot sites; PS) in terms of fire activity across the European territory. These PS encompass different wildfire regimes in contrasting environmental settings: PS-1 Northern Europe, Kalmar Iän (South-East Sweden); PS-2 Central Europe, Southern Brandenburg and Eastern Saxony (Germany), North Bohemia (Czechia), and Lower Silesia (Poland); PS-3 Central Portugal; PS-4 Barcelona province (Spain); and PS-5 Attica region (Greece). Our main goal was to develop a common approach to model human-caused ignitions at a fine-grained spatial resolution (100 meters). For each pilot site we: (i) ascertain which factors influence ignition, hence, addressing potential differences in driving forces and, (ii) provide a spatial-explicit depiction of the patterns of ignition probability. For that propose, we fitted a Random Forest (RF) model in each PS from historical fire records (compiled by local fire agencies) and geospatial layers for land cover, accessibility, and population related factors. All models attained a high predictive accuracy, with AUCs that ranging from 0.69 (Northern Europe) to 0.89 (Attica Region). In turn, the most relevant explanatory variable was the population density that ranked most influential in four out of the five PS, followed by the fuel type, distance to roads, distance to the WUI, and percent cover of forest and wildlands. These findings are a valuable product to upscale future solutions at regional level (beyond NUTS3-type areas), conduct fire behavior modelling simulations, and enrich the science-based decisions which come from the forest and fire management agents at national and European level. © 2023 University of Split, FESB.
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