| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Delios, A., et al.
(författare)
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Examining the generalizability of research findings from archival data
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:30
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Tidskriftsartikel (refereegranskat)abstract
- This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability-for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples.
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| 8. |
- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 9. |
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| 10. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 11. |
- Teumer, A, et al.
(författare)
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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4130-
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Tidskriftsartikel (refereegranskat)abstract
- Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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| 12. |
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| 13. |
- Cruz, Raquel, et al.
(författare)
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Novel genes and sex differences in COVID-19 severity
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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| 14. |
- Bammer, G., et al.
(författare)
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Expertise in research integration and implementation for tackling complex problems: when is it needed, where can it be found and how can it be strengthened?
- 2020
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Ingår i: Palgrave Communications. - : Springer Science and Business Media LLC. - 2055-1045. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Expertise in research integration and implementation is an essential but often overlooked component of tackling complex societal and environmental problems. We focus on expertise relevant to any complex problem, especially contributory expertise, divided into 'knowing-that' and 'knowing-how.' We also deal with interactional expertise and the fact that much expertise is tacit. We explore three questions. First, in examining 'when is expertise in research integration and implementation required?,' we review tasks essential (a) to developing more comprehensive understandings of complex problems, plus possible ways to address them, and (b) for supporting implementation of those understandings into government policy, community practice, business and social innovation, or other initiatives. Second, in considering 'where can expertise in research integration and implementation currently be found?,' we describe three realms: (a) specific approaches, including interdisciplinarity, transdisciplinarity, systems thinking and sustainability science; (b) case-based experience that is independent of these specific approaches; and (c) research examining elements of integration and implementation, specifically considering unknowns and fostering innovation. We highlight examples of expertise in each realm and demonstrate how fragmentation currently precludes clear identification of research integration and implementation expertise. Third, in exploring 'what is required to strengthen expertise in research integration and implementation?,' we propose building a knowledge bank. We delve into three key challenges: compiling existing expertise, indexing and organising the expertise to make it widely accessible, and understanding and overcoming the core reasons for the existing fragmentation. A growing knowledge bank of expertise in research integration and implementation on the one hand, and accumulating success in addressing complex societal and environmental problems on the other, will form a virtuous cycle so that each strengthens the other. Building a coalition of researchers and institutions will ensure this expertise and its application are valued and sustained.
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| 15. |
- Zamora, Juan Carlos, et al.
(författare)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Tidskriftsartikel (refereegranskat)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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| 16. |
- Kabir, Md Alamgir, et al.
(författare)
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Cross-Version Software Defect Prediction Considering Concept Drift and Chronological Splitting
- 2023
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Ingår i: Symmetry. - : Multidisciplinary Digital Publishing Institute (MDPI). - 2073-8994. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Concept drift (CD) refers to a phenomenon where the data distribution within datasets changes over time, and this can have adverse effects on the performance of prediction models in software engineering (SE), including those used for tasks like cost estimation and defect prediction. Detecting CD in SE datasets is difficult, but important, because it identifies the need for retraining prediction models and in turn improves their performance. If the concept drift is caused by symmetric changes in the data distribution, the model adaptation process might need to account for this symmetry to maintain accurate predictions. This paper explores the impact of CD within the context of cross-version defect prediction (CVDP), aiming to enhance the reliability of prediction performance and to make the data more symmetric. A concept drift detection (CDD) approach is further proposed to identify data distributions that change over software versions. The proposed CDD framework consists of three stages: (i) data pre-processing for CD detection; (ii) notification of CD by triggering one of the three flags (i.e., CD, warning, and control); and (iii) providing guidance on when to update an existing model. Several experiments on 30 versions of seven software projects reveal the value of the proposed CDD. Some of the key findings of the proposed work include: (i) An exponential increase in the error-rate across different software versions is associated with CD. (ii) A moving-window approach to train defect prediction models on chronologically ordered defect data results in better CD detection than using all historical data with a large effect size (Formula presented.).
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| 17. |
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| 18. |
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| 19. |
- Jensen, Gordon L., et al.
(författare)
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GLIM Criteria for the Diagnosis of Malnutrition : A Consensus Report From the Global Clinical Nutrition Community
- 2019
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Ingår i: JPEN - Journal of Parenteral and Enteral Nutrition. - : Wiley. - 0148-6071 .- 1941-2444. ; 43:1, s. 32-40
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Tidskriftsartikel (refereegranskat)abstract
- Background: This initiative aims to build a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.Methods: The Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. Empirical consensus was reached through a series of face‐to‐face meetings, telephone conferences, and e‐mail communications.Results: A 2‐step approach for the malnutrition diagnosis was selected, that is, first screening to identify at risk status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among GLIM participants that selected 3 phenotypic criteria (non‐volitional weight loss, low body mass index, and reduced muscle mass) and 2 etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least 1 phenotypic criterion and 1 etiologic criterion should be present. Phenotypic metrics for grading severity are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology‐related diagnosis categories.Conclusions: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The construct should be re‐considered every 3–5 years.
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| 20. |
- Whiffin, N, et al.
(författare)
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The effect of LRRK2 loss-of-function variants in humans
- 2020
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:6, s. 869-877
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Tidskriftsartikel (refereegranskat)abstract
- Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Ekker, Merel, et al.
(författare)
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Global Outcome Assessment Life-long after stroke in young adults initiative-the GOAL initiative: study protocol and rationale of a multicentre retrospective individual patient data meta-analysis.
- 2019
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients.The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence.Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.
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| 25. |
- Gerasimcik, Natalija, et al.
(författare)
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Deletion of Dock10 in B cells results in normal Development but a Mild Deficiency upon In Vivo and In Vitro stimulations
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- We sought to identify genes necessary to induce cytoskeletal change in B cells. Using gene expression microarray, we compared B cells stimulated with interleukin-4 (IL-4) and anti-CD40 antibodies that induce B cell spreading, cell motility, tight aggregates, and extensive microvilli with B cells stimulated with lipopolysaccharide that lack these cytoskeletal changes. We identified 84 genes with 10-fold or greater expression in anti-CD40 + IL-4 stimulated B cells, one of these encoded the guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 10 (Dock10). IL-4 selectively induced Dock10 expression in B cells. Using lacZ expression to monitor Dock10 promoter activity, we found that Dock10 was expressed at all stages during B cell development. However, specific deletion of Dock10 in B cells was associated with a mild phenotype with normal B cell development and normal B cell spreading, polarization, motility, chemotaxis, aggregation, and Ig class switching. Dock10-deficient B cells showed lower proliferation in response to anti-CD40 and IL-4 stimulation. Moreover, the IgG response to soluble antigen in vivo was lower when Dock10 was specifically deleted in B cells. Together, we found that most B cell responses were intact in the absence of Dock10. However, specific deletion of Dock10 in B cells was associated with a mild reduction in B cell activation in vitro and in vivo.
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| 26. |
- Hernández-Moreno, Laura, et al.
(författare)
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The Portuguese version of the activity inventory
- 2015
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Ingår i: Investigative Ophthalmology and Visual Science. - 0146-0404 .- 1552-5783. ; 56:7
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To characterize interventions needed by the population with visual impairment or to assess interventions in vision rehabilitation validated and standardized instruments used in different cultural contexts are necessary. The aim of this work was to characterize the functional status of a sample of people with visual impairment with the Portuguese version of the activity inventory (AI)Methods: A group of participants in the study Prevalence and Costs of Visual Impairment in Portugal (PC-VIP) was recruit to face-to-face interviews and the activity inventory was administered. The AI examines 50 goals split between three objectives: social functioning, recreation and daily living. Goals rated ‘not important’ were skipped, but for all other goals the participant was asked to rate its difficulty on a five point scale ranging from ‘not difficult’ to ‘impossible without help’. The difficulty responses were Rasch analysed (Winsteps v3.81.0) to produce a continuous measure of visual ability (AI score). Additional information about distance and near visual acuity (ETDRS scale), contrast sensitivity (MARS test) and critical print size (MNREAD test) was collected.Results: A total of 94 persons participated in this study. Some participants were not able to read or recognize letters due to their poor vision or poor literacy and were excluded from further analysis. Data reported here are from 62 participants, median age 63y (range=12-85) and the most common cause of visual impairment were retinal diseases. Mean presenting acuity in the better eye was 0.93logMAR (SD=0.5). The mean difficulty (item measure) in the AI was -0.33 logits (SD=0.96). The most difficult items were "sew or do needlework", "read the newspaper", "drive" and the easiest items were "provide care for a pet", "eat your meals", "use the restroom in a public place". The mean ability score (person measures) was 1.11 logits (SD=2.04). The ability measures in the AI were correlated with distance visual acuity (r=-0.57, p<.001), near visual acuity (r=-0.66, p<0.001), contrast sensitivity (r=0.62, p<.001) and critical print size (r=-0.60, p<.001).Conclusions: Our results indicate that the AI scores in a sample of people Portuguese people with visual impairment were in line with what has been found in other cultural contexts. The visual ability measured by the AI was correlated with visual function assessed by different visual tests, which shows that this instrument can be used with confidence.
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| 27. |
- Jacob, Mina A, et al.
(författare)
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Global Differences in Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults: A Worldwide Meta-analysis: The GOAL-Initiative.
- 2022
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Ingår i: Neurology. - 1526-632X. ; 98:6
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Tidskriftsartikel (refereegranskat)abstract
- There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional healthcare services. To study the global distribution of risk factors, causes and 3-month mortality of young ischemic stroke patients, by performing a patient data meta-analysis form different cohorts worldwide.We did a pooled analysis of individual patient data from cohort studies which included consecutive ischemic stroke patients aged 18-50 years. We studied differences in prevalence of risk factors and causes between different ethnic and racial groups, geographic regions and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression.We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Blacks (hypertension, 52.1%; diabetes, 20.7%) and Asians (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often cause of stroke in high-income countries (HICs; both p<0.001), whereas ''other determined stroke'' and ''undetermined stroke'' were higher in low and middle-income countries (LMICs; both p<0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (OR 2.49; 95% CI 1.42-4.36).The ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial, and regional differences in incidence of ischemic stroke. Our results also visualize the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve healthcare facilities in LMICs.
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| 28. |
- Keszei, M, et al.
(författare)
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A Mouse Model of X-Linked Neutropenia
- 2014
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Ingår i: JOURNAL OF CLINICAL IMMUNOLOGY. - 0271-9142. ; 34, s. S248-S248
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 29. |
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| 30. |
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| 31. |
- L. B. Almeida, Bilena, et al.
(författare)
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The transcription factor network of E. coli steers global responses to shifts in RNAP concentration
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 50:12, s. 6801-6819
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Tidskriftsartikel (refereegranskat)abstract
- The robustness and sensitivity of gene networks to environmental changes is critical for cell survival. How gene networks produce specific, chronologically ordered responses to genome-wide perturbations, while robustly maintaining homeostasis, remains an open question. We analysed if short- and mid-term genome-wide responses to shifts in RNA polymerase (RNAP) concentration are influenced by the known topology and logic of the transcription factor network (TFN) of Escherichia coli. We found that, at the gene cohort level, the magnitude of the single-gene, mid-term transcriptional responses to changes in RNAP concentration can be explained by the absolute difference between the gene's numbers of activating and repressing input transcription factors (TFs). Interestingly, this difference is strongly positively correlated with the number of input TFs of the gene. Meanwhile, short-term responses showed only weak influence from the TFN. Our results suggest that the global topological traits of the TFN of E. coli shape which gene cohorts respond to genome-wide stresses.
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| 32. |
- Moran, M. C., et al.
(författare)
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DNA gel nanoparticles: preparation and controlling the size
- 2009
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-6848 .- 1744-683X. ; 5:13, s. 2538-2542
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Tidskriftsartikel (refereegranskat)abstract
- A simple and novel method was used for the preparation of nano-/micro-sized DNA gel particles by nebulisation of a solution of DNA (single-or double-stranded) into an oppositely charged surfactant (cetyltrimethylammonium bromide) or protein (lysozyme, protamine sulfate) solution. The size and size distribution of the particle populations were investigated by means of fluorescence microscopy (FM), photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM). Particles measuring from 0.1 to 10 mu m were obtained. FM studies suggest that the formation of the particles was carried out with conservation of the secondary structure of the nucleic acid molecules. SEM on freeze-dried and Au-shadowed samples showed a distribution of virtually spherical particles. It was found that, in addition to the size of the initial DNA droplets, the cationic agent is a controlling parameter of the particle size.
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| 33. |
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| 34. |
- Pedro, Joana Reis, et al.
(författare)
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Transient gain of function of cannabinoid CB1 receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes
- 2020
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Ingår i: Brain Research Bulletin. - : Elsevier BV. - 0361-9230. ; 161, s. 106-115
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Tidskriftsartikel (refereegranskat)abstract
- Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB1 receptor (CB1R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB1R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes (T1D). We report that frontocortical CB1R protein density was biphasically altered in the first month of T1D, which was accompanied with a reduction of resting glucose uptake ex vivo in acute frontocortical slices that was normalized after eight weeks in T1D. This early reduction of glucose uptake in slices was also restored by ex vivo treatment with both the non-selective CB1R agonists, WIN55212−2 (500 nM) and the CB1R-selective agonist, ACEA (3 μM) while it was exacerbated by the CB1R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB1Rs in the control of glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities remained unaffected, phosphorylated GSKα and GSKβ levels showed different profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the biphasic response in frontocortical CB1R density within a month after T1D induction resolves previous controversial reports on forebrain CB1R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex.
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| 35. |
- Upton, Caryn M., et al.
(författare)
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Safety and efficacy of BCG re-vaccination in relation to COVID-19 morbidity in healthcare workers : A double- blind, randomised, controlled, phase 3 trial
- 2022
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Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 48
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Tidskriftsartikel (refereegranskat)abstract
- Background BCG vaccination prevents severe childhood tuberculosis (TB) and was introduced in South Africa in the 1950s. It is hypothesised that BCG trains the innate immune system by inducing epigenetic and functional reprogramming, thus providing non-specific protection from respiratory tract infections. We evaluated BCG for reduction of morbidity and mortality due to COVID-19 in healthcare workers in South Africa. Methods This randomised, double-blind, placebo-controlled trial recruited healthcare workers at three facilities in the Western Cape, South Africa, unless unwell, pregnant, breastfeeding, immunocompromised, hypersensitivity to BCG, or undergoing experimental COVID-19 treatment. Participants received BCG or saline intradermally (1:1) and were contacted once every 4 weeks for 1 year. COVID-19 testing was guided by symptoms. Hospitalisation, COVID-19, and respiratory tract infections were assessed with Cox proportional hazard modelling and time-to-event analyses, and event severity with post hoc Markovian analysis. This study is registered with ClinicalTrials.gov, NCT04379336. Findings Between May 4 and Oct 23, 2020, we enrolled 1000 healthcare workers with a median age of 39 years (IQR 30-49), 70.4% were female, 16.5% nurses, 14.4% medical doctors, 48.5% had latent TB, and 15.3% had evidence of prior SARS-CoV-2 exposure. Hospitalisation due to COVID-19 occurred in 15 participants (1.5%); ten (66.7%) in the BCG group and five (33.3%) in the placebo group, hazard ratio (HR) 2.0 (95% CI 0.69-5.9, p= 0.20), indicating no statistically significant protection. Similarly, BCG had no statistically significant effect on COVID-19 (p= 0.63, HR = 1.08, 95% CI 0.82-1.42). Two participants (0.2%) died from COVID-19 and two (0.2%) from other reasons, all in the placebo group. Interpretation BCG did not protect healthcare workers from SARS-CoV-2 infection or related severe COVID-19 disease and hospitalisation.
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| 36. |
- Baptista, Antonio M. G., et al.
(författare)
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Causes of Vision Impairment in Portugal : A hospital based study
- 2015
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Ingår i: Investigative Ophthalmology and Visual Science. - 0146-0404 .- 1552-5783. ; 56:7
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Causes of vision impairment (VI) are influenced by factors such as race or socio-economic circumstances. Because of this collecting national information is important for planning reduction of vision loss. The aim of this study was to determine causes of vision impairment in a population visiting ophthalmology departments in public hospitals in Portugal.Methods This study was designed according with the guidelines of the Vancouver Economic Burden of Vision Loss Group (IOVS, 2010, V51/4/1801). Recommendations are to collect hospital data during 1 year to determine causes of VI. We selected four public hospitals that are expected to have over 120-140K appointments per year. Files are analysed weekly to detect patients with vision impairment. Inclusion criteria are: visual acuity with the current refractive correction equal or less than 0.5 (20/40) in the better-seeing eye and/or a visual field of less than 20 degrees. Patients were selected by trained hospital staff (medics and orthoptists) and inserted in a database. Diagnoses were classified according the ICD9. Data collected included fundamental demographic information, main diagnosis, secondary diagnosis and comorbidities.Results We have now 2462 patients selected that correspond to 4 to 33 weeks of data collection. The number of weeks is variable because we did not start all hospitals simultaneously. From the current number of cases detected, 58% are female, 1.9% are under 20, 8.2% are between 20 and 50 and 89.9% are 50 years or older. The leading causes of vision impairment among these patients are diabetic retinopathy (DR), cataract (C), glaucoma (GC) and age-related macular degeneration (AMD). Using the North American definition of VI the proportions are 26.8% for DR, 25.5% for C, 10.4% for GC and 8.2% for AMD. The remaining causes of VI have percentages below 5% and in total they correspond to approximately 29% of the cases detected.Conclusions Our results show that the most common causes of vision impairment are eye diseases related with systemic conditions and aging of the population. Vision impairment was relatively low under the age of 20 and the causes were mostly inherited diseases. Numbers reported now will be more accurate at the end of the study but they already highlight the importance of targeting conditions such as diabetes.
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| 37. |
- Baptista, António M. G., et al.
(författare)
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The macular photostress test in diabetes, glaucoma, and cataract
- 2013
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Ingår i: 8th Iberoamerican Optics Meeting and 11th Latin American Meeting on Optics, Lasers, and Applications. - : SPIE - International Society for Optical Engineering.
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Konferensbidrag (refereegranskat)abstract
- Purpose. The photostress recovery time test (PSRT) has been widely reported as a helpful screening clinical tool. However, the poor standardization of its measurement technique remains to be a limitation among clinicians. The purpose of this study is to apply a recommended clinical technique to measure the PSRT in some of the most commons eye diseases to ascertain whether these diseases affect the PSRT values. Methods. One hundred and one controls and 105 patients, with diagnosed diabetes (without visible signs of diabetic retinopathy), primary open angle glaucoma (POAG) or cataracts underwent photostress testing. The test was performed with a direct ophthalmoscope for illuminating the macula for 30 seconds. Participants belonged to three age classes: A, B and C; and were divided into four groups: control, diabetic, POAG and cataract. The age range for A, B and C classes were respectively 43-54, 55-64 and 65-74 years. The groups were also further compared within each age class. In addition, the influence of age on PSRT was evaluated using the control group. Results. Results demonstrate that PSRT changes with age (p<0.02). In class A, diabetic group had a faster PSRT than control group, (mean ± standard deviation) 20.22±7.51 and 26.14±8.34 seconds. The difference between these groups was statistical significant (t-test, p=0.012). Cataract and POAG groups did not affect the PSRT significantly. Conclusions. The technique used for the Photostress showed that diabetics, younger than 54 years, may have faster PSRT and that, aging delays PSRT
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| 38. |
- Baptista, Ines S. C., et al.
(författare)
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Sequence-dependent model of genes with dual s factor preference
- 2022
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Ingår i: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms. - : Elsevier. - 1874-9399 .- 1876-4320. ; 1865:3
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Tidskriftsartikel (refereegranskat)abstract
- Escherichia coli uses sigma factors to quickly control large gene cohorts during stress conditions. While most of its genes respond to a single sigma factor, approximately 5% of them have dual sigma factor preference. The most common are those responsive to both sigma(70), which controls housekeeping genes, and sigma(38), which activates genes during stationary growth and stresses. Using RNA-seq and flow-cytometry measurements, we show that 'sigma(70+38) genes' are nearly as upregulated in stationary growth as 'sigma(38) genes'. Moreover, we find a clear quantitative relationship between their promoter sequence and their response strength to changes in sigma(38) levels. We then propose and validate a sequence dependent model of sigma(70+38) genes, with dual sensitivity to sigma(38) and sigma(70), that is applicable in the exponential and stationary growth phases, as well in the transient period in between. We further propose a general model, applicable to other stresses and sigma factor combinations. Given this, promoters controlling sigma 70+38 genes (and variants) could become important building blocks of synthetic circuits with predictable, sequence-dependent sensitivity to transitions between the exponential and stationary growth phases.
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| 39. |
- Baptista, Marisa A. P., et al.
(författare)
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Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.
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| 40. |
- Baptista, Marcia Lourenco, et al.
(författare)
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A self-organizing map and a normalizing multi-layer perceptron approach to baselining in prognostics under dynamic regimes
- 2021
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Ingår i: Neurocomputing. - : Elsevier. - 0925-2312 .- 1872-8286. ; 456, s. 268-287
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Tidskriftsartikel (refereegranskat)abstract
- When the influence of changing operational and environmental conditions is not factored out, it can be dificult to observe a clear deterioration path. This can significantly affect the task of prognostics and other analytic operations. To address this issue, it is necessary to baseline the data, typically by first finding the operating regimes and then normalizing the data within each regime. In this paper, we propose the use of machine learning techniques to perform baselining. A self-organizing map identifies the regimes, and a multi-layer perceptron normalizes the data based on the detected regimes. Tests are performed on the C-MAPSS data. The approach is capable of producing similar results to classical methods without the need to specify in advance the number of regimes and the explicit computation of the statistical properties of a hold-out dataset. Importantly, the techniques can be integrated into a deep learning system to perform prognostics in a single pass.
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| 41. |
- Baptista, Marcia L., et al.
(författare)
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More effective prognostics with elbow point detection and deep learning
- 2021
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Ingår i: Mechanical systems and signal processing. - : Elsevier. - 0888-3270 .- 1096-1216. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- Prior to failure, most systems exhibit signs of changed characteristics. The early detection of this change is important to remaining useful life estimation. To have the ability to detect the inflection point or “elbow point” of an asset, i.e. the point of the degradation curve that marks the transition from nominal to faulty condition, can enable more sophisticated prognostics because this divide and conquer tactic allows the prediction to focus on the window before failure when significant changes are being expected. In this work, we compare prognostics with and without change point detection. We use different recurrent neural network techniques (standard recurrent neural network, long short-term memory and gated recurrent unit) to find the elbow point location. The actual estimation of the remaining time to failure is based on the echo state network, a state-of-the-art approach in prognostics. Two different experiments are performed on simulated data obtained from NASA Ames prognostics repository. We first compare the performance of the elbow point detectors based on recurrent neural networks against three baseline models: the Z-test, multi-layer perceptron and random forests. Results indicate that recurrent neural networks can outperform the baseline approaches. In the second experiment, the best elbow detection model, the gated recurrent unit, is integrated within an echo state network, with a significant increase in overall performance in terms of remaining useful life estimation.
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| 42. |
- Baptista, Marcia L., et al.
(författare)
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Relation between prognostics predictor evaluation metrics and local interpretability SHAP values
- 2022
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Ingår i: Artificial Intelligence. - : Elsevier. - 0004-3702 .- 1872-7921. ; 306
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Tidskriftsartikel (refereegranskat)abstract
- Maintenance decisions in domains such as aeronautics are becoming increasingly dependent on being able to predict the failure of components and systems. When data-driven techniques are used for this prognostic task, they often face headwinds due to their perceived lack of interpretability. To address this issue, this paper examines how features used in a data-driven prognostic approach correlate with established metrics of monotonicity, trendability, and prognosability. In particular, we use the SHAP model (SHapley Additive exPlanations) from the field of eXplainable Artificial Intelligence (XAI) to analyze the outcome of three increasingly complex algorithms: Linear Regression, Multi-Layer Perceptron, and Echo State Network. Our goal is to test the hypothesis that the prognostics metrics correlate with the SHAP model's explanations, i.e., the SHAP values. We use baseline data from a standard data set that contains several hundred run-to-failure trajectories for jet engines. The results indicate that SHAP values track very closely with these metrics with differences observed between the models that support the assertion that model complexity is a significant factor to consider when explainability is a consideration in prognostics.
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