| 1. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 2. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 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
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 3. |
- Andersson, Lena, et al.
(författare)
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Pancreatic lipase related protein 2, but not classical lipase hydrolyzes galactolipids
- 1996
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002. ; 1302:3, s. 236-240
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Tidskriftsartikel (refereegranskat)abstract
- The pancreatic lipase family contains three subfamilies, the 'classical' lipases and the pancreatic lipase-related proteins 1 (PLRP1) and 2 (PLRP2). Galactolipids are present in membranes of leaves and vegetables and consist of digalactosyldiacylglycerol (DGalDG) monogalactosyldiacylglycerol (MGalDG) and sulfoquinovosyldiacylglycerol (SQDG). These lipids were incubated with PLRP2 from guinea-pig (GPLRP2) and rat (RPLRP2). In the presence of bile salts DGalDG was efficiently hydrolyzed by GPLRP2 and, although less efficiently, by RPLRP2 to digalactosylmonoacylglycerol (DGalMG), free fatty acids and water-soluble galactose-containing compounds. Also, MGalDG and SQDG were hydrolyzed by GPLRP2 and RPLRP2. These data suggest a possible role of PLRP2 in the digestion of dietary galactolipids
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| 4. |
- Clark, Douglas S., et al.
(författare)
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Klaus Mosbach Tribute
- 2015
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Ingår i: Biotechnology and Bioengineering. - : Wiley. - 1097-0290 .- 0006-3592. ; 112:4, s. 645-647
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Liu, Xueping, et al.
(författare)
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Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P=3.96×10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
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| 6. |
- Lowe, Robert, et al.
(författare)
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Affective-associative two-process theory: a neurocomputational account of partial reinforcement extinction effects
- 2017
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Ingår i: Biological Cybernetics. - : Springer Science and Business Media LLC. - 0340-1200 .- 1432-0770. ; 111:5-6, s. 365-388
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Tidskriftsartikel (refereegranskat)abstract
- The partial reinforcement extinction effect (PREE) is an experimentally established phenomenon: behavioural response to a given stimulus is more persistent when previously inconsistently rewarded than when consistently rewarded. This phenomenon is, however, controversial in animal/human learning theory. Contradictory findings exist regarding when the PREE occurs. One body of research has found a within-subjects PREE, while another has found a within-subjects reversed PREE (RPREE). These opposing findings constitute what is considered the most important problem of PREE for theoreticians to explain. Here, we provide a neurocomputational account of the PREE, which helps to reconcile these seemingly contradictory findings of within-subjects experimental conditions. The performance of our model demonstrates how omission expectancy, learned according to low probability reward, comes to control response choice following discontinuation of reward presentation (extinction). We find that a PREE will occur when multiple responses become controlled by omission expectation in extinction, but not when only one omission-mediated response is available. Our model exploits the affective states of reward acquisition and reward omission expectancy in order to differentially classify stimuli and differentially mediate response choice. We demonstrate that stimulus-response (retrospective) and stimulus-expectation-response (prospective) routes are required to provide a necessary and sufficient explanation of the PREE versus RPREE data and that Omission representation is key for explaining the nonlinear nature of extinction data.
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| 7. |
- Lowe, Robert, et al.
(författare)
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Bridging Connectionism and Relational Cognition through Bi-directional Affective-Associative Processing
- 2019
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Ingår i: Open Information Science. - : Walter de Gruyter GmbH. - 2451-1781. ; 3:1, s. 235-260
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Tidskriftsartikel (refereegranskat)abstract
- Connectionist architectures constitute a popular method for modelling animal associative learning processes in order to glean insights into the formation of cognitive capacities. Such approaches (based on purely feedforward activity) are considered limited in their ability to capture relational cognitive capacities. Pavlovian learning value-based models, being not based purely on fully connected feedforward structure, have demonstrated learning capabilities that often mimic those of ‘higher’ relational cognition. Capturing data using such models often reveals how associative mechanisms can exploit structure in the experimental setting, so that ‘explicit’ relational cognitive capacities are not, in fact, required. On the other hand, models of relational cognition, implemented as neural networks, permit formation and retrieval of relational representations of varying levels of complexity. The flexible processing capacities of such models are, however, are subject to constraints as to how offline relational versus online (real-time, real-world) processing may be mediated. In the current article, we review the potential for building a connectionist-relational cognitive architecture with reference to the representational rank view of cognitive capacity put forward by Halford et al. Through interfacing system 1-like (connectionist/associative learning) and system 2-like (relational-cognition) computations through a bidirectional affective processing approach, continuity between Halford et al’s cognitive systems may be operationalized according to real world/online constraints. By addressing i) and ii) in this manner, this paper puts forward a testable unifying framework for system 1-like and system 2-like cognition.
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| 8. |
- Lowe, Robert, et al.
(författare)
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Vicarious Value Learning and Inference in Human-Human and Human-Robot Interaction
- 2019
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Ingår i: 2019 8th International Conference on Affective Computing and Intelligent Interaction Workshops and Demos, ACIIW 2019. - 9781728138923 - 9781728138916
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Konferensbidrag (refereegranskat)abstract
- © 2019 IEEE. Among the biggest challenges for researchers of human-robot interaction is imbuing robots with lifelong learning capacities that allow efficient interactions between humans and robots. In order to address this challenge we are developing computational mechanisms for a humanoid robotic agent utilizing both system 1 and system 2-like cognitive processing capabilities. At the core of this processing is a Social Affective Appraisal model that allows for vicarious value learning and inference. Using a multi-dimensional reinforcement learning approach the robotic agent learns affective value-based functions (system 1). This learning can ground representations of affective relations (predicates) relevant to interacting agents. In this article we discuss the existing theoretical basis for developing our neural network model as a system 1-like process. We also discuss initial ideas for developing system 2-like top-down/generative affective (semantic relation-based) processing. The aim of the symbolic-connectionist architectural development is to promote autonomous capabilities in humanoid robots for interacting efficiently/intelligently (recombinant application of learned associations) with humans in changing and challenging environments.
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| 9. |
- Middeldorp, Christel M., et al.
(författare)
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The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
- 2019
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
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Tidskriftsartikel (refereegranskat)abstract
- The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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| 10. |
- Paul, Dirk S., et al.
(författare)
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Increased DNA methylation variability in type 1 diabetes across three immune effector cell types
- 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
- The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
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