Aims/hypothesis
While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors ...that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD).
Methods
C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle.
Results
Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic–euglycaemic clamp, was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance.
Conclusions/interpretation
HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Transgenic maize engineered to express insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) has become widely adopted in U.S. agriculture. In 2009, Bt maize was planted on more than ...22.2 million hectares, constituting 63% of the U.S. crop. Using statistical analysis of per capita growth rate estimates, we found that areawide suppression of the primary pest Ostrinia nubilalis (European corn borer) is associated with Bt maize use. Cumulative benefits over 14 years are an estimated $3.2 billion for maize growers in Illinois, Minnesota, and Wisconsin, with more than $2.4 billion of this total accruing to non-Bt maize growers. Comparable estimates for Iowa and Nebraska are $3.6 billion in total, with $1.9 billion for non-Bt maize growers. These results affirm theoretical predictions of pest population suppression and highlight economic incentives for growers to maintain non-Bt maize refugia for sustainable insect resistance management.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Marine litter presents a global problem, with increasing quantities documented in recent decades. The distribution and abundance of marine litter on the seafloor off the United Kingdom's (UK) coasts ...were quantified during 39 independent scientific surveys conducted between 1992 and 2017. Widespread distribution of litter items, especially plastics, were found on the seabed of the North Sea, English Channel, Celtic Sea and Irish Sea. High variation in abundance of litter items, ranging from 0 to 1835 pieces km−2 of seafloor, was observed. Plastic tems such as bags, bottles and fishing related debris were commonly observed across all areas. Over the entire 25-year period (1992–2017), 63% of the 2461 trawls contained at least one plastic litter item. There was no significant temporal trend in the percentage of trawls containing any or total plastic litter items across the long-term datasets. Statistically significant trends, however, were observed in specific plastic litter categories only. These trends were all positive except for a negative trend in plastic bags in the Greater North Sea - suggesting that behavioural and legislative changes could reduce the problem of marine litter within decades.
Marine litter abundance (litter items km−2) on the seafloor in North West European Seas, all data from 2011 interpolated using R, Shiny and PostGIS. The black line surrounding the UK represents the 12nm boundary. The black line in the Western Channel and starting near the tip of Shetland symbolizes the MSFD boundary for the Celtic Sea (CS) and Greater North Sea (GNS). Key to regional divisions: GNS-off, Greater North Sea offshore stations outside 12nm; GNS-in, Greater North Sea inshore stations within 12nm; CS-off, Celtic Sea offshore stations outside 12nm; CS-in, Celtic Sea inshore stations within 12nm. Display omitted
•Widespread distribution of litter items on the seabed, up to 1835 pieces km−2•Over the 25-year period, 63% of the trawls contained at least one plastic litter item.•No significant temporal trend in total number of litter items km−2•Significant trends in plastic bags (down) and fishing debris (up)•Potential influence of behavioural changes on litter abundance?
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Magnetoresistance is the change in a material's electrical resistance in response to an applied magnetic field. Materials with large magnetoresistance have found use as magnetic sensors, in magnetic ...memory, and in hard drives at room temperature, and their rarity has motivated many fundamental studies in materials physics at low temperatures. Here we report the observation of an extremely large positive magnetoresistance at low temperatures in the non-magnetic layered transition-metal dichalcogenide WTe2: 452,700 per cent at 4.5 kelvins in a magnetic field of 14.7 teslas, and 13 million per cent at 0.53 kelvins in a magnetic field of 60 teslas. In contrast with other materials, there is no saturation of the magnetoresistance value even at very high applied fields. Determination of the origin and consequences of this effect, and the fabrication of thin films, nanostructures and devices based on the extremely large positive magnetoresistance of WTe2, will represent a significant new direction in the study of magnetoresistivity.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dunes on Pluto Telfer, Matt W; Parteli, Eric J R; Radebaugh, Jani ...
Science (American Association for the Advancement of Science),
06/2018, Volume:
360, Issue:
6392
Journal Article
Peer reviewed
Open access
The surface of Pluto is more geologically diverse and dynamic than had been expected, but the role of its tenuous atmosphere in shaping the landscape remains unclear. We describe observations from ...the New Horizons spacecraft of regularly spaced, linear ridges whose morphology, distribution, and orientation are consistent with being transverse dunes. These are located close to mountainous regions and are orthogonal to nearby wind streaks. We demonstrate that the wavelength of the dunes (~0.4 to 1 kilometer) is best explained by the deposition of sand-sized (~200 to ~300 micrometer) particles of methane ice in moderate winds (<10 meters per second). The undisturbed morphology of the dunes, and relationships with the underlying convective glacial ice, imply that the dunes have formed in the very recent geological past.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Summary
We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource ...comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures.
Introduction
The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors.
Methods
A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible.
Results
Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed.
Conclusions
These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We ...genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 × 10−34) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 × 10−100). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We identify multi-wavelength counterparts to 1147 submillimeter sources from the S2COSMOS SCUBA-2 survey of the COSMOS field by employing a recently developed radio+machine-learning method trained on ...a large sample of Atacama Large Millimeter/submillimeter Array (ALMA)-identified submillimeter galaxies (SMGs), including 260 SMGs identified in the AS2COSMOS pilot survey. In total, we identify 1222 optical/near-infrared (NIR)/radio counterparts to the 897 S2COSMOS submillimeter sources with S850 > 1.6 mJy, yielding an overall identification rate of (78 9)%. We find that (22 5)% of S2COSMOS sources have multiple identified counterparts. We estimate that roughly 27% of these multiple counterparts within the same SCUBA-2 error circles very likely arise from physically associated galaxies rather than line-of-sight projections by chance. The photometric redshift of our radio+machine-learning-identified SMGs ranges from z = 0.2 to 5.7 and peaks at z = 2.3 0.1. The AGN fraction of our sample is (19 4)%, which is consistent with that of ALMA SMGs in the literature. Comparing with radio/NIR-detected field galaxy population in the COSMOS field, our radio+machine-learning-identified counterparts of SMGs have the highest star formation rates and stellar masses. These characteristics suggest that our identified counterparts of S2COSMOS sources are a representative sample of SMGs at z 3. We employ our machine-learning technique to the whole COSMOS field and identified 6877 potential SMGs, most of which are expected to have submillimeter emission fainter than the confusion limit of our S2COSMOS surveys ( mJy). We study the clustering properties of SMGs based on this statistically large sample, finding that they reside in high-mass dark matter halos ((1.2 0.3) × 1013 h−1 ), which suggests that SMGs may be the progenitors of massive ellipticals we see in the local universe.
Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical ...consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis.
This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality.
Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (
=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2;
=0.001). This was driven predominantly by
-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly
-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6;
=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (
=0.08).
We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of
-tv in those with normal left ventricular ejection fraction and
-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.
Tardigrades, commonly known as 'waterbears', are eight-legged microscopic invertebrates renowned for their ability to withstand extreme stressors, including high osmotic pressure, freezing ...temperatures, and complete desiccation. Limb retraction and substantial decreases to their internal water stores results in the tun state, greatly increasing their ability to survive. Emergence from the tun state and/or activity regain follows stress removal, where resumption of life cycle occurs as if stasis never occurred. However, the mechanism(s) through which tardigrades initiate tun formation is yet to be uncovered. Herein, we use chemobiosis to demonstrate that tardigrade tun formation is mediated by reactive oxygen species (ROS). We further reveal that tuns are dependent on reversible cysteine oxidation, and that this reversible cysteine oxidation is facilitated by the release of intracellular reactive oxygen species (ROS). We provide the first empirical evidence of chemobiosis and map the initiation and survival of tardigrades via osmobiosis, chemobiosis, and cryobiosis. In vivo electron paramagnetic spectrometry suggests an intracellular release of reactive oxygen species following stress induction; when this release is quenched through the application of exogenous antioxidants, the tardigrades can no longer survive osmotic stress. Together, this work suggests a conserved dependence of reversible cysteine oxidation across distinct tardigrade cryptobioses.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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