Characterizing the Key Metabolic Pathways of the Neonatal Mouse Heart Using a Quantitative Combinatorial Omics Approach

The heart of a newborn mouse has an exceptional capacity to regenerate from myocardial injury that is lost within the first week of its life. In order to elucidate the molecular mechanisms taking place in the mouse heart during this critical period we applied an untargeted combinatory multiomics approach using large-scale mass spectrometry-based quantitative proteomics, metabolomics and mRNA sequencing on hearts from 1-day-old and 7-day-old mice. As a result, we quantified 1.937 proteins (366 differentially expressed), 612 metabolites (263 differentially regulated) and revealed 2.586 differentially expressed gene loci (2.175 annotated genes). The analyses pinpointed the fructose-induced glycolysis-pathway to be markedly active in 1-day-old neonatal mice. Integrated analysis of the data convincingly demonstrated cardiac metabolic reprogramming from glycolysis to oxidative phosphorylation in 7-days old mice, with increases of key enzymes and metabolites in fatty acid transport (acylcarnitines) and beta-oxidation. An upsurge in the formation of reactive oxygen species and an increase in oxidative stress markers, e.g., lipid peroxidation, altered sphingolipid and plasmalogen metabolism were also evident in 7-days mice. In vitro maintenance of physiological fetal hypoxic conditions retained the proliferative capacity of cardiomyocytes isolated from newborn mice hearts. In summary, we provide here a holistic, multiomics view toward early postnatal changes associated with loss of a tissue regenerative capacity in the neonatal mouse heart. These results may provide insight into mechanisms of human cardiac diseases associated with tissue regenerative incapacity at the molecular level, and offer a prospect to discovery of novel therapeutic targets.Peer reviewe

Q_EC values of the Superallowed beta-Emitters 10-C, 34-Ar, 38-Ca and 46-V

The Q_EC values of the superallowed beta+ emitters 10-C, 34-Ar, 38-Ca and 46-V have been measured with a Penning-trap mass spectrometer to be 3648.12(8), 6061.83(8), 6612.12(7) and 7052.44(10) keV, respectively. All four values are substantially improved in precision over previous results.Comment: 9 pages, 7 figures, 5 table

Precision mass measurements on neutron-rich rare-earth isotopes at JYFLTRAP - reduced neutron pairing and implications for the rr-process calculations

The rare-earth peak in the $r$-process abundance pattern depends sensitively on both the astrophysical conditions and subtle changes in nuclear structure in the region. This work takes an important step elucidating the nuclear structure and reducing the uncertainties in $r$-process calculations via precise atomic mass measurements at the JYFLTRAP double Penning trap. $^{158}$Nd, $^{160}$Pm, $^{162}$Sm, and $^{164-166}$Gd have been measured for the first time and the precisions for $^{156}$Nd, $^{158}$Pm, $^{162,163}$Eu, $^{163}$Gd, and $^{164}$Tb have been improved considerably. Nuclear structure has been probed via two-neutron separation energies $S_{2n}$ and neutron pairing energy metrics $D_n$. The data do not support the existence of a subshell closure at $N=100$. Neutron pairing has been found to be weaker than predicted by theoretical mass models. The impact on the calculated $r$-process abundances has been studied. Substantial changes resulting in a smoother abundance distribution and a better agreement with the solar $r$-process abundances are observed.Comment: 8 pages, 4 figures, accepted for publication in Physical Review Letter

Mass measurements in the vicinity of the doubly-magic waiting point 56Ni

Masses of 56,57Fe, 53Co^m, 53,56Co, 55,56,57Ni, 57,58Cu, and 59,60Zn have been determined with the JYFLTRAP Penning trap mass spectrometer at IGISOL with a precision of dm/m \le 3 x 10^{-8}. The QEC values for 53Co, 55Ni, 56Ni, 57Cu, 58Cu, and 59Zn have been measured directly with a typical precision of better than 0.7 keV and Coulomb displacement energies have been determined. The Q values for proton captures on 55Co, 56Ni, 58Cu, and 59Cu have been measured directly. The precision of the proton-capture Q value for 56Ni(p,gamma)57Cu, Q(p,gamma) = 689.69(51) keV, crucial for astrophysical rp-process calculations, has been improved by a factor of 37. The excitation energy of the proton emitting spin-gap isomer 53Co^m has been measured precisely, Ex = 3174.3(10) keV, and a Coulomb energy difference of 133.9(10) keV for the 19/2- state has been obtained. Except for 53Co, the mass values have been adjusted within a network of 17 frequency ratio measurements between 13 nuclides which allowed also a determination of the reference masses 55Co, 58Ni, and 59Cu.Comment: 14 pages, 13 figures, submitted to Phys. Rev.

Penning-trap mass measurement of 173^{173}Hf

We report on the precise mass measurement of the $^{173}$Hf isotope performed at the Ion Guide Isotope Separator On-Line facility using the JYFLTRAP double Penning trap mass spectrometer. The new mass-excess value, ${\mathrm{ME} = -55390.8(30)}$~keV, is in agreement with the literature while being nine times more precise. The newly determined $^{173}$Hf electron-capture $Q$ value, $Q_{EC} = 1490.2(34)$~keV, allows us to firmly reject the population of an excited state at 1578 keV in $^{173}$Lu and 11 transitions tentatively assigned to the decay of $^{173}$Hf. Our refined mass value of $^{173}$Hf reduces mass-related uncertainties in the reaction rate of $^{174}$Hf$(\gamma,n)^{173}$Hf. Thus, the rate for the main photodisintegration destruction channel of the $p$ nuclide $^{174}$Hf in the relevant temperature region for the $\gamma$ process is better constrained.Comment: 4 pages, 2 figure

Effect of Donor Simvastatin Treatment on Gene Expression Profiles in Human Cardiac Allografts during Ischemia-Reperfusion Injury

Purpose Numerous studies have shown that statin therapy initiated early after heart transplantation has beneficial effects on the development of cardiac allograft vasculopathy. Recently, we were able to show in a randomized clinical trial that simvastatin treatment of brain-dead donors conditions the heart transplant to withstand ischemia-reperfusion injury and to reduce the need for rejection treatments early after transplantation. In this study, we analyzed myocardial gene expression profiles in cardiac allografts after donor simvastatin treatment. Methods 84 heart transplant donors received 80 mg of simvastatin via nasogastric tube (n=42), or no treatment (n=42) in a prospective, double-blinded randomized controlled trial. Transmural Tru-Cut biopsies were taken from the apex of left ventricle of the donor heart immediately before reperfusion and 1 hour after reperfusion. 20 heart biopsies from donors without treatment and 20 heart biopsies from donors with simvastatin treatment will be analyzed with RNA sequencing. Results The preliminary analysis of RNA sequencing data from myocardial biopsies revealed altogether 137 significantly differentially expressed genes in all pairwise comparisons. The overall biological functions of these genes were related to gene ontology terms such as response to toxic substance, leukocyte migration, neutrophil mediated immunity, response to lipopolysaccharide, and response to oxidative stress. At the KEGG pathway level, our results indicated alterations in IL-17, TNF, MAPK and the AGE-RAGE signaling pathways. Conclusion We have shown in previous studies that donor simvastatin treatment induces protective effects against IRI in heart transplant recipients. In this study, we were able to detect significantly differentially expressed genes related to effects of simvastatin treatment. In order to single out genes that show beneficial effects of simvastatin treatment, further analysis will be conducted by exploring gene expression changes in specific biological functional categories, such as interleukin signaling and neutrophil degranulation. The complete analysis will be presented at the ISHLT 2019 congress.Peer reviewe

Metatranscriptomic assessment of burn wound infection clearance

Peer reviewe

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for similar to 15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.Peer reviewe