Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis

anus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo.Jonel Trebicka is supported by the German Research Foundation project ID 403224013–SFB 1382 (A09); by the German Federal Ministry of Education and Research (BMBF) for the DEEP‐HCC project; by the Hessian Ministry of Higher Education, Research, and the Arts (HMWK) for the ENABLE cluster project; and by Eurostars (Grant ID 12350). The MICROB‐PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031), LIVERHOPE (project ID 731875), and IHMCSA (project ID 964590) projects have received funding from the European Union's Horizon 2020 research and innovation program. The manuscript reflects only the authors' views, and the European Commission is not responsible for any use that may be made of the information it contains. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript

Improved Upper Limit on the Neutrino Mass from a Direct Kinematic Method by KATRIN.

We report on the neutrino mass measurement result from the first four-week science run of the Karlsruhe Tritium Neutrino experiment KATRIN in spring 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are energy analyzed by a high-resolution MAC-E filter. A fit of the integrated electron spectrum over a narrow interval around the kinematic end point at 18.57 keV gives an effective neutrino mass square value of (-1.0_{-1.1}^{+0.9})  eV^{2}. From this, we derive an upper limit of 1.1 eV (90% confidence level) on the absolute mass scale of neutrinos. This value coincides with the KATRIN sensitivity. It improves upon previous mass limits from kinematic measurements by almost a factor of 2 and provides model-independent input to cosmological studies of structure formation

Commissioning of the vacuum system of the KATRIN Main Spectrometer

The KATRIN experiment will probe the neutrino mass by measuring the beta-electron energy spectrum near the endpoint of tritium beta-decay. An integral energy analysis will be performed by an electro-static spectrometer (Main Spectrometer), an ultra-high vacuum vessel with a length of 23.2 m, a volume of 1240 m^3, and a complex inner electrode system with about 120000 individual parts. The strong magnetic field that guides the beta-electrons is provided by super-conducting solenoids at both ends of the spectrometer. Its influence on turbo-molecular pumps and vacuum gauges had to be considered. A system consisting of 6 turbo-molecular pumps and 3 km of non-evaporable getter strips has been deployed and was tested during the commissioning of the spectrometer. In this paper the configuration, the commissioning with bake-out at 300{\deg}C, and the performance of this system are presented in detail. The vacuum system has to maintain a pressure in the 10^{-11} mbar range. It is demonstrated that the performance of the system is already close to these stringent functional requirements for the KATRIN experiment, which will start at the end of 2016.Comment: submitted for publication in JINST, 39 pages, 15 figure

Preventing stroke in people with atrial fibrillation: a cross-sectional study.

The annual stroke rate in atrial fibrillation is around 5 per cent with increased risk in those with hypertension, diabetes, left ventricular dysfunction and other cardiovascular risk factors. This study set out to identify the patients with atrial fibrillation and modifiable risk factors for stroke

TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor

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 construction of viewpoint aspect: the imperfective revisited

This paper argues for a constructionist approach to viewpoint Aspect by exploring the idea that it does not exert any altering force on the situation-aspect properties of predicates. The proposal is developed by analyzing the syntax and semantics of the imperfective, which has been attributed a coercer role in the literature as a de-telicizer and de-stativizer in the progressive, and as a de-eventivizer in the so-called ability (or attitudinal) and habitual readings. This paper proposes a unified semantics for the imperfective, preserving the properties of eventualities throughout the derivation. The paper argues that the semantics of viewpoint aspect is encoded in a series of functional heads containing interval-ordering predicates and quantifiers. This richer structure allows us to account for a greater amount of phenomena, such as the perfective nature of the individual instantiations of the event within a habitual construction or the nonculminating reading of perfective accomplishments in Spanish. This paper hypothesizes that nonculminating accomplishments have an underlying structure corresponding to the perfective progressive. As a consequence, the progressive becomes disentangled from imperfectivity and is given a novel analysis. The proposed syntax is argued to have a corresponding explicit morphology in languages such as Spanish and a nondifferentiating one in languages such as English; however, the syntax-semantics underlying both of these languages is argued to be the same

Ectopic T Cell Receptor-α Locus Control Region Activity in B Cells Is Suppressed by Direct Linkage to Two Flanking Genes at Once

The molecular mechanisms regulating the activity of the TCRα gene are required for the production of the circulating T cell repertoire. Elements of the mouse TCRα locus control region (LCR) play a role in these processes. We previously reported that TCRα LCR DNA supports a gene expression pattern that mimics proper thymus-stage, TCRα gene-like developmental regulation. It also produces transcription of linked reporter genes in peripheral T cells. However, TCRα LCR-driven transgenes display ectopic transcription in B cells in multiple reporter gene systems. The reasons for this important deviation from the normal TCRα gene regulation pattern are unclear. In its natural locus, two genes flank the TCRα LCR, TCRα (upstream) and Dad1 (downstream). We investigated the significance of this gene arrangement to TCRα LCR activity by examining transgenic mice bearing a construct where the LCR was flanked by two separate reporter genes. Surprisingly, the presence of a second, distinct, reporter gene downstream of the LCR virtually eliminated the ectopic B cell expression of the upstream reporter observed in earlier studies. Downstream reporter gene activity was unaffected by the presence of a second gene upstream of the LCR. Our findings indicate that a gene arrangement in which the TCRα LCR is flanked by two distinct transcription units helps to restrict its activity, selectively, on its 5′-flanking gene, the natural TCRα gene position with respect to the LCR. Consistent with these findings, a TCRα/Dad1 locus bacterial artificial chromosome dual-reporter construct did not display the ectopic upstream (TCRα) reporter expression in B cells previously reported for single TCRα transgenes

A Review of the Evidence Germane to the Putative Protective Role of the Macular Carotenoids for Age-Related Macular Degeneration

There is a consensus that age-related macular degeneration (AMD) is the result of (photo)- oxidative-induced retinal injury and its inflammatory sequelae, the latter being influenced by genetic background. The dietary carotenoids, lutein (L), zeaxanthin (Z), and meso-zeaxanthin (meso-Z), accumulate at the macula, where they are collectively known as macular pigment (MP). The anatomic (central retinal), biochemical (anti-oxidant) and optical (short-wavelength- filtering) properties of this pigment have generated interest in the biologically plausible rationale that MP may confer protection against AMD. Level 1 evidence has shown that dietary supplementation with broad-spectrum anti-oxidants results in risk reduction for AMD progression. Studies have demonstrated that MP rises in response to supplementation with the macular carotenoids, although level 1 evidence that such supplementation results in risk reduction of AMD and/or its progression is still lacking. Although appropriately weighted attention should be accorded to higher levels of evidence, the totality of available data should be appraised in an attempt to inform professional practice. In this context, the literature demonstrates that supplementation with the macular carotenoids is probably the best means of fortifying the anti-oxidant defenses of the macula, thus putatively reducing the risk of AMD and/or its progression