Abstract
Magnetic fields in galaxies and galaxy clusters are believed to be the result of the amplification of intergalactic seed fields during the formation of large-scale structures in the ...universe. However, the origin, strength, and morphology of this intergalactic magnetic field (IGMF) remain unknown. Lower limits on (or indirect detection of) the IGMF can be obtained from observations of high-energy gamma rays from distant blazars. Gamma rays interact with the extragalactic background light to produce electron−positron pairs, which can subsequently initiate electromagnetic cascades. The gamma-ray signature of the cascade depends on the IGMF since it deflects the pairs. Here we report on a new search for this cascade emission using a combined data set from the Fermi Large Area Telescope and the High Energy Stereoscopic System. Using state-of-the-art Monte Carlo predictions for the cascade signal, our results place a lower limit on the IGMF of
B
> 7.1 × 10
−16
G for a coherence length of 1 Mpc even when blazar duty cycles as short as 10 yr are assumed. This improves on previous lower limits by a factor of 2. For longer duty cycles of 10
4
(10
7
) yr, IGMF strengths below 1.8 × 10
−14
G (3.9 × 10
−14
G) are excluded, which rules out specific models for IGMF generation in the early universe.
Here we present a novel hyperpolarization method, Chemical Reaction-Induced Multi-molecular Polarization (CRIMP), which could be applied to the study of several in vivo processes simultaneously ...including glycolysis, TCA cycle, fatty acid synthesis and pH mapping. Through the use of non-enzymatic decarboxylation, we generate four hyperpolarized imaging agents from hyperpolarized 1,2-(13)C pyruvic acid.
Von Hippel Lindau (VHL) inactivation, which is common in clear cell renal cell carcinoma (ccRCC), leads directly to the disruption of oxygen homoeostasis. VHL works through hypoxia-inducible factors ...(HIFs). Within this VHL-HIF system, prolyl hydroxylases (PHDs) are the intermediary proteins that initiate the degradation of HIFs. PHD isoform 3's (PHD3) role in ccRCC growth in vivo is poorly understood. Using viral transduction, we knocked down the expression of PHD3 in the human ccRCC cell line UMRC3. Compared with control cells transduced with scrambled vector (UMRC3-SC cells), PHD3-knockdown cells (UMRC3-PHD3KD cells) showed increased cell invasion, tumor growth, and response to sunitinib. PHD3 knockdown reduced HIF2α expression and increased phosphorylated epidermal growth factor (EGFR) expression in untreated tumor models. However, following sunitinib treatment, expression of HIF2α and phosphorylated EGFR were equivalent in both PHD3 knockdown and control tumors. PHD3 knockdown changed the overall redox state of the cell as seen by the increased concentration of glutathione in PHD3 knockdown tumors relative to control tumors. UMRC3-PHD3KD cells had increased proliferation in cell culture when grown in the presence of hydrogen peroxide compared to UMRC3-SC control cells. Our findings illustrate (1) the variable effect of PHD3 on HIF2α expression, (2) an inverse relationship between PHD3 expression and tumor growth in ccRCC animal models, and (3) the role of PHD3 in maintaining the redox state of UMRC3 cells and their proliferative rate under oxidative stress.
Context. The broadband spectral energy distributions (SED) of blazars show two distinct components which in leptonic models are associated with synchrotron and synchrotron self-Compton (SSC) emission ...of highly relativistic electrons. In some sources the SSC component dominates the synchrotron peak by one or more orders of magnitude implying that the electrons mainly cool by inverse Compton collisions with their self-made synchrotron photons. Therefore, the linear synchrotron loss of electrons, which is normally invoked in emission models, has to be replaced by a nonlinear loss rate depending on an energy integral of the electron distribution. This modified electron cooling changes significantly the emerging radiation spectra. Aims. It is the purpose of this work to apply this new cooling scenario to relativistic power-law distributed electrons, which are injected instantaneously into the jet. Methods. We assume a spherical, uniform, nonthermal source, where the distribution of the electrons is spatially and temporally isotropic throughout the source. We will first solve the differential equation of the volume-averaged differential number density of the electrons, and then discuss their temporal evolution. Since any non-linear cooling will turn into linear cooling after some time, we also calculated the electron number density for a combined cooling scenario consisting of both the linear and non-linear cooling. For all cases, we will also calculate analytically the emerging optically thin time-integrated synchrotron intensity spectrum, also named the fluence, and compare it to a numerical solution. Results. The first result is that the combined cooling scenario depends critically on the value of the injection parameter α0. For values α0 ≪ 1 the electrons cool mainly linear, while in the opposite case the cooling begins non-linear and becomes linear for later times. Secondly, in all cased we find that for small normalized frequencies f < 1 the fluence spectra F(f) exhibit power-laws with constant spectral indices F(f) ~ f − ϑ. We find for purely linear cooling ϑSYN = 1/2, and for purely non-linear cooling ϑSSC = 3/2. In the combined cooling scenario we obtain for the small injection parameter ϑ1 = 1/2, and for the large injection parameter ϑ2 = 3/2, which becomes ϑ1 = 1/2 for very small frequencies. These identical behaviors, as compared to the existing calculations for monoenergetically injected electrons, prove that the spectral behavior of the total synchrotron fluence is independent from the functional form of the energy injection spectrum.
ABSTRACT
We report on the detection of very high energy (VHE; E > 100 GeV) γ-ray emission from the BL Lac objects KUV 00311−1938 and PKS 1440−389 with the High Energy Stereoscopic System (H.E.S.S.). ...H.E.S.S. observations were accompanied or preceded by multiwavelength observations with Fermi/LAT, XRT and UVOT onboard the Swift satellite, and ATOM. Based on an extrapolation of the Fermi/LAT spectrum towards the VHE γ-ray regime, we deduce a 95 per cent confidence level upper limit on the unknown redshift of KUV 00311−1938 of $z$ < 0.98 and of PKS 1440−389 of $z$ < 0.53. When combined with previous spectroscopy results, the redshift of KUV 00311−1938 is constrained to 0.51 ≤ $z$ < 0.98 and of PKS 1440−389 to 0.14 ⪅ $z$ < 0.53.
While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and ...therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (1H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized 1-13C pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (kPA and kPL) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations.
When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development ...versus therapy development. Importantly, overcoming the challenges of drug resistance may provide invaluable clues about the origin and nature of cancer. From this perspective, we discuss how chemoresistance and chemosensitivity in cancer therapy could be directly linked to the stem cell origin of cancer. A stem cell theory of cancer stipulates that both normal stem cells and cancer stem cells are similarly endowed with robust efflux pumps, potent antiapoptotic mechanisms, redundant DNA repair systems, and abundant antioxidation reserves. Cancer stem cells, like their normal stem cell counterparts, are equipped with the same drug resistance phenotypes (e.g., ABC transporters, anti-apoptotic pathways, and DNA repair mechanisms). Drug resistance, like other cancer hallmarks (e.g., tumor heterogeneity and cancer dormancy), could be intrinsically ingrained and innately embedded within malignancy. We elaborate that cellular context and the microenvironment may attenuate the effects of cancer treatments. We examine the role of circadian rhythms and the value of chronotherapy to maximize efficacy and minimize toxicity. We propose that a stem cell theory of drug resistance and drug sensitivity will ultimately empower us to enhance drug development and enable us to improve therapy development in patient care.
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