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Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.
The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-Å resolution X-ray crystal structure of a TSEN15–34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes.
The HITRAP linear decelerator currently being set up at GSI will provide slow, few keV/u highly charged ions for atomic physics experiments. The expected beam intensity is up to 105 ions per shot. To optimize phase and amplitude of the RF systems intensity, bunch length and kinetic energy of the particles need to be monitored. The bunch length that we need to fit is about 2 ns, which is typically measured by capacitive pickups. However, they do not work for the low beam intensities that we face. We investigated the bunch length with a fast CVD diamond detector working in single particle counting mode. Averaging over 8 shots yields a clear, regular picture of the bunched beam. Energy measurements by capacitive pickups are limited by the presence of intense primary and partially decelerated beam and hence make tuning of the IH-structure impossible. The energy of the decelerated fraction of the beam behind the first deceleration cavity was determined to about 10 % accuracy with a permanent dipole magnet combined with a MCP. Better detector calibration should help reaching the required 1%. Design of the detectors as well as the results of the measurements will be presented.
Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.
Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).
Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.
Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.
Trial registration: ClinicalTrials.gov identifier: NCT01915524.
Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology
(2017)
Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
Objectives: A conometric concept was recently introduced in which conical implant abutments hold the matching crown copings by friction alone, eliminating the need for cement or screws. The aim of this in vitro study was to assess the presence of microgap formation and bacterial leakage at the Acuris conometric restorative interface of three different implant abutment systems. Material and methods: A total of 75 Acuris samples of three implant-abutment systems (Ankylos, Astra Tech EV, Xive) were subjected to microbiological (n = 60) and scanning electron microscopic (SEM) investigation (n = 15). Bacterial migration into and out of the conical coupling system were analyzed in an anaerobic workstation for 48, 96, 144, and 192 h. Bacterial DNA quantification using qrt-PCR was performed at each time point. The precision of the conometric coupling and internal fit of cemented CAD/CAM crowns on corresponding Acuris TiN copings were determined by means of SEM. Results: qrt-PCR results failed to demonstrate microbial leakage from or into the Acuris system. SEM analysis revealed minute punctate microgaps at the apical aspect of the conometric junction (2.04 to 2.64 µm), while mean cement gaps of 12 to 145 µm were observed at the crown-coping interface. Conclusions: The prosthetic morse taper connection of all systems examined does not allow bacterial passage. Marginal integrity and internal luting gap between the ceramic crown and the coping remained within the clinically acceptable limits. Clinical relevance: Conometrically seated single crowns provide sufficient sealing efficiency, relocating potential misfits from the crown-abutment interface to the crown-coping interface.
Activation of Mitochondrial complex II-dependent respiration is beneficial for α-Synucleinopathies
(2015)
Parkinson’s disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APP-transgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synuclein-transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNAArg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.
Although the 12C(n,p)12B and 12C(n,d)11B reactions are of interest in several fields of basic and applied Nuclear Physics the present knowledge of these two cross-sections is far from being accurate and reliable, with both evaluations and data showing sizable discrepancies. As part of the challenging n_TOF program on (n,cp) nuclear reactions study, the energy differential cross-sections of the 12C(n,p)12B and 12C(n,d)11 B reactions have been measured at CERN from the reaction thresholds up to 30 MeV neutron energy. Both measurements have been recently performed at the long flight-path (185 m) experimental area of the n_TOF facility at CERN using a pure (99.95%) rigid graphite target and two silicon telescopes. In this paper an overview of the experiment is presented together with a few preliminary results.
Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-Å resolution X-ray crystal structure of a TSEN15–34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes.