Systematic evaluation of 99mTc-tetrofosmin versus 99mTc-sestamibi to study murine myocardial perfusion in small animal SPECT/CT

Background: The “back-translation” of clinically available protocols to measure myocardial perfusion to preclinical imaging in mouse models of human disease is attractive for basic biomedical research. With respect to singlephoton emission computed tomography (SPECT) approaches, clinical myocardial perfusion imaging protocols are established with different 99mTc-labeled perfusion tracers; however, studies evaluating and optimizing protocols for these tracers in high-resolution pinhole SPECT in mice are lacking. This study aims at evaluating two clinically available 99mTc-labeled myocardial perfusion tracers (99mTc-sestamibi vs. 99mTc-Tetrofosmin) in mice using four different imaging protocols. Methods: Adult C57BL/6 male mice were injected with 99mTc-sestamibi (MIBI) or 99mTc-Tetrofosmin (TETRO) (4 MBq/g body weight) either intravenously through the tail vein (n = 5) or retroorbitally (n = 5) or intraperitoneally (i. p.) under anesthesia (n = 3) or i.p. in an awake state (n = 3) at rest. Immediately after injection, a multi-frame singlephoton emission computed tomography/computed tomography (SPECT/CT) acquisition was initiated with six subsequent time frames of 10 min each. Reconstructed images of the different protocols were assessed and compared by visual analysis by experts and by time-activity-curves generated from regions-of-interest for various organs (normalized uptake values). Results: Visually assessing overall image quality, the best image quality was found for MIBI for both intravenous injection protocols, whereas TETRO only had comparable image quality after retroorbital injections. These results were confirmed by quantitative analysis where left ventricular (LV) uptake of MIBI after tail vein injections was found significantly higher for all time points accompanied with a significantly slower washout of 16% for MIBI vs. 33% for TETRO (p = 0.009) from 10 to 60 min post injection (PI). Interestingly, LV washout from 10 to 60 min PI was significantly higher for TETRO when applied by tail vein injections when compared to retroorbital injections (22%, p = 0.008). However, liver uptake was significant and comparable for both tracers at all time points. Radioactivity concentration in the lungs was negligible for all time points and both tracers. Conclusion: Intravenous MIBI injection (both tail vein and retroorbital) results in the best image quality for assessing myocardial perfusion of the murine heart by SPECT/CT. TETRO has a comparable image quality only for the retroorbital injection route

A Light Stop with Flavor in Natural SUSY

The discovery of a SM-like Higgs boson near 125 GeV and the flavor texture of the Standard Model motivate the investigation of supersymmetric quiver-like BSM extensions. We study the properties of such a minimal class of models which deals naturally with the SM parameters. Considering experimental bounds as well as constraints from flavor physics and Electro-Weak Precision Data, we find the following. In a self-contained minimal model - including the full dynamics of the Higgs sector - top squarks below a TeV are in tension with b->s{\gamma} constraints. Relaxing the assumption concerning the mass generation of the heavy Higgses, we find that a stop not far from half a TeV is allowed. The models have some unique properties, e.g. an enhancement of the h-> b\bar{b},\tau\bar{{\tau}} decays relative to the h->\gamma{\gamma} one, a gluino about 3 times heavier than the stop, an inverted hierarchy of about 3-20 between the squarks of the first two generations and the stop, relatively light Higgsino neutralino or stau NLSP, as well as heavy Higgses and a W' which may be within reach of the LHC.Comment: LaTeX, 22 pages, 4 figures; V2: references adde

Safe vs. Fair: A formidable trade-off in tackling climate change

Global warming requires a response characterized by forward-looking management of atmospheric carbon and respect for ethical principles. Both safety and fairness must be pursued, and there are severe trade-offs as these are intertwined by the limited headroom for additional atmospheric CO2 emissions. This paper provides a simple numerical mapping at the aggregated level of developed vs. developing countries in which safety and fairness are formulated in terms of cumulative emissions and cumulative per capita emissions respectively. It becomes evident that safety and fairness cannot be achieved simultaneously for strict definitions of both. The paper further posits potential global trading in future cumulative emissions budgets in a world where financial transactions compensate for physical emissions: the safe vs. fair tradeoff is less severe but remains formidable. Finally, we explore very large deployment of engineered carbon sinks and show that roughly 1,000 Gt CO2 of cumulative negative emissions over the century are required to have a significant effect, a remarkable scale of deployment. We also identify the unexplored issue of how such sinks might be treated in sub-global carbon accounting

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Vulnerability of Polarised Intestinal Porcine Epithelial Cells to Mycotoxin Deoxynivalenol Depends on the Route of Application

BACKGROUND AND AIMS: Deoxynivalenol (DON) is a Fusarium derived mycotoxin, often occurring on cereals used for human and animal nutrition. The intestine, as prominent barrier for nutritional toxins, has to handle the mycotoxin from the mucosa protected luminal side (apical exposure), as well as already absorbed toxin, reaching the cells from basolateral side via the blood stream. In the present study, the impact of the direction of DON exposure on epithelial cell behaviour and intestinal barrier integrity was elucidated. METHODS: A non-transformed intestinal porcine epithelial cell line (IPEC-J2), cultured in membrane inserts, serving as a polarised in vitro model to determine the effects of deoxynivalenol (DON) on cellular viability and tight junction integrity. RESULTS: Application of DON in concentrations up to 4000 ng/mL for 24, 48 and 72 hours on the basolateral side of membrane cultured polarised IPEC-J2 cells resulted in a breakdown of the integrity of cell connections measured by transepithelial electrical resistance (TEER), as well as a reduced expression of the tight junction proteins ZO-1 and claudin 3. Epithelial cell number decreased and nuclei size was enlarged after 72 h incubation of 4000 ng/mL DON from basolateral. Although necrosis or caspase 3 mediated apoptosis was not detectable after basolateral DON application, cell cycle analysis revealed a significant increase in DNA fragmentation, decrease in G0/G1 phase and slight increase in G2/M phase after 72 hours incubation with DON 2000 ng/mL. CONCLUSIONS: Severity of impact of the mycotoxin deoxynivalenol on the intestinal epithelial barrier is dependent on route of application. The epithelium appears to be rather resistant towards apical (luminal) DON application whereas the same toxin dose from basolateral severely undermines barrier integrity