This paper analyzes the impact of the EU ETS on CO2 reduction in the German electricity sector. We find an ETS-induced emission abatement which is not exceeding 6% of total emissions with a maximum ...already in 2010. Thereafter the ETS has not induced additional reductions. This outcome corresponds to the recent debate about sub-optimal performance of the EU ETS caused by excessive allowances. Following up on this we develop a unilateral flexible cap to eliminate demand side effects which lead to excessive allowances. The unilateral flexible cap is based on emission intensities. Using the works of Newell and Pizer (2008); Sue Wing et al. (2009) we prove that an intensity-based emission cap is advantageous in the German electricity sector when compared to an absolute cap. An ex-post analysis shows that the amount of excessive allowances resulting from the economic crisis during the second trading period could have been significantly lowered with a unilateral flexible cap. This approach also decouples the EU ETS from a simultaneous promotion of renewable energy.
•A unilateral flexible cap can decouple the ETS from demand side effects.•It still guarantees compliance with a cap in absolute emissions.•ETS has a lower impact on emissions from German electricity than assumed.•Intensity-based emission cap is more effective in the German electricity sector.
We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH.
We ...stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1–/–) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays.
HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1–/– mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1–/– mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1.
Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.
Display omitted
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here, we show that interleukin-11 (
) ...is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2
), collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent, posttranscriptional manner. In mice, fibroblast-specific transgenic expression or administration of murine IL-11 induces lung myofibroblasts and causes lung fibrosis. IL-11 receptor subunit alpha-1 (
)-deleted mice, whose lung fibroblasts are unresponsive to profibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11-neutralizing antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice. These data prioritize IL-11 as a drug target for lung fibrosis and IPF.
Human mutations that truncate the massive sarcomere protein titin TTN-truncating variants (TTNtvs) are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure ...and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell–derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.
Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ∼1% of the general population, where they may be silent, perhaps reflecting allelic ...factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.
The characteristics of an x-ray spectrum can greatly influence imaging and related tasks. In practice, due to the pile-up effect of the detector, it's difficult to directly measure the spectrum of a ...CT scanner using an energy resolved detector. An alternative solution is to estimate the spectrum using transmission measurements with a step phantom or another CT phantom. In this work, we present a new spectrum estimation method based on indirect transmission measurement and a model spectra mixture approach. The estimated x-ray spectrum was expressed as a weighted summation of a set of model spectra, which can significantly reduce the degrees of freedom of the spectrum estimation problem. Next, an estimated projection was calculated with the assumed spectrum. By iteratively updating the unknown weights, we minimized the difference between the estimated projection data and the raw projection data. The final spectrum was calculated with these calibrated weights and the model spectra. Both simulation and experimental data were used to evaluate the proposed method. In the simulation study, the estimated spectra were compared to the raw spectra which were used to generate the raw projection data. For the experimental study, the ground truth measurement of the raw x-ray spectrum was not available. Therefore, the estimated spectrum was compared against the spectra generated using the SpekCalc software with tube configurations provided by the scanner manufacturer. The results show the proposed method has the potential to accurately estimate x-ray spectra using the raw projection data. The difference between the mean energy of the raw spectra and the mean energy of the estimated spectra was less than 0.5 keV for both the simulation and experimental data. Further tests show the method was robust with respect to the model spectra generator.
IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. ...Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.
Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning ...using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.
Objectives
Dual-energy computed tomography allows for an accurate and reliable quantification of iodine. However, data on physiological distribution of iodine concentration (IC) is still sparse. This ...study aims to establish guidance for IC in abdominal organs and important anatomical landmarks using a large cohort of individuals without radiological tumor burden.
Methods
Five hundred seventy-one oncologic, portal venous phase dual-layer spectral detector CT studies of the chest and abdomen without tumor burden at time point of imaging confirmed by > 3-month follow-up were included. ROI were placed in parenchymatous organs (
n
= 25), lymph nodes (
n
= 6), and vessels (
n
= 3) with a minimum of two measurements per landmark. ROI were placed on conventional images and pasted to iodine maps to retrieve absolute IC. Normalization to the abdominal aorta was conducted to obtain iodine perfusion ratios. Bivariate regression analysis,
t
tests, and ANOVA with Tukey-Kramer post hoc test were used for statistical analysis.
Results
Absolute IC showed a broad scatter and varied with body mass index, between different age groups and between the sexes in parenchymatous organs, lymph nodes, and vessels (range 0.0 ± 0.0 mg/ml–6.6 ± 1.3 mg/ml). Unlike absolute IC, iodine perfusion ratios did not show dependency on body mass index; however, significant differences between the sexes and age groups persisted, showing a tendency towards decreased perfusion ratios in elderly patients (e.g., liver 18–44 years/≥ 64 years: 0.50 ± 0.11/0.43 ± 0.10,
p
≤ 0.05).
Conclusions
Distribution of IC obtained from a large-scale cohort is provided. As significant differences between sexes and age groups were found, this should be taken into account when obtaining quantitative iodine concentrations and applying iodine thresholds.
Key Points
•
Absolute iodine concentration showed a broad variation and differed between body mass index, age groups, and between the sexes in parenchymatous organs, lymph nodes, and vessels.
•
The iodine perfusion ratios did not show dependency on body mass index while significant differences between sexes and age groups persisted.
•
Provided guidance values may serve as reference when aiming to differentiate healthy and abnormal tissue based on iodine perfusion ratios.
Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria to regulate metabolism. Motivated by an intriguing negative association between mito-SEPs and inflammation, ...here we screen for mito-SEPs that modify inflammatory outcomes and report a mito-SEP named "Modulator of cytochrome C oxidase during Inflammation" (MOCCI) that is upregulated during inflammation and infection to promote host-protective resolution. MOCCI, a paralog of the NDUFA4 subunit of cytochrome C oxidase (Complex IV), replaces NDUFA4 in Complex IV during inflammation to lower mitochondrial membrane potential and reduce ROS production, leading to cyto-protection and dampened immune response. The MOCCI transcript also generates miR-147b, which targets the NDUFA4 mRNA with similar immune dampening effects as MOCCI, but simultaneously enhances RIG-I/MDA-5-mediated viral immunity. Our work uncovers a dual-component pleiotropic regulation of host inflammation and immunity by MOCCI (C15ORF48) for safeguarding the host during infection and inflammation.
PDF
