| 1. |
-
- 2019
-
Tidskriftsartikel (refereegranskat)
|
|
| 2. |
- Meagher, N. S., et al.
(författare)
-
Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes
- 2022
-
Ingår i: Clinical Cancer Research. - 1078-0432. ; 28:24, s. 5383-5395
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primaryMOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and geneexpression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors ( MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio ( HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
|
|
| 3. |
- Cronin, M. F., et al.
(författare)
-
Developing an Observing Air-Sea Interactions Strategy (OASIS) for the global ocean
- 2022
-
Ingår i: Ices Journal of Marine Science. - : Oxford University Press (OUP). - 1054-3139 .- 1095-9289. ; 80:2, s. 367-73
-
Tidskriftsartikel (refereegranskat)abstract
- The Observing Air-Sea Interactions Strategy (OASIS) is a new United Nations Decade of Ocean Science for Sustainable Development programme working to develop a practical, integrated approach for observing air-sea interactions globally for improved Earth system (including ecosystem) forecasts, CO2 uptake assessments called for by the Paris Agreement, and invaluable surface ocean information for decision makers. Our "Theory of Change" relies upon leveraged multi-disciplinary activities, partnerships, and capacity strengthening. Recommendations from >40 OceanObs'19 community papers and a series of workshops have been consolidated into three interlinked Grand Ideas for creating #1: a globally distributed network of mobile air-sea observing platforms built around an expanded array of long-term time-series stations; #2: a satellite network, with high spatial and temporal resolution, optimized for measuring air-sea fluxes; and #3: improved representation of air-sea coupling in a hierarchy of Earth system models. OASIS activities are organized across five Theme Teams: (1) Observing Network Design & Model Improvement; (2) Partnership & Capacity Strengthening; (3) UN Decade OASIS Actions; (4) Best Practices & Interoperability Experiments; and (5) Findable-Accessible-Interoperable-Reusable (FAIR) models, data, and OASIS products. Stakeholders, including researchers, are actively recruited to participate in Theme Teams to help promote a predicted, safe, clean, healthy, resilient, and productive ocean.
|
|
| 4. |
- Naito, R., et al.
(författare)
-
Impact of social isolation on mortality and morbidity in 20 high-income, middle-income and low-income countries in five continents
- 2021
-
Ingår i: Bmj Global Health. - : BMJ. - 2059-7908. ; 6:3
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To examine the association between social isolation and mortality and incident diseases in middle-aged adults in urban and rural communities from high-income, middle-income and low-income countries. Design Population-based prospective observational study. Setting Urban and rural communities in 20 high income, middle income and low income. Participants 119 894 community-dwelling middle-aged adults. Main outcome measures Associations of social isolation with mortality, cardiovascular death, non-cardiovascular death and incident diseases. Results Social isolation was more common in middle-income and high-income countries compared with low-income countries, in urban areas than rural areas, in older individuals and among women, those with less education and the unemployed. It was more frequent among smokers and those with a poorer diet. Social isolation was associated with greater risk of mortality (HR of 1.26, 95% CI: 1.17 to 1.36), incident stroke (HR: 1.23, 95% CI: 1.07 to 1.40), cardiovascular disease (HR: 1.15, 95% CI: 1.05 to 1.25) and pneumonia (HR: 1.22, 95% CI: 1.09 to 1.37), but not cancer. The associations between social isolation and mortality were observed in populations in high-income, middle-income and low-income countries (HR (95% CI): 1.69 (1.32 to 2.17), 1.27 (1.15 to 1.40) and 1.47 (1.25 to 1.73), respectively, interaction p=0.02). The HR associated with social isolation was greater in men than women and in younger than older individuals. Mediation analyses for the association between social isolation and mortality showed that unhealthy behaviours and comorbidities may account for about one-fifth of the association. Conclusion Social isolation is associated with increased risk of mortality in countries at different economic levels. The increasing share of older people in populations in many countries argues for targeted strategies to mitigate its adverse effects.
|
|
| 5. |
- Cheung, K. H., et al.
(författare)
-
Extending gene ontology in the context of extracellular RNA and vesicle communication
- 2016
-
Ingår i: Journal of Biomedical Semantics. - : Springer Science and Business Media LLC. - 2041-1480. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: To address the lack of standard terminology to describe extracellular RNA (exRNA) data/metadata, we have launched an inter-community effort to extend the Gene Ontology (GO) with subcellular structure concepts relevant to the exRNA domain. By extending GO in this manner, the exRNA data/metadata will be more easily annotated and queried because it will be based on a shared set of terms and relationships relevant to extracellular research. Methods: By following a consensus-building process, we have worked with several academic societies/consortia, including ERCC, ISEV, and ASEMV, to identify and approve a set of exRNA and extracellular vesicle-related terms and relationships that have been incorporated into GO. In addition, we have initiated an ongoing process of extractions of gene product annotations associated with these terms from Vesiclepedia and ExoCarta, conversion of the extracted annotations to Gene Association File (GAF) format for batch submission to GO, and curation of the submitted annotations by the GO Consortium. As a use case, we have incorporated some of the GO terms into annotations of samples from the exRNA Atlas and implemented a faceted search interface based on such annotations. Results: We have added 7 new terms and modified 9 existing terms (along with their synonyms and relationships) to GO. Additionally, 18,695 unique coding gene products (mRNAs and proteins) and 963 unique non-coding gene products (ncRNAs) which are associated with the terms: "extracellular vesicle", "extracellular exosome", "apoptotic body", and "microvesicle" were extracted from ExoCarta and Vesiclepedia. These annotations are currently being processed for submission to GO. Conclusions: As an inter-community effort, we have made a substantial update to GO in the exRNA context. We have also demonstrated the utility of some of the new GO terms for sample annotation and metadata search.
|
|
| 6. |
- Rosengren, Annika, 1951, et al.
(författare)
-
Education and risk for acute myocardial infarction in 52 high, middle and low-income countries: INTERHEART case-control study
- 2009
-
Ingår i: Heart. - 1468-201X. ; 95:24, s. 2014-22
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the effect of education and other measures of socioeconomic status (SES) on risk of acute myocardial infarction (AMI) in patients and controls from countries with diverse economic circumstances (high, middle, and low income countries). DESIGN: Case-control study. SETTING: 52 countries from all inhabited regions of the world. PARTICIPANTS: 12242 cases and 14622 controls. MAIN OUTCOME MEASURES: First non-fatal AMI. RESULTS: SES was measured using education, family income, possessions in the household and occupation. Low levels of education (< or =8 years) were more common in cases compared to controls (45.0% and 38.1%; p<0.0001). The odds ratio (OR) for low education adjusted for age, sex and region was 1.56 (95% confidence interval 1.47 to 1.66). After further adjustment for psychosocial, lifestyle, other factors and mutually for other socioeconomic factors, the OR associated with education < or =8 years was 1.31 (1.20 to 1.44) (p<0.0001). Modifiable lifestyle factors (smoking, exercise, consumption of vegetables and fruits, alcohol and abdominal obesity) explained about half of the socioeconomic gradient. Family income, numbers of possessions and non-professional occupation were only weakly or not at all independently related to AMI. In high-income countries (World Bank Classification), the risk factor adjusted OR associated with low education was 1.61 (1.33 to 1.94), whereas it was substantially lower in low-income and middle-income countries: 1.25 (1.14 to 1.37) (p for interaction 0.045). CONCLUSION: Of the SES measures we studied, low education was the marker most consistently associated with increased risk for AMI globally, most markedly in high-income countries.
|
|
| 7. |
- Corsi, D. J., et al.
(författare)
-
Prospective Urban Rural Epidemiology (PURE) study: Baseline characteristics of the household sample and comparative analyses with national data in 17 countries
- 2013
-
Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 166:4, s. 636-646 e4
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The PURE study was established to investigate associations between social, behavioural, genetic, and environmental factors and cardiovascular diseases in 17 countries. In this analysis we compare the age, sex, urban/rural, mortality, and educational profiles of the PURE participants to national statistics. METHODS: PURE employed a community-based sampling and recruitment strategy where urban and rural communities were selected within countries. Within communities, representative samples of adults aged 35 to 70 years and their household members (n = 424,921) were invited for participation. RESULTS: The PURE household population compared to national statistics had more women (sex ratio 95.1 men per 100 women vs 100.3) and was older (33.1 years vs 27.3), although age had a positive linear relationship between the two data sources (Pearson's r = 0.92). PURE was 59.3% urban compared to an average of 63.1% in participating countries. The distribution of education was less than 7% different for each category, although PURE households typically had higher levels of education. For example, 37.8% of PURE household members had completed secondary education compared to 31.3% in the national data. Age-adjusted annual mortality rates showed positive correlation for men (r = 0.91) and women (r = 0.92) but were lower in PURE compared to national statistics (7.9 per 1000 vs 8.7 for men; 6.7 vs 8.1 for women). CONCLUSIONS: These findings indicate that modest differences exist between the PURE household population and national data for the indicators studied. These differences, however, are unlikely to have much influence on exposure-disease associations derived in PURE. Further, incidence estimates from PURE, stratified according to sex and/or urban/rural location will enable valid comparisons of the relative rates of various cardiovascular outcomes across countries.
|
|
| 8. |
- Coombes, D., et al.
(författare)
-
The basis for non-canonical ROK family function in the N-acetylmannosamine kinase from the pathogen Staphylococcus aureus
- 2020
-
Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 295:10, s. 3301-3315
-
Tidskriftsartikel (refereegranskat)abstract
- In environments where glucose is limited, some pathogenic bacteria metabolize host-derived sialic acid as a nutrient source. N-Acetylmannosamine kinase (NanK) is the second enzyme of the bacterial sialic acid import and degradation pathway and adds phosphate to N-acetylmannosamine using ATP to prime the molecule for future pathway reactions. Sequence alignments reveal that Gram-positive NanK enzymes belong to the Repressor, ORF, Kinase (ROK) family, but many lack the canonical Zn-binding motif expected for this function, and the sugar-binding EXGH motif is altered to EXGY. As a result, it is unclear how they perform this important reaction. Here, we study the Staphylococcus aureus NanK (SaNanK), which is the first characterization of a Gram-positive NanK. We report the kinetic activity of SaNanK along with the ligand?free, N-acetylmannosamine?bound and substrate analog GlcNAc?bound crystal structures (2.33, 2.20, and 2.20 ? resolution, respectively). These demonstrate, in combination with small-angle X-ray scattering, that SaNanK is a dimer that adopts a closed conformation upon substrate binding. Analysis of the EXGY motif reveals that the tyrosine binds to the N-acetyl group to select for the ?boat? conformation of N-acetylmannosamine. Moreover, SaNanK has a stacked arginine pair coordinated by negative residues critical for thermal stability and catalysis. These combined elements serve to constrain the active site and orient the substrate in lieu of Zn binding, representing a significant departure from canonical NanK binding. This characterization provides insight into differences in the ROK family and highlights a novel area for antimicrobial discovery to fight Gram-positive and S. aureus infections.
|
|
| 9. |
- Currie, Michael J., et al.
(författare)
-
Structural and biophysical analysis of a Haemophilus influenzae tripartite ATP-independent periplasmic (TRAP) transporter
- 2024
-
Ingår i: ELIFE. - 2050-084X. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Tripartite ATP-independent periplasmic (TRAP) transporters are secondary-active transporters that receive their substrates via a soluble-binding protein to move bioorganic acids across bacterial or archaeal cell membranes. Recent cryo-electron microscopy (cryo-EM) structures of TRAP transporters provide a broad framework to understand how they work, but the mechanistic details of transport are not yet defined. Here we report the cryo-EM structure of the Haemophilus influenzae N-acetylneuraminate TRAP transporter (HiSiaQM) at 2.99 & Aring; resolution (extending to 2.2 & Aring; at the core), revealing new features. The improved resolution (the previous HiSiaQM structure is 4.7 & Aring; resolution) permits accurate assignment of two Na+ sites and the architecture of the substrate-binding site, consistent with mutagenic and functional data. Moreover, rather than a monomer, the HiSiaQM structure is a homodimer. We observe lipids at the dimer interface, as well as a lipid trapped within the fusion that links the SiaQ and SiaM subunits. We show that the affinity (K-D) for the complex between the soluble HiSiaP protein and HiSiaQM is in the micromolar range and that a related SiaP can bind HiSiaQM. This work provides key data that enhances our understanding of the 'elevator-with-an-operator' mechanism of TRAP transporters.
|
|
| 10. |
- Davies, James S., et al.
(författare)
-
Structure and mechanism of a tripartite ATP-independent periplasmic TRAP transporter
- 2023
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- In bacteria and archaea, tripartite ATP-independent periplasmic (TRAP) transporters uptake essential nutrients. TRAP transporters receive their substrates via a secreted soluble substrate-binding protein. How a sodium ion-driven secondary active transporter is strictly coupled to a substrate-binding protein is poorly understood. Here we report the cryo-EM structure of the sialic acid TRAP transporter SiaQM from Photobacterium profundum at 2.97 Å resolution. SiaM comprises a “transport” domain and a “scaffold” domain, with the transport domain consisting of helical hairpins as seen in the sodium ion-coupled elevator transporter VcINDY. The SiaQ protein forms intimate contacts with SiaM to extend the size of the scaffold domain, suggesting that TRAP transporters may operate as monomers, rather than the typically observed oligomers for elevator-type transporters. We identify the Na+ and sialic acid binding sites in SiaM and demonstrate a strict dependence on the substrate-binding protein SiaP for uptake. We report the SiaP crystal structure that, together with docking studies, suggest the molecular basis for how sialic acid is delivered to the SiaQM transporter complex. We thus propose a model for substrate transport by TRAP proteins, which we describe herein as an ‘elevator-with-an-operator’ mechanism.
|
|
