| 1. |
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| 2. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 3. |
- Berdahl, Andrew, et al.
(författare)
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Dynamics of beneficial epidemics
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Pathogens can spread epidemically through populations. Beneficial contagions, such as viruses that enhance host survival or technological innovations that improve quality of life, also have the potential to spread epidemically. How do the dynamics of beneficial biological and social epidemics differ from those of detrimental epidemics? We investigate this question using a breadth-first modeling approach involving three distinct theoretical models. First, in the context of population genetics, we show that a horizontally-transmissible element that increases fitness, such as viral DNA, spreads superexponentially through a population, more quickly than a beneficial mutation. Second, in the context of behavioral epidemiology, we show that infections that cause increased connectivity lead to superexponential fixation in the population. Third, in the context of dynamic social networks, we find that preferences for increased global infection accelerate spread and produce superexponential fixation, but preferences for local assortativity halt epidemics by disconnecting the infected from the susceptible. We conclude that the dynamics of beneficial biological and social epidemics are characterized by the rapid spread of beneficial elements, which is facilitated in biological systems by horizontal transmission and in social systems by active spreading behavior of infected individuals.
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| 4. |
- Berné, O., et al.
(författare)
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Formation of the methyl cation by photochemistry in a protoplanetary disk
- 2023
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 621:7977, s. 56-59
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Tidskriftsartikel (refereegranskat)abstract
- Forty years ago, it was proposed that gas-phase organic chemistry in the interstellar medium can be initiated by the methyl cation CH3+ (refs. 1–3), but so far it has not been observed outside the Solar System 4,5. Alternative routes involving processes on grain surfaces have been invoked 6,7. Here we report James Webb Space Telescope observations of CH3+ in a protoplanetary disk in the Orion star-forming region. We find that gas-phase organic chemistry is activated by ultraviolet irradiation.
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| 5. |
- Cam, Morgane, et al.
(författare)
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Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides.
- 2018
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 62:4, s. 1663-1681
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Tidskriftsartikel (refereegranskat)abstract
- Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations ofAβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500+compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.
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| 6. |
- Chown, Ryan, et al.
(författare)
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PDRs4All: IV. An embarrassment of riches: Aromatic infrared bands in the Orion Bar
- 2024
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Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 685
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Tidskriftsartikel (refereegranskat)abstract
- Context. Mid-infrared observations of photodissociation regions (PDRs) are dominated by strong emission features called aromatic infrared bands (AIBs). The most prominent AIBs are found at 3.3, 6.2, 7.7, 8.6, and 11.2 µm. The most sensitive, highest-resolution infrared spectral imaging data ever taken of the prototypical PDR, the Orion Bar, have been captured by JWST. These high-quality data allow for an unprecedentedly detailed view of AIBs. Aims. We provide an inventory of the AIBs found in the Orion Bar, along with mid-IR template spectra from five distinct regions in the Bar: the molecular PDR (i.e. the three H2 dissociation fronts), the atomic PDR, and the H II region. Methods. We used JWST NIRSpec IFU and MIRI MRS observations of the Orion Bar from the JWST Early Release Science Program, PDRs4All (ID: 1288). We extracted five template spectra to represent the morphology and environment of the Orion Bar PDR. We investigated and characterised the AIBs in these template spectra. We describe the variations among them here. Results. The superb sensitivity and the spectral and spatial resolution of these JWST observations reveal many details of the AIB emission and enable an improved characterization of their detailed profile shapes and sub-components. The Orion Bar spectra are dominated by the well-known AIBs at 3.3, 6.2, 7.7, 8.6, 11.2, and 12.7 µm with well-defined profiles. In addition, the spectra display a wealth of weaker features and sub-components. The widths of many AIBs show clear and systematic variations, being narrowest in the atomic PDR template, but showing a clear broadening in the H II region template while the broadest bands are found in the three dissociation front templates. In addition, the relative strengths of AIB (sub-)components vary among the template spectra as well. All AIB profiles are characteristic of class A sources as designated by Peeters (2022, A&A, 390, 1089), except for the 11.2 µm AIB profile deep in the molecular zone, which belongs to class B11.2. Furthermore, the observations show that the sub-components that contribute to the 5.75, 7.7, and 11.2 µm AIBs become much weaker in the PDR surface layers. We attribute this to the presence of small, more labile carriers in the deeper PDR layers that are photolysed away in the harsh radiation field near the surface. The 3.3/11.2 AIB intensity ratio decreases by about 40% between the dissociation fronts and the H II region, indicating a shift in the polycyclic aromatic hydrocarbon (PAH) size distribution to larger PAHs in the PDR surface layers, also likely due to the effects of photochemistry. The observed broadening of the bands in the molecular PDR is consistent with an enhanced importance of smaller PAHs since smaller PAHs attain a higher internal excitation energy at a fixed photon energy. Conclusions. Spectral-imaging observations of the Orion Bar using JWST yield key insights into the photochemical evolution of PAHs, such as the evolution responsible for the shift of 11.2 µm AIB emission from class B11.2 in the molecular PDR to class A11.2 in the PDR surface layers. This photochemical evolution is driven by the increased importance of FUV processing in the PDR surface layers, resulting in a “weeding out” of the weakest links of the PAH family in these layers. For now, these JWST observations are consistent with a model in which the underlying PAH family is composed of a few species: the so-called ‘grandPAHs’.
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| 7. |
- Coria, Jessica, 1979, et al.
(författare)
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What drives the substitution of hazardous flame retardants in electronic appliances in Sweden?
- 2023
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Ingår i: Cleaner Waste Systems. - 2772-9125. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Chemical substitution can mitigate risks from chemical substances for individuals and the environment. This study investigates the preferences of companies regarding the adoption of safer alternatives to hazardous flame retardants in electronic appliances in Sweden. Through a choice experiment, we assess the relative importance of four key factors determining firms’ preferences for chemical substitution: health and environmental hazards, the likelihood of chemical regulations, product pricing, and the presence of a label indicating the use of safer alternatives. Our findings indicate that the avoidance of health and environmental hazards is the primary motivator for firms to pursue chemical substitution. Our study also shows that companies are hesitant to accept tax policies that may result in price increases for their products. However, we propose that this reluctance could be mitigated through the implementation of a label that informs consumers about the utilization of less hazardous chemicals in the products. Such a label would not only serve as a means of product differentiation but also discourage consumers from opting for cheaper alternatives offered by competitors.
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| 8. |
- De Putte, Dries Van, et al.
(författare)
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PDRs4All VIII. Mid-infrared emission line inventory of the Orion Bar
- 2024
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Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 687
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Tidskriftsartikel (refereegranskat)abstract
- Context . Mid-infrared emission features are important probes of the properties of ionized gas and hot or warm molecular gas, which are difficult to probe at other wavelengths. The Orion Bar photodissociation region (PDR) is a bright, nearby, and frequently studied target containing large amounts of gas under these conditions. Under the “PDRs4All” Early Release Science Program for JWST, a part of the Orion Bar was observed with MIRI integral field unit (IFU) spectroscopy, and these high-sensitivity IR spectroscopic images of very high angular resolution (0.2′′) provide a rich observational inventory of the mid-infrared (MIR) emission lines, while resolving the H II region, the ionization front, and multiple dissociation fronts. Aims . We list, identify, and measure the most prominent gas emission lines in the Orion Bar using the new MIRI IFU data. An initial analysis summarizes the physical conditions of the gas and demonstrates the potential of these new data and future IFU observations with JWST. Methods. The MIRI IFU mosaic spatially resolves the substructure of the PDR, its footprint cutting perpendicularly across the ionization front and three dissociation fronts. We performed an up-to-date data reduction, and extracted five spectra that represent the ionized, atomic, and molecular gas layers. We identified the observed lines through a comparison with theoretical line lists derived from atomic data and simulated PDR models. The identified species and transitions are summarized in the main table of this work, with measurements of the line intensities and central wavelengths. Results . We identified around 100 lines and report an additional 18 lines that remain unidentified. The majority consists of H I recombination lines arising from the ionized gas layer bordering the PDR. The H I line ratios are well matched by emissivity coefficients from H recombination theory, but deviate by up to 10% because of contamination by He I lines. We report the observed emission lines of various ionization stages of Ne, P, S, Cl, Ar, Fe, and Ni. We show how the Ne III/Ne II, S IV/S III, and Ar III/Ar II ratios trace the conditions in the ionized layer bordering the PDR, while Fe III/Fe II and Ni III/Ni II exhibit a different behavior, as there are significant contributions to Fe II and Ni II from the neutral PDR gas. We observe the pure-rotational H2 lines in the vibrational ground state from 0–0 S(1) to 0–0 S(8), and in the first vibrationally excited state from 1–1 S(5) to 1–1 S(9). We derive H2 excitation diagrams, and for the three observed dissociation fronts, the rotational excitation can be approximated with one thermal (∼700 K) component representative of an average gas temperature, and one nonthermal component (∼2700 K) probing the effect of UV pumping. We compare these results to an existing model of the Orion Bar PDR, and find that the predicted excitation matches the data qualitatively, while adjustments to the parameters of the PDR model are required to reproduce the intensity of the 0–0 S(6) to S(8) lines.
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| 9. |
- Girousse, Amandine, et al.
(författare)
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Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass
- 2013
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.
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| 10. |
- Habart, Emilie, et al.
(författare)
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PDRs4All II. JWST’s NIR and MIR imaging view of the Orion Nebula
- 2024
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Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 685
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Tidskriftsartikel (refereegranskat)abstract
- Context. The James Webb Space Telescope (JWST) has captured the most detailed and sharpest infrared (IR) images ever taken of the inner region of the Orion Nebula, the nearest massive star formation region, and a prototypical highly irradiated dense photo-dissociation region (PDR). Aims. We investigate the fundamental interaction of far-ultraviolet (FUV) photons with molecular clouds. The transitions across the ionization front (IF), dissociation front (DF), and the molecular cloud are studied at high-angular resolution. These transitions are relevant to understanding the effects of radiative feedback from massive stars and the dominant physical and chemical processes that lead to the IR emission that JWST will detect in many Galactic and extragalactic environments. Methods. We utilized NIRCam and MIRI to obtain sub-arcsecond images over ∼150′′ and 42′′ in key gas phase lines (e.g., Pa α, Br α, [FeII] 1.64 µm, H2 1–0 S(1) 2.12 µm, 0–0 S(9) 4.69 µm), aromatic and aliphatic infrared bands (aromatic infrared bands at 3.3–3.4 µm, 7.7, and 11.3 µm), dust emission, and scattered light. Their emission are powerful tracers of the IF and DF, FUV radiation field and density distribution. Using NIRSpec observations the fractional contributions of lines, AIBs, and continuum emission to our NIRCam images were estimated. A very good agreement is found for the distribution and intensity of lines and AIBs between the NIRCam and NIRSpec observations. Results. Due to the proximity of the Orion Nebula and the unprecedented angular resolution of JWST, these data reveal that the molecular cloud borders are hyper structured at small angular scales of ∼0.1–1′′ (∼0.0002–0.002 pc or ∼40–400 au at 414 pc). A diverse set of features are observed such as ridges, waves, globules and photoevaporated protoplanetary disks. At the PDR atomic to molecular transition, several bright features are detected that are associated with the highly irradiated surroundings of the dense molecular condensations and embedded young star. Toward the Orion Bar PDR, a highly sculpted interface is detected with sharp edges and density increases near the IF and DF. This was predicted by previous modeling studies, but the fronts were unresolved in most tracers. The spatial distribution of the AIBs reveals that the PDR edge is steep and is followed by an extensive warm atomic layer up to the DF with multiple ridges. A complex, structured, and folded H0/H2 DF surface was traced by the H2 lines. This dataset was used to revisit the commonly adopted 2D PDR structure of the Orion Bar as our observations show that a 3D “terraced” geometry is required to explain the JWST observations. JWST provides us with a complete view of the PDR, all the way from the PDR edge to the substructured dense region, and this allowed us to determine, in detail, where the emission of the atomic and molecular lines, aromatic bands, and dust originate. Conclusions. This study offers an unprecedented dataset to benchmark and transform PDR physico-chemical and dynamical models for the JWST era. A fundamental step forward in our understanding of the interaction of FUV photons with molecular clouds and the role of FUV irradiation along the star formation sequence is provided.
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