| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
- Bousquet, J., et al.
(författare)
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MACVIA-ARIA Sentinel NetworK for allergic rhinitis (MASK-rhinitis): the new generation guideline implementation
- 2015
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : WILEY-BLACKWELL. - 0105-4538 .- 1398-9995. ; 70:11, s. 1372-1392
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Tidskriftsartikel (refereegranskat)abstract
- Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards.
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| 3. |
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| 4. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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| 5. |
- Holmes, Michael V., et al.
(författare)
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Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:21, s. 1966-1976
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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| 6. |
- Govaere, O., et al.
(författare)
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Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 76:5, s. 1001-1012
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. © 2021 The Authors
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| 7. |
- Pedersen, T.R., et al.
(författare)
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Design and baseline characteristics of the Incremental Decrease in End Points through Aggressive Lipid Lowering study
- 2004
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 94:6, s. 720-724
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Tidskriftsartikel (refereegranskat)abstract
- The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) study is an investigator-initiated trial designed to determine whether additional clinical benefit might be gained through a strategy that decreases levels of low-density lipoprotein cholesterol levels better than those currently achieved with established statin therapy in patients who have coronary heart disease. IDEAL is a multicenter prospective, randomized, open-label, blinded, end point classification study. Patients who had myocardial infarction were randomized to prescription treatment with 80 mg/day of atorvastatin or 20 mg/day of simvastatin (the dose was increased to 40 mg/day at week 24 in those patients whose plasma total cholesterol remained >5.0 mmol/L, or 190 mg/dl, or whose low-density lipoprotein cholesterol remained >3.0 mmol/L, or 115 mg/dl). The primary clinical outcome variable is the time to initial occurrence of a major coronary event, which is defined as nonfatal acute myocardial infarction, coronary death, or resuscitated cardiac arrest. The study is designed to have a power of 90% to detect a relative decrease of 20% in the atorvastatin-group compared with the simvastatin-group in the number of major events caused by coronary heart disease over ~5.5 years. The 8,888 randomized patients had the following characteristics: mean age 61.7 ± 9.5 years, 19.1% women (mean age 64.0 ± 9.5 years), baseline total cholesterol 5.1 ± 1.0 mmol/L (197 mg/dl), low-density lipoprotein cholesterol 3.2 ± 0.9 mmol/L (124 mg/dl), and high-density lipoprotein cholesterol 1.2 ± 0.3 mmol/L (46 mg/dl). Drug treatment before randomization consisted of statins in 77% of patients, aspirin in 78.9%, ß blockers in 75.1%, and angiotensin-converting enzyme inhibitors in 30%. © 2004 by Excerpta Medica, Inc.
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| 8. |
- Petrescu, Ana Maria Roxana, et al.
(författare)
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The consolidated European synthesis of CH4 and N2O emissions for the European Union and United Kingdom: 1990-2019
- 2023
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Ingår i: Earth System Science Data. - : COPERNICUS GESELLSCHAFT MBH. - 1866-3508 .- 1866-3516. ; 15:3, s. 1197-1268
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge of the spatial distribution of the fluxes of greenhouse gases (GHGs) and their temporal variability as well as flux attribution to natural and anthropogenic processes is essential to monitoring the progress in mitigating anthropogenic emissions under the Paris Agreement and to inform its global stocktake. This study provides a consolidated synthesis of CH4 and N2O emissions using bottom-up (BU) and top-down (TD) approaches for the European Union and UK (EU27 + UK) and updates earlier syntheses (Petrescu et al., 2020, 2021). The work integrates updated emission inventory data, process-based model results, data-driven sector model results and inverse modeling estimates, and it extends the previous period of 1990-2017 to 2019. BU and TD products are compared with European national greenhouse gas inventories (NGHGIs) reported by parties under the United Nations Framework Convention on Climate Change (UNFCCC) in 2021. Uncertainties in NGHGIs, as reported to the UNFCCC by the EU and its member states, are also included in the synthesis. Variations in estimates produced with other methods, such as atmospheric inversion models (TD) or spatially disaggregated inventory datasets (BU), arise from diverse sources including within-model uncertainty related to parameterization as well as structural differences between models. By comparing NGHGIs with other approaches, the activities included are a key source of bias between estimates, e.g., anthropogenic and natural fluxes, which in atmospheric inversions are sensitive to the prior geospatial distribution of emissions. For CH4 emissions, over the updated 2015-2019 period, which covers a sufficiently robust number of overlapping estimates, and most importantly the NGHGIs, the anthropogenic BU approaches are directly comparable, accounting for mean emissions of 20.5 TgCH(4) yr(-1) (EDGARv6.0, last year 2018) and 18.4 TgCH(4) yr(-1) (GAINS, last year 2015), close to the NGHGI estimates of 17 :5 +/- 2 :1 TgCH(4) yr(-1). TD inversion estimates give higher emission estimates, as they also detect natural emissions. Over the same period, high-resolution regional TD inversions report a mean emission of 34 TgCH(4) yr(-1). Coarser-resolution global-scale TD inversions result in emission estimates of 23 and 24 TgCH(4) yr(-1) inferred from GOSAT and surface (SURF) network atmospheric measurements, respectively. The magnitude of natural peatland and mineral soil emissions from the JSBACH-HIMMELI model, natural rivers, lake and reservoir emissions, geological sources, and biomass burning together could account for the gap between NGHGI and inversions and account for 8 TgCH(4) yr(-1). For N2O emissions, over the 2015-2019 period, both BU products (EDGARv6.0 and GAINS) report a mean value of anthropogenic emissions of 0.9 TgN(2)Oyr(-1), close to the NGHGI data (0 :8 +/- 55% TgN(2)Oyr(-1)). Over the same period, the mean of TD global and regional inversions was 1.4 TgN(2)Oyr(-1) (excluding TOMCAT, which reported no data). The TD and BU comparison method defined in this study can be operationalized for future annual updates for the calculation of CH4 and N2O budgets at the national and EU27 C UK scales. Future comparability will be enhanced with further steps involving analysis at finer temporal resolutions and estimation of emissions over intra-annual timescales, which is of great importance for CH4 and N2O, and may help identify sector contributions to divergence between prior and posterior estimates at the annual and/or inter-annual scale. Even if currently comparison between CH4 and N2O inversion estimates and NGHGIs is highly uncertain because of the large spread in the inversion results, TD inversions inferred from atmospheric observations represent the most independent data against which inventory totals can be compared. With anticipated improvements in atmospheric modeling and observations, as well as modeling of natural fluxes, TD inversions may arguably emerge as the most powerful tool for verifying emission inventories for CH4, N2O and other GHGs. The referenced dataset srelated to figures are visualized at https://doi.org/10.5281/zenodo.7553800 (Petrescu et al., 2023).
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| 9. |
- Östman, Jan, et al.
(författare)
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Ketoacidosis in young adults is not related to the islet antibodies at the diagnosis of Type 1 diabetes mellitus - A nationwide study
- 2000
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 17, s. 269-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To test the hypothesis that there is lower prevalence of islet antibodies in subjects with newly diagnosed Type 1 diabetes mellitus in young adulthood than in children is associated with less severe diabetes at time of diagnosis. Methods: This investigation was based on a nationwide study (Diabetes Incidence Study in Sweden) of 15-34-year-old newly diagnosed diabetic subjects. During 1992-1993, all diabetic subjects (excluding secondary and gestational diabetes) were reported on standardized forms, with information about clinical characteristics at diagnosis. The study examined islet cell antibodies (ICA) by indirect immunofluorescence, and autoantibodies to glutamic acid decarboxylase (GADA), tyrosine phosphatase- like antigen (IA-2A) and insulin (IAA) as well as C-peptide by radioimmunoassay. Results: Blood samples were available from 78 patients with diabetic ketoacidosis (DKA) and 517 non-acidotic patients. The prevalence of ICA (63% vs. 57%), GADA (63% vs. 66%), IA-2A (35% vs. 44%) and IAA (20% vs. 15%) were very similar in patients with or without DKA. The median levels of the four autoantibodies did not differ between the two groups. High blood glucose (P < 0.001) and low C-peptide levels (P < 0.001) were the only parameters found to be related to DKA. Conclusions: The similarities in findings of newly diagnosed diabetic patients with or without DKA regarding ICA, GADA, IA-2A and IAA suggest that there is no relationship between the expression of antigenicity and the severity of β-cell dysfunction. The lower prevalence of the four autoantibodies in 15-34-year-old diabetic subjects compared with previous findings in children is not explained by misclassification of diabetes type.
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| 10. |
- Bellamy, R., et al.
(författare)
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Incentivising bioenergy with carbon capture and storage (BECCS) responsibly : Comparing stakeholder policy preferences in the United Kingdom and Sweden
- 2021
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Ingår i: Environmental Science and Policy. - : Elsevier Ltd. - 1462-9011 .- 1873-6416. ; 116, s. 47-55
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Tidskriftsartikel (refereegranskat)abstract
- Bioenergy with carbon capture and storage (BECCS) plays a central role in scenario pathways that limit global warming in line with the objectives of the Paris Agreement. Yet deliberate policy efforts to incentivise BECCS—whether through amending existing climate policies or introducing entirely new ones—remain rare. In this paper, we contend that BECCS must be incentivised responsibly, through policy-making processes which account for diverse and geographically varying societal values and interests. More specifically, we make the case for responsible incentivisation by undertaking a comparative analysis of stakeholder attitudes to four idealised policy scenarios for BECCS, including representatives of government, business, nongovernmental and academic communities, in the UK and Sweden. The scenarios were: business as usual; international policy reform; national BECCS policy; and national policy for negative emissions technologies. Based on our findings, we recommend that policymakers 1) recognise the need to develop new incentives and make enabling reforms to existing policy instruments; 2) consider the risk of mitigation deterrence in their real world (and not abstracted) contexts; 3) employ multi-instrument approaches to incentivisation that do not overly rely on carbon pricing or 4) force a choice between technology specific or technology neutral policies; and 5) attend to the diversity of stakeholder and wider public perspectives that will ultimately determine the success—or failure—of their policy designs.
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