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Sökning: WFRF:(Lena Philippe)

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1.
  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • 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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3.
  • Benzinou, Michael, et al. (författare)
  • Common nonsynonymous variants in PCSK1 confer risk of obesity.
  • 2008
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:8, s. 943-5
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.
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4.
  • Fava, Cristiano, et al. (författare)
  • Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes
  • 2007
  • Ingår i: DNA Sequence. - : Informa UK Limited. - 1029-2365 .- 1042-5179. ; 18:5, s. 395-399
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Gitelman's syndrome (GS) is an inherited autosomal recessive disorder due to loss of function mutations in the SLC12A3 gene encoding the Na-Cl co-transporter (NCCT), the target of thiazide diuretics. The defective function of the NCCT, which normally is expressed in the apical membrane of the distal convolute tubule in the kidney, leads to mild hypotension, hypokalemia, hyperreninemic hyperaldosteronism, mild metabolic alkalosis, hypomagnesemia and hypocalciuria. Up to now, more than 100 mutations of the SLC12A3 gene have been described in GS patients. METHODS: We have collected 30 patients from Sweden with a clinical diagnosis of GS and undertaken a mutation screening by SSCP and successive sequencing of the 26 exons and intronic boundaries. Both mutations were identified in most (n = 28, 93%) and at least one mutation was identified in all patients. RESULTS: We found 22 different mutations evenly distributed throughout the gene, 11 of which have not been described previously. The new variants include 8 missense mutations (Glu68Lys, His69Asn, Argl45His, Vall53Met, Gly230Asp, Gly342Ala, Val677Leu and Gly867Ser), 1 insertion (c.834_835insG on exon 6) and 2 splice-site mutations (c.2667 + lT>G substitution in splicing donor site after exon 22, c.1569-1G>A substitution in the splicing acceptor site before exon 13). CONCLUSION: In Swedish patients with the clinical features of GS, disease-causing mutations in the SLC12A3 gene were identified in most patients. The spectrum of GS mutations is wide making full mutation screening of the SLC12A3 gene necessary to confirm the diagnosis.
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5.
  • Jung, Christian, et al. (författare)
  • A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
  • 2019
  • Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery. 
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6.
  • Kehoe, Laura, et al. (författare)
  • Make EU trade with Brazil sustainable
  • 2019
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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7.
  • Petrescu, Ana Maria Roxana, et al. (författare)
  • The consolidated European synthesis of CH4 and N2O emissions for the European Union and United Kingdom: 1990-2017
  • 2021
  • Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3508 .- 1866-3516. ; 13:5, s. 2307-2362
  • Tidskriftsartikel (refereegranskat)abstract
    • Reliable quantification of the sources and sinks of greenhouse gases, together with trends and uncertainties, is essential to monitoring the progress in mitigating anthropogenic emissions under the Paris Agreement. This study provides a consolidated synthesis of CH4 and N2O emissions with consistently derived state-of-the-art bottom-up (BU) and top-down (TD) data sources for the European Union and UK (EU27 C UK). We integrate recent emission inventory data, ecosystem process-based model results and inverse modeling estimates over the period 1990-2017. BU and TD products are compared with European national greenhouse gas inventories (NGHGIs) reported to the UN climate convention UNFCCC secretariat in 2019. For uncertainties, we used for NGHGIs the standard deviation obtained by varying parameters of inventory calculations, reported by the member states (MSs) following the recommendations of the IPCC Guidelines. For atmospheric inversion models (TD) or other inventory datasets (BU), we defined uncertainties from the spread between different model estimates or model-specific uncertainties when reported. In comparing NGHGIs with other approaches, a key source of bias is the activities included, e.g., anthropogenic versus anthropogenic plus natural fluxes. In inversions, the separation between anthropogenic and natural emissions is sensitive to the geospatial prior distribution of emissions. Over the 2011-2015 period, which is the common denominator of data availability between all sources, the anthropogenic BU approaches are directly comparable, reporting mean emissions of 20.8 TgCH(4) yr (-1) (EDGAR v5.0) and 19.0 TgCH(4) yr(-1) (GAINS), consistent with the NGHGI estimates of 18.9 +/- 1.7 TgCH(4) yr(-1). The estimates of TD total inversions give higher emission estimates, as they also include natural emissions. Over the same period regional TD inversions with higher-resolution atmospheric transport models give a mean emission of 28.8 TgCH(4) yr(-1). Coarser-resolution global TD inversions are consistent with regional TD inversions, for global inversions with GOSAT satellite data (23.3 TgCH(4) yr(-1)) and surface network (24.4 TgCH(4) yr (-1)). The magnitude of natural peatland emissions from the JSBACH-HIMMELI model, natural rivers and lakes emissions, and geological sources together account for the gap between NGHGIs and inversions and account for 5.2 TgCH(4) yr(-1). For N2O emissions, over the 2011-2015 period, both BU approaches (EDGAR v5.0 and GAINS) give a mean value of anthropogenic emissions of 0.8 and 0.9 TgN(2)Oyr(-1), respectively, agreeing with the NGHGI data (0.9 0.6 TgN(2)Oyr(-1)). Over the same period, the average of the three total TD global and regional inversions was 1.3 +/- 0.4 and 1.3 +/- 0.1 TgN(2)Oyr(-1), respectively. The TD and BU comparison method defined in this study can be operationalized for future yearly updates for the calculation of CH4 and N2O budgets both at the EU CUK scale and at the national scale.
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8.
  • Petrescu, Ana Maria Roxana, et al. (författare)
  • The consolidated European synthesis of CH4 and N2O emissions for the European Union and United Kingdom: 1990-2019
  • 2023
  • Ingår i: Earth System Science Data. - : COPERNICUS GESELLSCHAFT MBH. - 1866-3508 .- 1866-3516. ; 15:3, s. 1197-1268
  • 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.
  • Saunois, Marielle, et al. (författare)
  • The Global Methane Budget 2000–2017
  • 2020
  • Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3516 .- 1866-3508. ; 12:3, s. 1561-1623
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding and quantifying the global methane (CH4) budget is important for assessing realistic pathways to mitigate climate change. Atmospheric emissions and concentrations of CH4 continue to increase, making CH4 the second most important human-influenced greenhouse gas in terms of climate forcing, after carbon dioxide (CO2). The relative importance of CH4 compared to CO2 depends on its shorter atmospheric lifetime, stronger warming potential, and variations in atmospheric growth rate over the past decade, the causes of which are still debated. Two major challenges in reducing uncertainties in the atmospheric growth rate arise from the variety of geographically overlapping CH4 sources and from the destruction of CH4 by short-lived hydroxyl radicals (OH). To address these challenges, we have established a consortium of multidisciplinary scientists under the umbrella of the Global Carbon Project to synthesize and stimulate new research aimed at improving and regularly updating the global methane budget. Following Saunois et al. (2016), we present here the second version of the living review paper dedicated to the decadal methane budget, integrating results of top-down studies (atmospheric observations within an atmospheric inverse-modelling framework) and bottom-up estimates (including process-based models for estimating land surface emissions and atmospheric chemistry, inventories of anthropogenic emissions, and data-driven extrapolations).For the 2008–2017 decade, global methane emissions are estimated by atmospheric inversions (a top-down approach) to be 576 Tg CH4 yr−1 (range 550–594, corresponding to the minimum and maximum estimates of the model ensemble). Of this total, 359 Tg CH4 yr−1 or ∼ 60 % is attributed to anthropogenic sources, that is emissions caused by direct human activity (i.e. anthropogenic emissions; range 336–376 Tg CH4 yr−1 or 50 %–65 %). The mean annual total emission for the new decade (2008–2017) is 29 Tg CH4 yr−1 larger than our estimate for the previous decade (2000–2009), and 24 Tg CH4 yr−1 larger than the one reported in the previous budget for 2003–2012 (Saunois et al., 2016). Since 2012, global CH4 emissions have been tracking the warmest scenarios assessed by the Intergovernmental Panel on Climate Change. Bottom-up methods suggest almost 30 % larger global emissions (737 Tg CH4 yr−1, range 594–881) than top-down inversion methods. Indeed, bottom-up estimates for natural sources such as natural wetlands, other inland water systems, and geological sources are higher than top-down estimates. The atmospheric constraints on the top-down budget suggest that at least some of these bottom-up emissions are overestimated. The latitudinal distribution of atmospheric observation-based emissions indicates a predominance of tropical emissions (∼ 65 % of the global budget, < 30∘ N) compared to mid-latitudes (∼ 30 %, 30–60∘ N) and high northern latitudes (∼ 4 %, 60–90∘ N). The most important source of uncertainty in the methane budget is attributable to natural emissions, especially those from wetlands and other inland waters.Some of our global source estimates are smaller than those in previously published budgets (Saunois et al., 2016; Kirschke et al., 2013). In particular wetland emissions are about 35 Tg CH4 yr−1 lower due to improved partition wetlands and other inland waters. Emissions from geological sources and wild animals are also found to be smaller by 7 Tg CH4 yr−1 by 8 Tg CH4 yr−1, respectively. However, the overall discrepancy between bottom-up and top-down estimates has been reduced by only 5 % compared to Saunois et al. (2016), due to a higher estimate of emissions from inland waters, highlighting the need for more detailed research on emissions factors. Priorities for improving the methane budget include (i) a global, high-resolution map of water-saturated soils and inundated areas emitting methane based on a robust classification of different types of emitting habitats; (ii) further development of process-based models for inland-water emissions; (iii) intensification of methane observations at local scales (e.g., FLUXNET-CH4 measurements) and urban-scale monitoring to constrain bottom-up land surface models, and at regional scales (surface networks and satellites) to constrain atmospheric inversions; (iv) improvements of transport models and the representation of photochemical sinks in top-down inversions; and (v) development of a 3D variational inversion system using isotopic and/or co-emitted species such as ethane to improve source partitioning.The data presented here can be downloaded from https://doi.org/10.18160/GCP-CH4-2019 (Saunois et al., 2020) and from the Global Carbon Project.
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10.
  • Tschiderer, Lena, et al. (författare)
  • Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque : Individual Participant Data Meta-Analysis of 20 Prospective Studies
  • 2023
  • Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 12:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development.Methods and Results: We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I-2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I-2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I-2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques).Conclusions: Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.
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12.
  • Arner, Marianne, et al. (författare)
  • CPUP - årsrapport 2007
  • 2007
  • Bok (populärvet., debatt m.m.)abstract
    • Detta är den andra årsrapporten för CPUP (Uppföljningsprogram för cerebral pares) som nationellt kvalitetsregister.
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13.
  • Augé, Céline, et al. (författare)
  • Experimental in vivo model to evaluate the impact of Cernitin™ on pain response on induced chronic bladder inflammation
  • 2022
  • Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:4, s. 320-328
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Inflammation of the urinary bladder may cause burdensome pain also called bladder pain syndrome (BPS). A limitation in understanding BPS pathophysiology is the lack of appropriate preclinical model. Previously published clinical and preclinical studies revealed positive impact of Cernitin™ on pain relief in chronic prostatitis. The objective of this study was to evaluate the effects of Cernitin™ on induced inflammation of the urinary bladder in rats. We also sought to identify biomarkers which might play a role in the management of BPS. Materials and methods: Cystitis was induced by injection of cyclophosphamide (CYP) in female rats. Thereafter, animals were randomly divided into four treatment groups and two control groups. Evaluation of pain scores was assessed by von Frey assay. Expression of pain- and pro-inflammatory biomarkers was determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Results: Treatments with Cernitin™ displayed significant anti-nociceptive effects on CYP-induced visceral pain (p <.01). In contrast, vehicle-treated animals showed high pain score even at the lowest force. Furthermore, results of ELISA showed that Cernitin™-treated animals had significantly reduced levels of COX-2 (T60, p <.01; GBX, p <.05) in bladder tissue homogenate. Immunohistochemical (IHC) staining of bladder tissues showed that Cernitin™-treated animals exhibited less CD45-positive cells, while massive CD45-positive cells infiltration was detected in vehicle-treated animals. IHC also revealed lower SP and PGD2 expression levels in Cernitin™-treated tissues. Conclusions: Cernitin™ components reduced pain score and inflammatory marker COX-2. Our findings suggest a potential therapeutic role for Cernitin™ in the management of BPS.
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14.
  • Barnard, Yvonne, et al. (författare)
  • Selection of operator support systems across modes
  • 2010
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • This Deliverable provides an outline of the process involved in task 2.2 of the ITERATE project forselecting an appropriate set of hypotheses to be tested inWorkpackages 3 (Experimental design andscenario specification), and 4 (Experimental studies).During a workshop with all partners involved in the project, hypotheses were formulated for thethree main system functionalities outlined in D2.1: those that support speed management (SpeedManagement), systems that support system object detection and avoidance (Collision Avoidance)and those that monitor operator state (Operator State). In formulating these hypotheses, partnerswere encouraged to consider systematically the effect of operator state and different operatorgroups on interaction with these three systems. To allow succinct formulation of hypotheses, fouroperator based parameters which are thought to affect operator behaviour with the system, wereidentified: sensation-seeking, hazard perception, fatigue and (high and low) task demand. Informulating hypotheses, partnerswere encouraged to consider the whole process linking a cause toan effect, with a clear mechanism that would link the two.
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15.
  • Blauhut, Veit, et al. (författare)
  • Lessons from the 2018-2019 European droughts : a collective need for unifying drought risk management
  • 2022
  • Ingår i: Natural hazards and earth system sciences. - : Copernicus Publications. - 1561-8633 .- 1684-9981. ; 22:6, s. 2201-2217
  • Tidskriftsartikel (refereegranskat)abstract
    • Drought events and their impacts vary spatially and temporally due to diverse pedo-climatic and hydrologic conditions, as well as variations in exposure and vulnerability, such as demographics and response actions. While hazard severity and frequency of past drought events have been studied in detail, little is known about the effect of drought management strategies on the actual impacts and how the hazard is perceived by relevant stakeholders. In a continental study, we characterised and assessed the impacts and the perceptions of two recent drought events (2018 and 2019) in Europe and examined the relationship between management strategies and drought perception, hazard, and impact. The study was based on a pan-European survey involving national representatives from 28 countries and relevant stakeholders responding to a standard questionnaire. The survey focused on collecting information on stakeholders' perceptions of drought, impacts on water resources and beyond, water availability, and current drought management strategies on national and regional scales. The survey results were compared with the actual drought hazard information registered by the European Drought Observatory (EDO) for 2018 and 2019. The results highlighted high diversity in drought perception across different countries and in values of the implemented drought management strategies to alleviate impacts by increasing national and sub-national awareness and resilience. The study identifies an urgent need to further reduce drought impacts by constructing and implementing a European macro-level drought governance approach, such as a directive, which would strengthen national drought management and mitigate damage to human and natural assets.
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16.
  • Blauhut, Veit, et al. (författare)
  • Lessons from the 2018–2019 European droughts: A collective need for unifying drought risk management
  • 2021
  • Ingår i: Natural hazards and earth system sciences. - : Copernicus Publications. - 1561-8633 .- 1684-9981.
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Drought events and their impacts vary spatially and temporally due to diverse pedo-climatic and hydrologic conditions, as well as variations in exposure and vulnerability, such as demographics and response actions. While hazardous severity and frequency of past drought events have been studied in detail, little is known about the effect of drought management strategies on the actual impacts, and how the hazard is perceived by relevant stakeholders for inducing action. In a continental study, we characterised and assessed the impacts and the perceptions of two recent drought events (2018 and 2019) in Europe and examined the relationship between management strategies and drought perception, hazard and impacts. The study was based on a pan-European survey involving national representatives from 28 countries and relevant stakeholders responding to a standard questionnaire. The survey focused on collecting information on stakeholders’ perceptions of drought, impacts on water resources and beyond, water availability and current drought management strategies at national and regional scales. The survey results were compared with the actual drought hazard information registered by the European Drought Observatory (EDO) for 2018 and 2019. The results highlighted high diversity in drought perceptions across different countries and in values of implemented drought management strategies to alleviate impacts by increasing national and sub-national awareness and resilience. The study concludes with an urgent need to further reduce drought impacts by constructing and implementing a European macro-level drought governance approach, such as a directive, which would strengthen national drought management and lessen harm to human and natural potentials.
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17.
  • Boysen, Lena R., et al. (författare)
  • Global climate response to idealized deforestation in CMIP6 models
  • 2020
  • Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4189. ; 17, s. 5615-5638
  • Tidskriftsartikel (refereegranskat)abstract
    • Changes in forest cover have a strong effect on climate through the alteration of surface biogeophysical and biogeochemical properties that affect energy, water and carbon exchange with the atmosphere. To quantify biogeophysical and biogeochemical effects of deforestation in a consistent setup, nine Earth system models (ESMs) carried out an idealized experiment in the framework of the Coupled Model Intercomparison Project, phase 6 (CMIP6). Starting from their pre-industrial state, models linearly replace 20×106 km2 of forest area in densely forested regions with grasslands over a period of 50 years followed by a stabilization period of 30 years. Most of the deforested area is in the tropics, with a secondary peak in the boreal region. The effect on global annual near-surface temperature ranges from no significant change to a cooling by 0.55 ∘C, with a multi-model mean of −0.22±0.21 ∘C. Five models simulate a temperature increase over deforested land in the tropics and a cooling over deforested boreal land. In these models, the latitude at which the temperature response changes sign ranges from 11 to 43∘ N, with a multi-model mean of 23∘ N. A multi-ensemble analysis reveals that the detection of near-surface temperature changes even under such a strong deforestation scenario may take decades and thus longer than current policy horizons. The observed changes emerge first in the centre of deforestation in tropical regions and propagate edges, indicating the influence of non-local effects. The biogeochemical effect of deforestation are land carbon losses of 259±80 PgC that emerge already within the first decade. Based on the transient climate response to cumulative emissions (TCRE) this would yield a warming by 0.46 ± 0.22 ∘C, suggesting a net warming effect of deforestation. Lastly, this study introduces the “forest sensitivity” (as a measure of climate or carbon change per fraction or area of deforestation), which has the potential to provide lookup tables for deforestation–climate emulators in the absence of strong non-local climate feedbacks. While there is general agreement across models in their response to deforestation in terms of change in global temperatures and land carbon pools, the underlying changes in energy and carbon fluxes diverge substantially across models and geographical regions. Future analyses of the global deforestation experiments could further explore the effect on changes in seasonality of the climate response as well as large-scale circulation changes to advance our understanding and quantification of deforestation effects in the ESM frameworks.
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18.
  • Cardeña, Etzel, et al. (författare)
  • A neurophenomenological fMRI study of a spontaneous automatic writer and a hypnotic cohort
  • 2023
  • Ingår i: Brain and Cognition. - 0278-2626. ; 170
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To evaluate the neurophenomenology of automatic writing (AW) in a spontaneous automatic writer (NN) and four high hypnotizables (HH). Methods: During fMRI, NN and the HH were cued to perform sponta- neous (NN) or induced (HH) AW, and a comparison task of copying complex symbols, and to rate their expe- rience of control and agency. Results: Compared to copying, for all participants AW was associated with less sense of control and agency and decreased BOLD signal responses in brain regions implicated in the sense of agency (left premotor cortex and insula, right premotor cortex, and supplemental motor area), and increased BOLD signal responses in the left and right temporoparietal junctions and the occipital lobes. During AW, the HH differed from NN in widespread BOLD decreases across the brain and increases in frontal and parietal regions. Conclusions: Spontaneous and induced AW had similar effects on agency, but only partly overlapping effects on cortical activity.
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19.
  • Carlsson, Lena M S, 1957, et al. (författare)
  • ALK7 expression is specific for adipose tissue, reduced in obesity and correlates to factors implicated in metabolic disease.
  • 2009
  • Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 382:2, s. 309-14
  • Tidskriftsartikel (refereegranskat)abstract
    • Human adipose tissue is a major site of expression of inhibin beta B (INHBB) which homodimerizes to form the novel adipokine activin B. Our aim was to determine if molecules needed for a local action of activin B are expressed in adipose tissue. Microarray analysis showed that adipose tissue expressed activin type I and II receptors and that the expression of activin receptor-like kinase 7 (ALK7) was adipose tissue specific. In obesity discordant siblings from the SOS Sib Pair study, adipose tissue ALK7 expression was higher in lean (n=90) compared to obese (n=90) subjects (p=4 x 10(-31)). Adipose tissue ALK7 expression correlated with several measures of body fat, carbohydrate metabolism and lipids. In addition, ALK7 and INHBB expression correlated but only in lean subjects and in subjects with normal glucose tolerance. We conclude that activin B may have local effects in adipose tissue and thereby influence obesity and its comorbidities.
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20.
  • Chabot, Sophie, et al. (författare)
  • Impact of Cernitin™ on induced chronic prostatitis in animal model for understanding management of lower urinary tract symptoms
  • 2021
  • Ingår i: Phytomedicine Plus. - : Elsevier BV. - 2667-0313. ; 1:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cernitin™ pollen extracts (brand name Cernilton®) alleviates symptoms related to common lower uro-genital tract disorders in men. The underlying mechanisms are ill-defined but the inflammatory pathway could be one of them. In a previous in vitro study it was shown that Cernitin™ induce a regulatory effect on inflammatory parameters. Methods: In this study, male Sprague Dawley rats were used to validate the effects of Cernitin™ in chronic prostatitis and benign prostatic hyperplasia. Pain was assessed by von Frey assay. Results: Cernitin™ exhibited significant pain relief in the induced prostatitis rat model and was associated with a significant decrease in the intraprostatic level of COX-2 and MCP-1 in the prostatic tissue homogenates. In a parallel study, Cernitin™ treatment led to a significant decrease in prostate weight in rats with testosterone induced BPH. Concurrently, a significant decrease in the percentage of proliferation marker, Ki-67, and androgen receptor expressing cells was observed. Similarly, a low level of cytoplasmic 5α-reductase expression was observed in Cernitin™- and finasteride-treated animals. Conclusion: The current in vivo experiments support the use of Cernitin™ as an anti-inflammatory and symptom reducing agent that could, in part, explain the impact of Cernitin™ on the management of chronic pelvic pain in men.
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21.
  • Chounti, A., et al. (författare)
  • Sex differences in cerebral palsy incidence and functional ability: a total population study
  • 2013
  • Ingår i: Acta Pædiatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 102:7, s. 712-717
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim To describe gender difference in a total population of children with cerebral palsy (CP), related to subtype, gross and fine motor function, and to compare CP incidence trends in girls and boys. Methods All 590 children with CP born in southern Sweden 1990-2005 were included. CP subtype was classified according to the Surveillance of Cerebral Palsy in Europe, gross motor function according to Gross Motor Function Classification System (GMFCS) and manual ability according to Manual Ability Classification System (MACS). Trends in CP incidence by birth year were analysed using Poisson regression modelling. Results There was a male predominance in all levels of GMFCS except level II, in all levels of MACS and in all CP subtypes except ataxic CP. There was no statistically significant difference between males and females regarding gross motor function or manual ability. The CP incidence trends in boys compared with girls did not change during the period 1990-2005. Conclusion No equalization was detected in the incidence of CP between girls and boys during recent years in this total population. We could not confirm any consistent sex difference in motor function levels. Male sex is a risk factor for CP.
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22.
  • Clark, Stephen J, et al. (författare)
  • Association of Sirtuin 1 (SIRT1) Gene SNPs and Transcript Expression Levels With Severe Obesity.
  • 2012
  • Ingår i: Obesity. - : Wiley. - 1930-7381. ; 20:1, s. 178-85
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies have reported associations of sirtuin 1 (SIRT1) single nucleotide polymorphisms (SNPs) to both obesity and BMI. This study was designed to investigate association between SIRT1 SNPs, SIRT1 gene expression and obesity. Case-control analyses were performed using 1,533 obese subjects (896 adults, BMI >40kg/m(2) and 637 children, BMI >97th percentile for age and sex) and 1,237 nonobese controls, all French Caucasians. Two SNPs (in high linkage disequilibrium (LD), r(2) = 0.96) were significantly associated with adult obesity, rs33957861 (P value = 0.003, odds ratio (OR) = 0.75, confidence interval (CI) = 0.61-0.92) and rs11599176 (P value: 0.006, OR = 0.74, CI = 0.61-0.90). Expression of SIRT1 mRNA was measured in BMI-discordant siblings from 154 Swedish families. Transcript expression was significantly correlated to BMI in the lean siblings (r(2) = 0.13, P value = 3.36 × 10(-7)) and lower SIRT1 expression was associated with obesity (P value = 1.56 × 10(-35)). There was also an association between four SNPs (rs11599176, rs12413112, rs33957861, and rs35689145) and BMI (P values: 4 × 10(-4), 6 × 10(-4), 4 × 10(-4), and 2 × 10(-3)) with the rare allele associated with a lower BMI. However, no SNP was associated with SIRT1 transcript expression level. In summary, both SNPs and SIRT1 gene expression are associated with severe obesity.
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23.
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24.
  • Dik, Vincent K., et al. (författare)
  • Coffee and tea consumption, genotype- based CYP1A2 and NAT2 activity and colorectal cancer risk- Results from the EPIC cohort study
  • 2014
  • Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:2, s. 401-412
  • Tidskriftsartikel (refereegranskat)abstract
    • Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotypes, enzymes involved in the metabolization of caffeine. Data from 477,071 participants (70.2% female) of the European Investigation into Cancer and Nutrition (EPIC) cohort study were analyzed. At baseline (1992-2000) habitual (total, caffeinated and decaffeinated) coffee and tea consumption was assessed with dietary questionnaires. Cox proportional hazards models were used to estimate adjusted hazard ratio's (HR) and 95% confidence intervals (95% CI). Potential effect modification by genotype-based CYP1A2 and NAT2 activity was studied in a nested case-control set of 1,252 cases and 2,175 controls. After a median follow-up of 11.6 years, 4,234 participants developed CRC (mean age 64.78.3 years). Total coffee consumption (high vs. non/low) was not associated with CRC risk (HR 1.06, 95% CI 0.95-1.18) or subsite cancers, and no significant associations were found for caffeinated (HR 1.10, 95% CI 0.97-1.26) and decaffeinated coffee (HR 0.96, 95% CI 0.84-1.11) and tea (HR 0.97, 95% CI 0.86-1.09). High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggests that caffeine metabolism does not affect the link between coffee and tea consumption and CRC risk. This study shows that coffee and tea consumption is not likely to be associated with overall CRC. What's new? Coffee and tea contain numerous compounds that may protect against colorectal cancer (CRC). In this study of more than 475,000 participants over more than a decade, the authors investigated whether coffee or tea consumption is associated with an altered risk of developing CRC. They also asked whether genetic variations in two enzymes involved in caffeine metabolism (CYP1A2 and NAT2) might affect this risk. They conclude that neither consumption patterns, nor genetic differences in caffeine metabolism, appear to have a significant impact on CRC risk.
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25.
  • Dina, Christian, et al. (författare)
  • Variation in FTO contributes to childhood obesity and severe adult obesity.
  • 2007
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:6, s. 724-6
  • Tidskriftsartikel (refereegranskat)abstract
    • We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.
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26.
  • Dumanski, Jan P., et al. (författare)
  • Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease
  • 2016
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 98:6, s. 1208-1219
  • Tidskriftsartikel (refereegranskat)abstract
    • Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.
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27.
  • Eleftherohorinou, Hariklia, et al. (författare)
  • famCNV: copy number variant association for quantitative traits in families.
  • 2011
  • Ingår i: Bioinformatics (Oxford, England). - : Oxford University Press (OUP). - 1367-4811 .- 1367-4803. ; 27:13, s. 1873-5
  • Tidskriftsartikel (refereegranskat)abstract
    • A program package to enable genome-wide association of copy number variants (CNVs) with quantitative phenotypes in families of arbitrary size and complexity. Intensity signals that act as proxies for the number of copies are modeled in a variance component framework and association with traits is assessed through formal likelihood testing. AVAILABILITY AND IMPLEMENTATION: The Java package is made available at www.imperial.ac.uk/medicine/people/m.falchi/. CONTACT: m.falchi@imperial.ac.uk.
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28.
  • Fava, Cristiano, et al. (författare)
  • 24-hour Ambulatory Blood Pressure is Linked to Chromosome 18q21-22 and Genetic Variation of NEDD4L Associates with Cross-Sectional and Longitudinal Blood Pressure in Swedes.
  • 2006
  • Ingår i: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 70:3, s. 562-569
  • Tidskriftsartikel (refereegranskat)abstract
    • Numerous linkage studies have indicated chromosome 18q21–22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70–104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.
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29.
  • Fava, Cristiano, et al. (författare)
  • Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure
  • 2008
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:3, s. 413-418
  • Tidskriftsartikel (refereegranskat)abstract
    • Gitelmans syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1 000 000, in Sweden, suggesting that similar to 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies.
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30.
  • Froguel, Philippe, et al. (författare)
  • A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels
  • 2012
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far. We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P overall = 8.1×10 -59), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23±0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P total cholesterol = 0.002 and P LDL = 0.0008). Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact. © 2012 Froguel et al.
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31.
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32.
  • Heuchel, Rainer, et al. (författare)
  • Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3' kinase signaling
  • 1999
  • Ingår i: Proc Natl Acad Sci U S A. ; 96:20, s. 11410-5
  • Tidskriftsartikel (refereegranskat)abstract
    • Platelet-derived growth factor (PDGF) isoforms lead to mitogenic, survival, and chemotactic responses in a variety of mesenchymal cell types during development and in the adult. We have studied the importance of phosphatidylinositol-3' kinase (PI3K) signaling in these responses by mutating the PI3K-binding sites in the PDGF-beta receptor by gene targeting in embryonic stem cells. Homozygous mutant mice developed normally; however, cells derived from the mutants were less chemotactic and had largely lost their ability to contract collagen gels in response to PDGF. Injection of a mast cell degranulating agent in mice led to a decrease in interstitial fluid pressure resulting in edema formation. In contrast to wild-type mice, mutant mice were unable to normalize the pressure after treatment with PDGF. Taken together, these observations suggest a function for PDGF signaling through PI3K in interstitial fluid homeostasis by modulating the tension between cells and extracellular matrix structures.
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33.
  • Hägglund, Gunnar, et al. (författare)
  • Prevention of dislocation of the hip in children with cerebral palsy : 20-year results of a population-based prevention programme.
  • 2014
  • Ingår i: The bone & joint journal. - 2049-4408. ; 96-B:11, s. 1546-52
  • Tidskriftsartikel (refereegranskat)abstract
    • In 1994 a cerebral palsy (CP) register and healthcare programme was established in southern Sweden with the primary aim of preventing dislocation of the hip in these children. The results from the first ten years were published in 2005 and showed a decrease in the incidence of dislocation of the hip, from 8% in a historical control group of 103 children born between 1990 and 1991 to 0.5% in a group of 258 children born between 1992 and 1997. These two cohorts have now been re-evaluated and an additional group of 431 children born between 1998 and 2007 has been added. By 1 January 2014, nine children in the control group, two in the first study group and none in the second study group had developed a dislocated hip (p < 0.001). The two children in the first study group who developed a dislocated hip were too unwell to undergo preventive surgery. Every child with a dislocated hip reported severe pain, at least periodically, and four underwent salvage surgery. Of the 689 children in the study groups, 91 (13%) underwent preventive surgery. A population-based hip surveillance programme enables the early identification and preventive treatment, which can result in a significantly lower incidence of dislocation of the hip in children with CP.
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34.
  • Jernås, Margareta, 1961, et al. (författare)
  • Regulation of carboxylesterase 1 (CES1) in human adipose tissue.
  • 2009
  • Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 383:1, s. 63-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Carboxylesterase 1 (CES1) has recently been suggested to play a role in lipolysis. Our aim was to study the regulation of CES1 expression in human adipose tissue. In the SOS Sib Pair Study, CES1 expression was higher in obese compared with lean sisters (n=78 pairs, P=8.7x10(-18)) and brothers (n=12 pairs, P=0.048). CES1 expression was higher in subcutaneous compared with omental adipose tissue in lean (P=0.027) and obese subjects (P=0.00036), and reduced during diet-induced weight loss (n=24, weeks 8, 16, and 18 compared to baseline, P<0.0001 for all time points). CES1 expression was higher in isolated adipocytes compared with intact adipose tissue (P=0.0018) and higher in large compared with small adipocytes (P=4.1x10(-6)). Basal and stimulated lipolysis was not different in individuals with high, intermediate, and low expression of CES1. Thus, CES1 expression was linked to body fat and adipocyte fat content but not to lipolytic activity.
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35.
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36.
  • Lindström, Lena, et al. (författare)
  • Nonlinear brain correlates of trait self-boundarylessness
  • 2023
  • Ingår i: Neuroscience of Consciousness. - 2057-2107.
  • Tidskriftsartikel (refereegranskat)abstract
    • Alterations of the sense of self induced by meditation include an increased sense of boundarylessness. In this study, we investigatedbehavioural and functional magnetic resonance imaging correlates of trait self-boundarylessness during resting state and the performanceof two experimental tasks. We found that boundarylessness correlated with greater self-endorsement of words related to fluidityand with longer response times in a math task. Boundarylessness also correlated negatively with brain activity in the posterior cingulatecortex/precuneus during mind-wandering compared to a task targeting a minimal sense of self. Interestingly, boundarylessnessshowed quadratic relations to several measures. Participants reporting low or high boundarylessness, as compared to those in between,showed higher functional connectivity within the default mode network during rest, less brain activity in the medial prefrontal cortexduring self-referential word processing, and less self-endorsement of words related to constancy. We relate these results to our previousfindings of a quadratic relation between boundarylessness and the sense of perspectival ownership of experience. Additionally,an instruction to direct attention to the centre of experience elicited brain activation similar to that of meditation onset, includingincreases in anterior precentral gyrus and anterior insula and decreases in default mode network areas, for both non-meditators andexperienced meditators.
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37.
  • Lundkvist, Annika, et al. (författare)
  • Functional performance in self-care and mobility after selective dorsal rhizotomy : a 10-year practice-based follow-up study.
  • 2015
  • Ingår i: Developmental Medicine & Child Neurology. - : Wiley. - 0012-1622 .- 1469-8749. ; 57:3, s. 286-293
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: To explore changes in performance in daily activities (self-care and mobility) 10 years after selective dorsal rhizotomy (SDR).METHOD: Twenty-four children with bilateral spastic cerebral palsy were followed; the median age at SDR was 4 years 1 month (range 2y 5mo-6y 4mo) and at 10-year follow-up was 14 years 6 months (range 12y 3mo-16y 9mo). The preoperative Gross Motor Function Classification System (GMFCS) levels were: I (n=1), II (n=7), III (n=4), IV (n=11), and V (n=1). The Pediatric Evaluation of Disability Inventory (PEDI) was used to assess performance in functional skills, caregiver assistance, and frequency of modifications and adaptive equipment (MAE) in self-care and mobility domains. Changes were analysed in relation to preoperative GMFCS levels, PEDI scores, and age at operation.RESULTS: All scores improved significantly (p<0.01) during the first 5 years in patients assigned to GMFCS levels I-III and IV-V. Between 5 years and 10 years, changes were seen in patients grouped in GMFCS levels I-III in the functional skills, mobility (p=0.04), caregiver assistance self-care (p=0.03), and caregiver assistance mobility (p=0.03) domains. Those grouped in GMFCS levels IV-V showed small changes between 5 years and 10 years after surgery. Changes were dependent on the preoperative GMFCS levels in all domains; caregiver assistance, self-care and mobility changes were dependent on preoperative values. The use of MAE increased in participants in GMFCS levels IV-V.INTERPRETATION: Children who underwent SDR and physiotherapy improved in functional performance in self-care and mobility and were more independent 10 years postoperatively.
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38.
  • Lundkvist, Annika, et al. (författare)
  • Motor function after selective dorsal rhizotomy: a 10-year practice-based follow-up study.
  • 2012
  • Ingår i: Developmental Medicine & Child Neurology. - : Wiley. - 0012-1622. ; 54:5, s. 429-435
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim The aim of this study was to explore changes in motor function up to 10 years after selective dorsal rhizotomy (SDR). Method The participants comprised 29 children (20 males, nine females) with bilateral spastic diplegia who were consecutively operated on at a median age of 4 years and 3 months and followed until a median age of 15 years. SDR was combined with physiotherapy and regular follow-up visits. The distribution of preoperative Gross Motor Function Classification System (GMFCS) levels was as follows: I, n=1; II, n=7; III, n=8; IV, n=12; and V, n=1. Muscle tone in hip flexors, hip adductors, knee flexors, and plantar flexors was assessed with the modified Ashworth scale, passive range of motion in hip abduction, popliteal angle, maximum knee extension, dorsiflexion of the foot was measured with a goniometer, and gross motor function was assessed using the Gross Motor Function Measure (GMFM-66). The results were compared with preoperative values, taking into account age at the time of SDR. Results After 10 years, muscle tone in hip flexors, hip adductors, knee flexors and plantar flexors was normalized in 19, 24, 13 and 23 participants respectively; mean change in passive range of motion ranged from -2.0° to 8.6°, and the mean increase in GMFM-66 was 10.6. Changes in GMFM-66 were associated with preoperative GMFCS level and GMFM-66 scores. Interpretation Children who underwent SDR and physiotherapy and were regularly followed up by an experienced team showed improved gross motor function for up to 10 years postoperatively.
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39.
  • Malcus Johnsson, Pia, et al. (författare)
  • Individualized outcome measures of daily activities are sensitive tools for evaluating hand surgery in rheumatic diseases.
  • 2012
  • Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324.
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives. To explore the ability of six outcome measures to capture clinically important changes in patients with rheumatic diseases undergoing hand surgery and to study predictors of changes in activity performance in different patient and surgery strata.Methods. A total of 172 patients (median age 59 years, disease duration 18 years) were stratified into subgroups: diagnosis, age, general function, type of surgery. Performance of daily activities and satisfaction were assessed by the Canadian Occupational Performance Measure (COPM). Clinically important improvement was defined as a two-step improvement in COPM. Hand function was assessed by reference to grip strength (Grippit), pinch strength (pinch gauge), hand pain (visual analogue scale) and grip ability (Grip Ability Test). Responsiveness was calculated as effect size (ES) at 6-month follow-up compared with baseline.Results. Clinically important improvement was reached by 25-69% depending on outcome measure and type of surgery. Improvement was smaller in patients with multiple simultaneous procedures. Regardless of diagnosis, age, general function and type of surgery, patients improved significantly in all measures, with the largest changes in COPM(performance) and COPM(satisfaction) (ES 0.7-1.9). The ES of pain ranged from 0.2 to 0.7, Grippit from 0.1 to 0.5 and pinch gauge from 0.4 to 0.8. Hand pain was the only significant predictor of clinically important improvement of COPM(performance): odds ratio 0.71, 95% CI 0.51, 0.98 (P = 0.041).Conclusion. COPM was the most sensitive instrument to capture clinically important improvement, and hand pain was a significant predictor of improvement, irrespective of diagnosis, age, general functional level and type of surgery.
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40.
  • Mardinoglu, Adil, 1982, et al. (författare)
  • Integration of clinical data with a genome-scale metabolic model of the human adipocyte
  • 2013
  • Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292 .- 1744-4292. ; 9, s. 649-
  • Tidskriftsartikel (refereegranskat)abstract
    • We evaluated the presence/absence of proteins encoded by 14 077 genes in adipocytes obtained from different tissue samples using immunohistochemistry. By combining this with previously published adipocyte-specific proteome data, we identified proteins associated with 7340 genes in human adipocytes. This information was used to reconstruct a comprehensive and functional genome-scale metabolic model of adipocyte metabolism. The resulting metabolic model, iAdipocytes1809, enables mechanistic insights into adipocyte metabolism on a genome-wide level, and can serve as a scaffold for integration of omics data to understand the genotype-phenotype relationship in obese subjects. By integrating human transcriptome and fluxome data, we found an increase in the metabolic activity around androsterone, ganglioside GM2 and degradation products of heparan sulfate and keratan sulfate, and a decrease in mitochondrial metabolic activities in obese subjects compared with lean subjects. Our study hereby shows a path to identify new therapeutic targets for treating obesity through combination of high throughput patient data and metabolic modeling.
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41.
  • Marquez, Marcel, et al. (författare)
  • Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk
  • 2012
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 61:2, s. 524-530
  • Tidskriftsartikel (refereegranskat)abstract
    • It has recently been suggested that the low-frequency c.136-14-136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14-136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14-136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease. © 2012 by the American Diabetes Association.
  •  
42.
  • Moro, Elena, et al. (författare)
  • Long-Term Results of a Multicenter Study on Subthalamic and Pallidal Stimulation in Parkinson's Disease
  • 2010
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 25:5, s. 578-586
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the 5 to 6 year follow-up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty-live STN patients and 16 GPi patienis were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross-over double-blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off- and on-medication states with and without stimulation, activities of daily living (ADL), anti-PD medications, and dyskinesias. In double-blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN. P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with of regardless of the sequence of stimulation. In open assessment. both STN- and GPi-DBS significantly improved the off-medication motor UPDRS when compared with before surgery (STN. P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti-PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long-term efficacy of STN and GPi DBS advanced PD. Although the surgical targets were not randomized, there was a trend to 1 better outcome of motor signs in the STN-DBS patients and fewer adverse events in the GPi-DBS group. (C) 2010 Movement Disorder Society
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43.
  • Nookaew, Intawat, 1977, et al. (författare)
  • Adipose Tissue Resting Energy Expenditure and Expression of Genes Involved in Mitochondrial Function Are Higher in Women than in Men.
  • 2013
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 98:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Context:Men and women differ in body fat distribution and adipose tissue metabolism as well as in obesity comorbidities and their response to obesity treatment.Objective:The objective of the study was a search for sex differences in adipose tissue function.Design and Setting:This was an exploratory study performed at a university hospital.Participants and Main Outcome Measures:Resting metabolic rate (RMR), body composition, and sc adipose tissue genome-wide expression were measured in the SOS Sib Pair study (n = 732).Results:The relative contribution of fat mass to RMR and the metabolic rate per kilogram adipose tissue was higher in women than in men (P value for sex by fat mass interaction = .0019). Women had increased expression of genes involved in mitochondrial function, here referred to as a mitochondrial gene signature. Analysis of liver, muscle, and blood showed that the pronounced mitochondrial gene signature in women was specific for adipose tissue. Brown adipocytes are dense in mitochondria, and the expression of the brown adipocyte marker uncoupling protein 1 was 5-fold higher in women compared with men in the SOS Sib Pair Study (P = 7.43 × 10(-7)), and this was confirmed in a cross-sectional, population-based study (n = 83, 6-fold higher in women, P = .00256).Conclusions:The increased expression of the brown adipocyte marker uncoupling protein 1 in women indicates that the higher relative contribution of the fat mass to RMR in women is in part explained by an increased number of brown adipocytes.
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44.
  • Nordmark, Eva, et al. (författare)
  • Development of lower limb range of motion from early childhood to adolescence in cerebral palsy: a population-based study
  • 2009
  • Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The decreasing range of joint motion caused by insufficient muscle length is a common problem in children with cerebral palsy (CP), often worsening with age. In 1994 a CP register and health care programme for children with CP was initiated in southern Sweden. The aim of this study was to analyse the development of the passive range of motion (ROM) in the lower limbs during all the growth periods in relation to gross motor function and CP subtype in the total population of children with CP. Methods: In total, 359 children with CP born during 1990-1999, living in the southernmost part of Sweden in the year during which they reached their third birthday and still living in the area in the year of their seventh birthday were analysed. The programme includes a continuous standardized follow-up with goniometric measurements of ROM in the lower limbs. The assessments are made by each child's local physiotherapist twice a year until 6 years of age, then once a year. In total, 5075 assessments from the CPUP database from 1994 to 1 January 2007 were analysed. Results: The study showed a decreasing mean range of motion over the period 2-14 years of age in all joints or muscles measured. The development of ROM varied according to GMFCS level and CP subtype. Conclusion: We found a decreasing ROM in children with CP from 2-14 years of age. This information is important for both the treatment and follow-up planning of the individual child as well as for the planning of health care programmes for all children with CP.
  •  
45.
  • Olsson, Maja, 1975, et al. (författare)
  • Expression of the selenoprotein S (SELS) gene in subcutaneous adipose tissue and SELS genotype are associated with metabolic risk factors.
  • 2011
  • Ingår i: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 60:1, s. 114-20
  • Tidskriftsartikel (refereegranskat)abstract
    • The selenoprotein S (SELS) is a putative receptor for serum amyloid A, and recent studies have suggested that SELS may be a link between type 2 diabetes mellitus and inflammation. Genetic studies of SELS polymorphisms have revealed associations with circulating levels of inflammatory markers and hard end points of cardiovascular disease. In this study, we analyzed SELS expression in subcutaneous adipose tissue and SELS genotype in relation to metabolic risk factors. DNA microarray expression analysis was used to study the expression of SELS in lean and obese siblings from the Swedish Obese Subjects Sib Pair Study. TaqMan genotyping was used to analyze 3 polymorphisms, previously found to be associated with circulating levels of inflammatory markers, in the INTERGENE case-control study of myocardial infarction and unstable angina pectoris. Possible associations between SELS genotype and/or expression with anthropometry and measures of metabolic status were investigated. Real-time polymerase chain reaction was used to analyze the SELS expression in isolated human adipocytes incubated with insulin. In lean subjects, we found correlations between SELS gene expression in subcutaneous adipose tissue and measures of obesity (waist, P = .045; sagittal diameter, P = .031) and blood pressure (diastolic, P = .016; systolic P = .015); and in obese subjects, we found correlations with measures of obesity (body mass index, P = .03; sagittal diameter, P = .008) and glycemic control (homeostasis model assessment of insulin resistance, P = .011; insulin, P = .009) after adjusting for age and sex. The 5227GG genotype was associated with serum levels of insulin (P = .006) and homeostasis model assessment of insulin resistance (P = .007). The expression of SELS increased after insulin stimulation in isolated human adipocytes (P = .008). In this study, we found an association between both SELS gene expression in adipose tissue and SELS genotype with measures of glycemic control. In vitro studies demonstrated that the SELS gene is regulated by insulin in human subcutaneous adipocytes. This study further supports a role for SELS in the development of metabolic disease, especially in the context of insulin resistance.
  •  
46.
  • Pernemalm, Maria, et al. (författare)
  • Quantitative Proteomics Profiling of Primary Lung Adenocarcinoma Tumors Reveals Functional Perturbations in Tumor Metabolism
  • 2013
  • Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:9, s. 3934-3943
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study, we have analyzed human primary lung adenocarcinoma tumors using global mass spectrometry to elucidate the biological mechanisms behind relapse post surgery. In total, we identified over 3000 proteins with high confidence. Supervised multivariate analysis was used to select 132 proteins separating the prognostic groups. Based on in-depth bioinformatics analysis, we hypothesized that the tumors with poor prognosis had a higher glycolytic activity and HIF activation. By measuring the bioenergetic cellular index of the tumors, we could detect a higher dependency of glycolysis among the tumors with poor prognosis. Further, we could also detect an up-regulation of HIF1 alpha mRNA expression in tumors with early relapse. Finally, we selected three proteins that were upregulated in the poor prognosis group (cathepsin D, ENO1, and VDAC1) to confirm that the proteins indeed originated from the tumor and not from a stromal or inflammatory component. Overall, these findings show how in-depth analysis of clinical material can lead to an increased understanding of the molecular mechanisms behind tumor progression.
  •  
47.
  • Persson-Bunke, Måns, et al. (författare)
  • Scoliosis in a Total Population of Children with Cerebral Palsy.
  • 2012
  • Ingår i: Spine. - 0362-2436. ; 37:12, s. 708-713
  • Tidskriftsartikel (refereegranskat)abstract
    • ABSTRACT: Study Design. Epidemiological total population study based on a prospective follow-up CP registry.Objective. To describe the prevalence of scoliosis in a total population of children with CP, to analyse the relation between scoliosis, gross motor function and CP subtype, and to describe the age at diagnosis of scoliosis.Summary of Background Data. Children with cerebral palsy (CP) have an increased risk of developing scoliosis. The reported incidence varies, partly due to different definitions and study groups. Knowledge of the prevalence and characteristics of scoliosis in an unselected group of children with different CP types and levels of function is important for health care planning and for analysing the risk in an individual child.Methods. A total population of 666 children with CP, aged 4-18 years 1 January 2008, followed with annual examinations in a healthcare program was analysed. Gross motor function (GMFCS level), CP subtype, age at clinical diagnosis of scoliosis, and the Cobb angle at the first radiographic examination were registered.Results. Of the 666 children 116 (17%) had mild and a further 76 (11%) had moderate or severe scoliosis based on clinical examination. Radiographic examination showed a Cobb angle >10 degrees in 54 (8%) children and >20 degrees in 45 (7%) children. The risk of developing scoliosis increased with GMFCS level and age. In most children the scoliosis was diagnosed after 8 years of age. Children in GMFCS level IV or V had a 50% risk of having moderate or severe scoliosis by the age of 18, while children in GMFCS level I or II had almost no risk.Conclusions. The incidence of scoliosis increased with GMFCS level and age. Observed variations related to CP subtype were confounded by GMFCS, reflecting the different distribution of GMFCS levels in the subtypes. Follow-up programs for early detection of scoliosis should be based on the child's GMFCS level and age.
  •  
48.
  • Pierrillas, Philippe B., et al. (författare)
  • Model-Based Adaptive Optimal Design (MBAOD) Improves Combination Dose Finding Designs : an Example in Oncology
  • 2018
  • Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 20:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Design of phase 1 combination therapy trials is complex compared to single therapy trials. In this work, model-based adaptive optimal design (MBAOD) was exemplified and evaluated for a combination of paclitaxel and a hypothetical new compound in a phase 1 study to determine the best dosing regimen for a phase 2 trial. Neutropenia was assumed as the main toxicity and the dose optimization process targeted a 33% probability of grade 4 neutropenia and maximal efficacy (based on preclinical studies) by changing the dose amount of both drugs and the dosing schedule for the new drug. Different starting conditions (e.g., initial dose), search paths (e.g., maximal change in dose intensity per step), and stopping criteria (e.g., "3 + 3 rule") were explored. The MBAOD approach was successfully implemented allowing the possibility of flexible designs with the modification of doses and dosing schedule throughout the trial. The 3 + 3 rule was shown to be highly conservative (selection of a dosing regimen with at least 90% of the possible maximal efficacy in less than 21% of the cases) but also safer (selection of a toxic design in less than 2% of the cases). Without the 3 + 3 rule, better performance was observed (>67% of selected designs were associated with at least 90% of possible maximal efficacy) while the proportion of DLTs per trial was similar. Overall, MBAOD is a promising tool in the context of dose finding studies of combination treatments and was showed to be flexible enough to be associated with requirements imposed by clinical protocols.
  •  
49.
  • Rigard, Melanie, et al. (författare)
  • Francisella tularensis IglG Belongs to a Novel Family of PAAR-Like T6SS Proteins and Harbors a Unique N-terminal Extension Required for Virulence
  • 2016
  • Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 12:9
  • Tidskriftsartikel (refereegranskat)abstract
    • The virulence of Francisella tularensis, the etiological agent of tularemia, relies on an atypical type VI secretion system ( T6SS) encoded by a genomic island termed the Francisella Pathogenicity Island ( FPI). While the importance of the FPI in F. tularensis virulence is clearly established, the precise role of most of the FPI-encoded proteins remains to be deciphered. In this study, using highly virulent F. tularensis strains and the closely related species F. novicida, IglG was characterized as a protein featuring a unique alpha-helical N-terminal extension and a domain of unknown function ( DUF4280), present in more than 250 bacterial species. Three dimensional modeling of IglG and of the DUF4280 consensus protein sequence indicates that these proteins adopt a PAAR-like fold, suggesting they could cap the T6SS in a similar way as the recently described PAAR proteins. The newly identified PAAR-like motif is characterized by four conserved cysteine residues, also present in IglG, which may bind a metal atom. We demonstrate that IglG binds metal ions and that each individual cysteine is required for T6SS-dependent secretion of IglG and of the Hcp homologue, IglC and for the F. novicida intracellular life cycle. In contrast, the Francisella-specific N-terminal alpha-helical extension is not required for IglG secretion, but is critical for F. novicida virulence and for the interaction of IglG with another FPI-encoded protein, IglF. Altogether, our data suggest that IglG is a PAAR-like protein acting as a bi-modal protein that may connect the tip of the Francisella T6SS with a putative T6SS effector, IglF.
  •  
50.
  • Saiki, Atsuhito, et al. (författare)
  • Tenomodulin is highly expressed in adipose tissue, increased in obesity, and down-regulated during diet-induced weight loss.
  • 2009
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:10, s. 3987-94
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: Tenomodulin (TNMD), a putative angiogenesis inhibitor, is expressed in hypovascular connective tissues. Global gene expression scans show that the TNMD gene also is expressed in human adipose tissue and that its expression is regulated in response to weight reduction; however, more detailed information is lacking. OBJECTIVE: The aim of this study was to investigate TNMD tissue distribution and TNMD gene expression in human adipose tissue in relation to obesity and metabolic disease. DESIGN, PATIENTS, AND INTERVENTIONS: TNMD gene expression, tissue distribution, and TNMD gene expression in adipose tissue from different depots, from lean and obese subjects, and during diet-induced weight reduction were analyzed by DNA microarray and real-time PCR. MAIN OUTCOME MEASURE: We primarily measured TNMD gene expression. RESULTS: The TNMD gene was predominantly expressed in sc adipose tissue. TNMD gene expression was higher in sc than omental adipose tissue both in lean (P = 0.002) and obese subjects (P = 0.014). In both women and men, TNMD gene expression was significantly higher in the obese subjects compared to the lean subjects (P = 1.1 x 10(-26) and P = 0.010, respectively). In a multiple linear regression analysis, BMI was a significant independent predictor of TNMD gene expression. TNMD gene expression was down-regulated during diet-induced weight loss, with a 65% decrease after 18 wk of diet (P < 0.0001). CONCLUSIONS: We conclude that human adipose tissue TNMD gene expression is highly affected by obesity, adipose tissue location, and weight loss, indicating that TNMD may play a role in adipose tissue function.
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