Self-Reporting Theranostic: Nano Tool for Arterial Thrombosis

Arterial thrombosis (AT) originates through platelet-mediated thrombus formation in the blood vessel and can lead to heart attack, stroke, and peripheral vascular diseases. Restricting the thrombus growth and its simultaneous monitoring by visualisation is an unmet clinical need for a better AT prognosis. As a proof-of-concept, we have engineered a nanoparticle-based theranostic (combined therapy and monitoring) platform that has the potential to monitor and restrain the growth of a thrombus concurrently. The theranostic nanotool is fabricated using biocompatible super-paramagnetic iron oxide nanoparticles (SPIONs) as a core module tethered with the anti-platelet agent Abciximab (ReoPro) on its surface. Our in vitro feasibility results indicate that ReoPro-conjugated SPIONS (Tx@ReoPro) can effectively prevent thrombus growth by inhibiting fibrinogen receptors (GPIIbIIIa) on the platelet surface, and simultaneously, it can also be visible through non-invasive magnetic resonance imaging (MRI) for potential reporting of the real-time thrombus status

Acetylations of Ftz-F1 and histone H4K5 are required for the fine-tuning of ecdysone biosynthesis during Drosophila metamorphosis

The molting during Drosophila development is tightly regulated by the ecdysone hormone. Several steps of the ecdysone biosynthesis have been already identified but the regulation of the entire process has not been clarified yet. We have previously reported that dATAC histone acetyltransferase complex is necessary for the steroid hormone biosynthesis process. To reveal possible mechanisms controlled by dATAC we made assumptions that either dATAC may influence directly the transcription of Halloween genes involved in steroid hormone biosynthesis or it may exert an indirect effect on it by acetylating the Ftz-F1 transcription factor which regulates the transcription of steroid converting genes. Here we show that the lack of dATAC complex results in increased mRNA level and decreased protein level of Ftz-F1. In this context, decreased mRNA and increased protein levels of Ftz-F1 were detected upon treatment of Drosophila S2 cells with histone deacetylase inhibitor trichostatin A. We showed that Ftz-F1, the transcriptional activator of Halloween genes, is acetylated in S2 cells. In addition, we found that ecdysone biosynthetic Halloween genes are transcribed in S2 cells and their expression can be influenced by deacetylase inhibitors. Furthermore, we could detect H4K5 acetylation at the regulatory regions of disembodied and shade Halloween genes, while H3K9 acetylation is absent on these genes. Based on our findings we conclude that the dATAC HAT complex might play a dual regulatory role in Drosophila steroid hormone biosynthesis through the acetylation of Ftz-F1 protein and the regulation of the H4K5 acetylation at the promoters of Halloween genes

Unexpected Fat Distribution in Adolescents With Narcolepsy

Narcolepsy type 1 is a chronic sleep disorder with significantly higher BMI reported in more than 50% of adolescent patients, putting them at a higher risk for metabolic syndrome in adulthood. Although well-documented, the body fat distribution and mechanisms behind weight gain in narcolepsy are still not fully understood but may be related to the loss of orexin associated with the disease. Orexin has been linked to the regulation of brown adipose tissue (BAT), a metabolically active fat involved in energy homeostasis. Previous studies have used BMI and waist circumference to characterize adipose tissue increases in narcolepsy but none have investigated its specific distribution. Here, we examine adipose tissue distribution in 19 adolescent patients with narcolepsy type 1 and compare them to 17 of their healthy peers using full body magnetic resonance imaging (MRI). In line with previous findings we saw that the narcolepsy patients had more overall fat than the healthy controls, but contrary to our expectations there were no group differences in supraclavicular BAT, suggesting that orexin may have no effect at all on BAT, at least under thermoneutral conditions. Also, in line with previous reports, we observed that patients had more total abdominal adipose tissue (TAAT), however, we found that they had a lower ratio between visceral adipose tissue (VAT) and TAAT indicating a relative increase of subcutaneous abdominal adipose tissue (ASAT). This relationship between VAT and ASAT has been associated with a lower risk for metabolic disease. We conclude that while weight gain in adolescents with narcolepsy matches that of central obesity, the lower VAT ratio may suggest a lower risk of developing metabolic disease

Feasibility of MR-Based Body Composition Analysis in Large Scale Population Studies

Introduction Quantitative and accurate measurements of fat and muscle in the body are important for prevention and diagnosis of diseases related to obesity and muscle degeneration. Manually segmenting muscle and fat compartments in MR body-images is laborious and time-consuming, hindering implementation in large cohorts. In the present study, the feasibility and success-rate of a Dixon-based MR scan followed by an intensity-normalised, non-rigid, multi-atlas based segmentation was investigated in a cohort of 3,000 subjects. Materials and Methods 3,000 participants in the in-depth phenotyping arm of the UK Biobank imaging study underwent a comprehensive MR examination. All subjects were scanned using a 1.5 T MR-scanner with the dual-echo Dixon Vibe protocol, covering neck to knees. Subjects were scanned with six slabs in supine position, without localizer. Automated body composition analysis was performed using the AMRA Profiler™ system, to segment and quantify visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT) and thigh muscles. Technical quality assurance was performed and a standard set of acceptance/rejection criteria was established. Descriptive statistics were calculated for all volume measurements and quality assurance metrics. Results Of the 3,000 subjects, 2,995 (99.83%) were analysable for body fat, 2,828 (94.27%) were analysable when body fat and one thigh was included, and 2,775 (92.50%) were fully analysable for body fat and both thigh muscles. Reasons for not being able to analyse datasets were mainly due to missing slabs in the acquisition, or patient positioned so that large parts of the volume was outside of the field-of-view. Discussion and Conclusions In conclusion, this study showed that the rapid UK Biobank MR-protocol was well tolerated by most subjects and sufficiently robust to achieve very high success-rate for body composition analysis. This research has been conducted using the UK Biobank Resource

Epitaxial growth of perovskite oxide films facilitated by oxygen vacancies

The authors would like to thank P. Yudin for valuable discussions, N. Nepomniashchaia for VASE studies, and S. Cichon for XPS analysis. The authors acknowledge support from the Czech Science Foundation (Grant No. 19-09671S), the European Structural and Investment Funds and the Ministry of Education, Youth and Sports of the Czech Republic through Programme ‘‘Research, Development and Education’’ (Project No. SOLID21 CZ.02.1.01/0.0/0.0/16-019/0000760), and ERA NET project Sun2Chem (E. K. and L. R.). Calculations have been done on the LASC Cluster in the ISSP UL.Single-crystal epitaxial films of technologically important and scientifically intriguing multifunctional ABO3 perovskite-type metal oxides are essential for advanced applications and understanding of these materials. In such films, a film-substrate misfit strain enables unprecedented crystal phases and unique properties that are not available in their bulk counterparts. However, the prerequisite growth of strained epitaxial films is fundamentally restricted by misfit relaxation. Here we demonstrate that introduction of a small oxygen deficiency concurrently stabilizes epitaxy and increases lattice strain in thin films of archetypal perovskite oxide SrTiO3. By combining experimental and theoretical methods, we found that lattice distortions around oxygen vacancies lead to anisotropic local stresses, which interact with the misfit strain in epitaxial films. Consequently, specific crystallographic alignments of the stresses are energetically favorable and can facilitate epitaxial growth of strained films. Because anisotropic oxygen-vacancy stresses are inherent to perovskite-type and many other oxides, we anticipate that the disclosed phenomenon of epitaxial stabilization by oxygen vacancies is relevant for a very broad range of functional oxides.This work is licensed under CC BY, CC BY-NC licenses.Czech Science Foundation (Grant No. 19-09671S); European Structural and Investment Funds and the Ministry of Education, Youth and Sports of the Czech Republic through Programme ‘‘Research, Development and Education’’ (Project No. SOLID21 CZ.02.1.01/0.0/0.0/16-019/0000760), and ERA NET project Sun2Chem; Institute of Solid State Physics, University of Latvia as the Center of Excellence has received funding from the European Union’s Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART²

Fat-Referenced MRI : Quanitaive MRI for Tissue Characterizaion and Volume Measurement

The amount and distribution of adipose and lean tissues has been shown to be predictive of mortality and morbidity in metabolic disease. Traditionally these risks are assessed by anthropometric measurements based on weight, length, girths or the body mass index (BMI). These measurements are predictive of risks on a population level, where a too low or a too high BMI indicates an increased risk of both mortality and morbidity. However, today a large part of the world’s population belongs to a group with an elevated risk according to BMI, many of which will live long and healthy lives. Thus, better instruments are needed to properly direct health-care resources to those who need it the most. Medical imaging method can go beyond anthropometrics. Tomographic modalities, such as magnetic resonance imaging (MRI), can measure how we have stored fat in and around organs. These measurements can eventually lead to better individual risk predictions. For instance, a tendency to store fat as visceral adipose tissue (VAT) is associated with an increased risk of diabetes type 2, cardio-vascular disease, liver disease and certain types of cancer. Furthermore, liver fat is associated with liver disease, diabetes type 2. Brown adipose tissue (BAT), is another emerging component of body-composition analysis. While the normal white adipose tissue stores fat, BAT burns energy to produce heat. This unique property makes BAT highly interesting, from a metabolic point of view. Magnetic resonance imaging can both accurately and safely measure internal adipose tissue compartments, and the fat infiltration of organs. Which is why MRI is often considered the reference method for non-invasive body-composition analysis. The two major challenges of MRI based body-composition analysis are, the between-scanner reproducibility and a cost-effective analysis of the images. This thesis presents a complete implementation of fat-referenced MRI, a technique that produces quantitative images that can increase both inter-scanner and automation of the image analysis. With MRI, it is possible to construct images where water and fat are separated into paired images. In these images, it easy to depict adipose tissue and lean tissue structures. This thesis takes water-fat MRI one step further, by introducing a quantitative framework called fat-referenced MRI. By calibrating the image using the subjects' own adipose tissue (paper II), the otherwise non-quantitative fat images are made quantitative. In these fat-referenced images it is possible to directly measure the amount of adipose tissue in different compartments. This quantitative property makes image analysis easy and accurate, as lean and adipose tissues can be separated on a sub-voxel level. Fat-referenced MRI further allows the quantification and characterization of BAT. This thesis work starts by formulating a method to produce water-fat images (paper I) based on two gradient recall images, i.e.\ 2-point Dixon images (2PD). It furthers shows that fat-referenced 2PD images can be corrected for T2*, making the 2PD body-composition measurements comparable with confounder-corrected Dixon measurements (paper III}). Both the water-fat separation method and fat image calibration are applied to BAT imaging. The methodology is first evaluated in an animal model, where it is shown that it can detect both BAT browning and volume increase following cold acclimatization (paper IV). It is then applied to postmortem imaging, were it is used to locate interscapular BAT in human infants (paper V). Subsequent analysis of biopsies, taken based on the MRI images, showed that the interscapular BAT was of a type not previously believed to exist in humans. In the last study, fat-referenced MRI is applied to BAT imaging of adults. As BAT structures are difficult to locate in many adults, the methodology was also extended with a multi-atlas segmentation methods (paper VI). In summary, this thesis shows that fat-referenced MRI is a quantitative method that can be used for body-composition analysis. It also shows that fat-referenced MRI can produce quantitative high-resolution images, a necessity for many BAT applications.DiVA-länken var felaktig i den tryckta versionen. Den är ändrad i den elektroniska versionen.</p

Fat quantification in skeletal muscle using multigradient-echo imaging: Comparison of fat and water references.

To investigate the precision, accuracy, and repeatability of water/fat imaging-based fat quantification in muscle tissue using a large flip angle (FA) and a fat reference for the calculation of the proton density fat fraction (FF). Comparison is made to a small FA water reference approach

Reproducibility and repeatability of MRI-based body composition analysis

Purpose There is an absence of reproducibility studies on MRI-based body composition analysis in current literature. Therefore, the aim of this study was to investigate the between-scanner reproducibility and the repeatability of a method for MRI-based body composition analysis. Methods Eighteen healthy volunteers of varying body mass index and adiposity were each scanned twice on five different 1.5T and 3T scanners from three different vendors. Two-point Dixon neck-to knee images and two additional liver scans were acquired with similar protocols. Visceral adipose tissue (VAT) volume, abdominal subcutaneous adipose tissue (ASAT) volume, thigh muscle volume, and muscle fat infiltration (MFI) in the thigh muscle were measured. Liver proton density fat fraction (PDFF) was assessed using two different methods, the scanner vendors 6-point method and an in-house 2-point method. Within-scanner test-retest repeatability and between-scanner reproducibility were calculated using analysis of variance. Results Repeatability coefficients were 13 centiliters (cl) (VAT), 24 cl (ASAT), 17 cl (total thigh muscle volume), 0.53% (MFI), and 1.27-1.37% for liver PDFF. Reproducibility coefficients were 24 cl (VAT), 42 cl (ASAT), 31 cl (total thigh muscle volume), 1.44% (MFI), and 2.37-2.40% for liver PDFF. Conclusion For all measures except MFI, the within-scanner repeatability explained much of the overall reproducibility. The two methods for measuring liver fat had similar reproducibility. This study showed that the investigated method eliminates effects due to scanner differences. The results can be used for power calculations in clinical studies or to better understand the scanner-induced variability in clinical applications.Funding Agencies|Swedish Research CouncilSwedish Research Council [VR 2019-04751]</p

Self-Reporting Theranostic: Nano Tool for Arterial Thrombosis

Arterial thrombosis (AT) originates through platelet-mediated thrombus formation in the blood vessel and can lead to heart attack, stroke, and peripheral vascular diseases. Restricting the thrombus growth and its simultaneous monitoring by visualisation is an unmet clinical need for a better AT prognosis. As a proof-of-concept, we have engineered a nanoparticle-based theranostic (combined therapy and monitoring) platform that has the potential to monitor and restrain the growth of a thrombus concurrently. The theranostic nanotool is fabricated using biocompatible super-paramagnetic iron oxide nanoparticles (SPIONs) as a core module tethered with the anti-platelet agent Abciximab (ReoPro) on its surface. Our in vitro feasibility results indicate that ReoPro-conjugated SPIONS (Tx@ReoPro) can effectively prevent thrombus growth by inhibiting fibrinogen receptors (GPIIbIIIa) on the platelet surface, and simultaneously, it can also be visible through non-invasive magnetic resonance imaging (MRI) for potential reporting of the real-time thrombus status.Funding Agencies|Shrimati Shetty, Abhishek Sharu and Ranjini Chowdhury.</p