| 41. |
- Goedecke, Julia H, et al.
(författare)
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Reduced gluteal expression of adipogenic and lipogenic genes in black south african women is associated with obesity-related insulin resistance
- 2011
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - Philadelphia : Lippincott Williams & Wilkins. - 0021-972X .- 1945-7197. ; 96:12, s. E2029-E2033
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Tidskriftsartikel (refereegranskat)abstract
- Context: Black South African women are less insulin sensitive than their White counterparts, despite less central and greater peripheral fat deposition. We hypothesized that this paradox may be explained, in part, by differences in the adipogenic capacity of sc adipose tissue (SAT). Objective: Our objective was to measure adipogenic and lipogenic gene expression in abdominal and gluteal SAT depots and determine their relationships with insulin sensitivity (S(I)) in South African women. Participants and Design: Fourteen normal-weight [body mass index (BMI) <25 kg/m(2)] Black, 13 normal-weight White, 14 obese (BMI >30 kg/m(2)) Black, and 13 obese White premenopausal South African women participated in this cross-sectional study.Main outcomes:S(I) (frequently sampled iv glucose tolerance test) in relation to expression of adipogenic and lipogenic genes in abdominal and gluteal SAT depots. Results: With increasing BMI, Black women had less visceral fat (P = 0.03) and more abdominal (P = 0.017) and gynoid (P = 0.041) SAT but had lower S(I) (P < 0.01) than White women. The expression of adipogenic and lipogenic genes was proportionately lower with obesity in Black but not White women in the gluteal and deep SAT depots (P < 0.05 for ethnicity × BMI effect). In Black women only, the expression of these genes correlated positively with S(I) (all P < 0.05), independently of age and fat mass. Conclusions: Obese Black women have reduced SAT expression of adipogenic and lipogenic genes compared with White women, which associates with reduced S(I). These findings suggest that obesity in Black women impairs SAT adipogenesis and storage, potentially leading to insulin resistance and increased risk of type 2 diabetes.
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| 42. |
- Homer, Natalie Z M, et al.
(författare)
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Quantitative analysis of RU38486 (mifepristone) by HPLC triple quadrupole mass spectrometry
- 2009
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 877:5-6, s. 497-501
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Tidskriftsartikel (refereegranskat)abstract
- A sensitive liquid chromatography-mass spectrometric method was validated for the quantification of RU38486 (mifepristone) in human and murine plasma. The analyte and internal standard (alfaxolone) were extracted by liquid-liquid extraction with diethyl ether, resolved on a C18 column using gradient elution with methanol and ammonium acetate and detected after positive electrospray ionization (m/z 430-->372; m/z 333-->297, respectively). Quantification was linear over the range 0.5-500ng (r(2)>0.997), precise and accurate (intra-assay RSD
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| 43. |
- Kleeman, Sam O, et al.
(författare)
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Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.
- 2023
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Ingår i: Cell genomics. - 2666-979X. ; 3:8
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Tidskriftsartikel (refereegranskat)abstract
- Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.
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| 44. |
- Levin, Simon A., et al.
(författare)
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Governance in the Face of Extreme Events : Lessons from Evolutionary Processes for Structuring Interventions, and the Need to Go Beyond
- 2022
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Ingår i: Ecosystems (New York. Print). - : Springer Science and Business Media LLC. - 1432-9840 .- 1435-0629. ; 25:3, s. 697-711
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Tidskriftsartikel (refereegranskat)abstract
- The increasing frequency of extreme events, exogenous and endogenous, poses challenges for our societies. The current pandemic is a case in point; but once-in-a-century weather events are also becoming more common, leading to erosion, wildfire and even volcanic events that change ecosystems and disturbance regimes, threaten the sustainability of our life-support systems, and challenge the robustness and resilience of societies. Dealing with extremes will require new approaches and large-scale collective action. Preemptive measures can increase general resilience, a first line of protection, while more specific reactive responses are developed. Preemptive measures also can minimize the negative effects of events that cannot be avoided. In this paper, we first explore approaches to prevention, mitigation and adaptation, drawing inspiration from how evolutionary challenges have made biological systems robust and resilient, and from the general theory of complex adaptive systems. We argue further that proactive steps that go beyond will be necessary to reduce unacceptable consequences.
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| 45. |
- Lind, Lars, et al.
(författare)
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Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
- 2014
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
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| 46. |
- Phillips, M. M., et al.
(författare)
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Carnegie Supernova Project-II : Extending the Near-infrared Hubble Diagram for Type Ia Supernovae to z ∼ 0.1
- 2019
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Ingår i: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 131:995
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Tidskriftsartikel (refereegranskat)abstract
- The Carnegie Supernova Project-II (CSP-II) was an NSF-funded, four-year program to obtain optical and near-infrared observations of a Cosmology sample of similar to 100 Type. Ia supernovae located in the smooth Hubble flow (0.03 less than or similar to z less than or similar to 0.10). Light curves were also obtained of a Physics sample composed of 90 nearby Type. Ia supernovae at z <= 0.04 selected for near-infrared spectroscopic timeseries observations. The primary emphasis of the CSP-II is to use the combination of optical and near-infrared photometry to achieve a distance precision of better than 5%. In this paper, details of the supernova sample, the observational strategy, and the characteristics of the photometric data are provided. In a companion paper, the near-infrared spectroscopy component of the project is presented.
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| 47. |
- Polasky, Stephen, et al.
(författare)
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Corridors of Clarity : Four Principles to Overcome Uncertainty Paralysis in the Anthropocene
- 2020
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Ingår i: BioScience. - : Oxford University Press (OUP). - 0006-3568 .- 1525-3244. ; 70:12, s. 1139-1144
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Tidskriftsartikel (refereegranskat)abstract
- Global environmental change challenges humanity because of its broad scale, long-lasting, and potentially irreversible consequences. Key to an effective response is to use an appropriate scientific lens to peer through the mist of uncertainty that threatens timely and appropriate decisions surrounding these complex issues. Identifying such corridors of clarity could help understanding critical phenomena or causal pathways sufficiently well to justify taking policy action. To this end, we suggest four principles: Follow the strongest and most direct path between policy decisions on outcomes, focus on finding sufficient evidence for policy purpose, prioritize no-regrets policies by avoiding options with controversial, uncertain, or immeasurable benefits, aim for getting the big picture roughly right rather than focusing on details.
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| 48. |
- Rasche, Leo, et al.
(författare)
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Low expression of hexokinase-2 is associated with false-negative FDG–positron emission tomography in multiple myeloma
- 2017
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 130:1, s. 30-34
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Tidskriftsartikel (refereegranskat)abstract
- 18F-Fluorodeoxyglucose (FDG)–positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging with background signal suppression (DWIBS) are 2 powerful functional imaging modalities in the evaluation of malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET (“PET false-negative”). The aim of this study was to describe the proportion of PET false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET false-negativity to be 11%. Neither tumor load–associated parameters, such as degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P < .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers.
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| 49. |
- Rockström, Johan, et al.
(författare)
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A safe operating space for humanity
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 461:7263, s. 472-475
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Tidskriftsartikel (refereegranskat)
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| 50. |
- Rockström, Johan, et al.
(författare)
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Planetary Boundaries : Exploring the Safe Operating Space for Humanity
- 2009
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Ingår i: Ecology and Society. - 1708-3087. ; 14:2, s. 32-
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Tidskriftsartikel (refereegranskat)abstract
- Anthropogenic pressures on the Earth System have reached a scale where abrupt global environmental change can no longer be excluded. We propose a new approach to global sustainability in which we define planetary boundaries within which we expect that humanity can operate safely. Transgressing one or more planetary boundaries may be deleterious or even catastrophic due to the risk of crossing thresholds that will trigger non-linear, abrupt environmental change within continental- to planetary-scale systems. We have identified nine planetary boundaries and, drawing upon current scientific understanding, we propose quantifications for seven of them. These seven are climate change (CO2 concentration in the atmosphere <350 ppm and/or a maximum change of +1 W m(-2) in radiative forcing); ocean acidification (mean surface seawater saturation state with respect to aragonite >= 80% of pre-industrial levels); stratospheric ozone (<5% reduction in O-3 concentration from pre-industrial level of 290 Dobson Units); biogeochemical nitrogen (N) cycle (limit industrial and agricultural fixation of N-2 to 35 Tg N yr(-1)) and phosphorus (P) cycle (annual P inflow to oceans not to exceed 10 times the natural background weathering of P); global freshwater use (<4000 km(3) yr(-1) of consumptive use of runoff resources); land system change (<15% of the ice-free land surface under cropland); and the rate at which biological diversity is lost (annual rate of <10 extinctions per million species). The two additional planetary boundaries for which we have not yet been able to determine a boundary level are chemical pollution and atmospheric aerosol loading. We estimate that humanity has already transgressed three planetary boundaries: for climate change, rate of biodiversity loss, and changes to the global nitrogen cycle. Planetary boundaries are interdependent, because transgressing one may both shift the position of other boundaries or cause them to be transgressed. The social impacts of transgressing boundaries will be a function of the social-ecological resilience of the affected societies. Our proposed boundaries are rough, first estimates only, surrounded by large uncertainties and knowledge gaps. Filling these gaps will require major advancements in Earth System and resilience science. The proposed concept of "planetary boundaries" lays the groundwork for shifting our approach to governance and management, away from the essentially sectoral analyses of limits to growth aimed at minimizing negative externalities, toward the estimation of the safe space for human development. Planetary boundaries define, as it were, the boundaries of the "planetary playing field" for humanity if we want to be sure of avoiding major human-induced environmental change on a global scale.
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