Subacute AMD3100 treatment is not efficient in neonatal hypoxic-schemic rats

Background and Purpose: Despite the advances in treating neonatal hypoxic-ischemic encephalopathy (HIE) with induced hypothermia, the rates of severe disability are still high among survivors. Preclinical studies have indicated that cell therapies with hematopoietic stem/progenitor cells could improve neurological outcomes in HIE. In this study, we investigated whether the administration of AMD3100, a CXCR4 antagonist that mobilizes hematopoietic stem/progenitor cells into the circulation, has therapeutic effects in HIE. Methods: P10 Wistar rats of both sexes were subjected to right common carotid artery occlusion or sham procedure, and then were exposed to hypoxia for 120 minutes. Two subcutaneous injections of AMD3100 or vehicle were given on the third and fourth day after HIE. We first assessed the interindividual variability in brain atrophy after experimental HIE and vehicle treatment in a small cohort of rats. Based on this exploratory analysis, we designed and conducted an experiment to test the efficacy of AMD3100. Brain atrophy on day 21 after HIE was defined as the primary end point. Secondary efficacy end points were cognitive (T-water maze) and motor function (rotarod) on days 17 and 18 after HIE, respectively. Results: AMD3100 did not decrease the brain atrophy in animals of either sex. Cognitive impairments were not observed in the T-water maze, but male hypoxic-ischemic animals exhibited motor coordination deficits on the rotarod, which were not improved by AMD3100. A separate analysis combining data from animals of both sexes also revealed no evidence of the effectiveness of AMD3100 treatment. Conclusions: These results indicate that the subacute treatment with AMD3100 does not improve structural and functional outcomes in a rat HIE model

Correction: optimized labeling of bone marrow mesenchymal cells with superparamagnetic iron oxide nanoparticles and in vivo visualization by magnetic resonance imaging

Abstract Background Stem cell therapy has emerged as a promising addition to traditional treatments for a number of diseases. However, harnessing the therapeutic potential of stem cells requires an understanding of their fate in vivo. Non-invasive cell tracking can provide knowledge about mechanisms responsible for functional improvement of host tissue. Superparamagnetic iron oxide nanoparticles (SPIONs) have been used to label and visualize various cell types with magnetic resonance imaging (MRI). In this study we performed experiments designed to investigate the biological properties, including proliferation, viability and differentiation capacity of mesenchymal cells (MSCs) labeled with clinically approved SPIONs. Results Rat and mouse MSCs were isolated, cultured, and incubated with dextran-covered SPIONs (ferumoxide) alone or with poly-L-lysine (PLL) or protamine chlorhydrate for 4 or 24 hrs. Labeling efficiency was evaluated by dextran immunocytochemistry and MRI. Cell proliferation and viability were evaluated in vitro with Ki67 immunocytochemistry and live/dead assays. Ferumoxide-labeled MSCs could be induced to differentiate to adipocytes, osteocytes and chondrocytes. We analyzed ferumoxide retention in MSCs with or without mitomycin C pretreatment. Approximately 95% MSCs were labeled when incubated with ferumoxide for 4 or 24 hrs in the presence of PLL or protamine, whereas labeling of MSCs incubated with ferumoxide alone was poor. Proliferative capacity was maintained in MSCs incubated with ferumoxide and PLL for 4 hrs, however, after 24 hrs it was reduced. MSCs incubated with ferumoxide and protamine were efficiently visualized by MRI; they maintained proliferation and viability for up to 7 days and remained competent to differentiate. After 21 days MSCs pretreated with mitomycin C still showed a large number of ferumoxide-labeled cells. Conclusions The efficient and long lasting uptake and retention of SPIONs by MSCs using a protocol employing ferumoxide and protamine may be applicable to patients, since both ferumoxides and protamine are approved for human use.</p

Analyses of zebrafish and Xenopus oocyte maturation reveal conserved and diverged features of translational regulation of maternal cyclin B1 mRNA

<p>Abstract</p> <p>Background</p> <p>Vertebrate development relies on the regulated translation of stored maternal mRNAs, but how these regulatory mechanisms may have evolved to control translational efficiency of individual mRNAs is poorly understood. We compared the translational regulation and polyadenylation of the cyclin B1 mRNA during zebrafish and <it>Xenopus </it>oocyte maturation. Polyadenylation and translational activation of cyclin B1 mRNA is well characterized during <it>Xenopus </it>oocyte maturation. Specifically, <it>Xenopus </it>cyclin B1 mRNA is polyadenylated and translationally activated during oocyte maturation by proteins that recognize the conserved AAUAAA hexanucleotide and U-rich Cytoplasmic Polyadenylation Elements (CPEs) within cyclin B1 mRNA's 3'<b>U</b>n<b>T</b>ranslated <b>R</b>egion (3'<b>UTR</b>).</p> <p>Results</p> <p>The zebrafish cyclin B1 mRNA was polyadenylated during zebrafish oocyte maturation. Furthermore, the zebrafish cyclin B1 mRNA's 3'UTR was sufficient to stimulate translation of a reporter mRNA during zebrafish oocyte maturation. This stimulation required both AAUAAA and U-rich CPE-like sequences. However, in contrast to AAUAAA, the positions and sequences of the functionally defined CPEs were poorly conserved between <it>Xenopus </it>and zebrafish cyclin B1 mRNA 3'UTRs. To determine whether these differences were relevant to translation efficiency, we analyzed the translational activity of reporter mRNAs containing either the zebrafish or <it>Xenopus </it>cyclin B1 mRNA 3'UTRs during both zebrafish and <it>Xenopus </it>oocyte maturation. The zebrafish cyclin B1 3'UTR was quantitatively less effective at stimulating polyadenylation and translation compared to the <it>Xenopus </it>cyclin B1 3'UTR during both zebrafish and <it>Xenopus </it>oocyte maturation.</p> <p>Conclusion</p> <p>Although the factors that regulate translation of maternal mRNAs are highly conserved, the target sequences and overall sequence architecture within the 3'UTR of the cyclin B1 mRNA have diverged to affect translational efficiency, perhaps to optimize levels of cyclin B1 protein required by these different species during their earliest embryonic cell divisions.</p

First detection of VHE gamma-ray emission from TXS 1515-273, study of its X-ray variability and spectral energy distribution

We report here on the first multi-wavelength (MWL) campaign on the blazar TXS 1515-273, undertaken in 2019 and extending from radio to very-high-energy gamma rays (VHE). Up until now, this blazar had not been the subject of any detailed MWL observations. It has a rather hard photon index at GeV energies and was considered a candidate extreme high-synchrotronpeaked source. MAGIC observations resulted in the first-time detection of the source in VHE with a statistical significance of 7.6$\sigma$. The average integral VHE flux of the source is 6 $\pm$ 1% of the Crab nebula flux above 400 GeV. X-ray coverage was provided by Swift-XRT, XMMNewton, and NuSTAR. The long continuous X-ray observations were separated by $\sim$ 9 h, both showing clear hour scale flares. In the XMM-Newton data, both the rise and decay timescales are longer in the soft X-ray than in the hard X-ray band, indicating the presence of a particle cooling regime. The X-ray variability timescales were used to constrain the size of the emission region and the strength of the magnetic field. The data allowed us to determine the synchrotron peak frequency and classify the source as a flaring high, but not extreme, synchrotron peaked object. Considering the constraints and variability patterns from the X-ray data, we model the broad-band spectral energy distribution. We applied a simple one-zone model, which could not reproduce the radio emission and the shape of the optical emission, and a two-component leptonic model with two interacting components, enabling us to reproduce the emission from radio to VHE band

Follow-up observations of GW170817 with the MAGIC telescopes

The discovery of the electromagnetic counterpart AT2017gfo and the GRB 170817A, associated to the binary neutron star merger GW170817, was one of the major advances in the study of gamma-ray bursts (GRBs) and the hallmark of the multi-messenger astronomy with gravitational waves. Another breakthrough in GRB physics is represented by the discovery of the highly energetic, teraelectronvolt (TeV) component in the GRB 190114C, possibly an universal component in all GRBs. This conclusion is also suggested by the hint of TeV emission in the short GRB 160821B and a few more events reported in the literature. The missing observational piece is the joint detection of TeV emission and gravitational waves from a short GRB and its progenitor. MAGIC observed the counterpart AT2017gfo as soon as the visibility conditions allowed it, namely from January to June 2018. These observations correspond to the maximum flux level observed in the radio and X-ray bands. The upper limits derived from TeV observations are compared with the modelling of the late non-thermal emission using the multi-frequency SED

MAGIC observations of the nearby short GRB 160821B

Gamma-ray bursts (GRBs), the most luminous explosions in the universe, have at least two types known. One of them, short GRBs, have been thought to originate from binary neutron star (BNS) mergers. The discovery of GW170817 together with a GRB was the first and only direct proof of the hypothesis, and thus the properties of the short GRBs are poorly known yet. Aiming to clarify the underlying physical mechanisms of the short GRBs, we analyzed GRB 160821B, one of the nearest short GRBs known at z=0.162, observed with the MAGIC telescopes. A hint of a gamma-ray signal is found above 0.5 TeV at a significance of &gt;3 sigma during observations from 24 seconds until 4 hours after the burst, as presented in the past. Recently, multi-wavelength data of its afterglow emission revealed a well-sampled kilonova component from a BNS merger, and the importance of GRB 160821B increased concerning GRB-GW studies. Accordingly, we investigated GRB afterglow models again, using the revised multi-wavelength data. We found that the straightforward interpretation with one-zone synchrotron self-Compton model from the external forward shock is in tension with the observed TeV flux, contradicting the suggestion reported previously. In this contribution we discuss the implication from the TeV observation, including alternative scenarios where the TeV emission can be enhanced. We also give a brief outlook of future GeV-TeV observations of short GRBs with imaging atmospheric Cherenkov telescopes, which could shed more light on the GRB-BNS merger relation

Performance and first measurements of the MAGIC stellar intensity interferometer

In recent years, a new generation of optical intensity interferometers has emerged, leveraging the existing infrastructure of Imaging Atmospheric Cherenkov Telescopes (IACTs). The MAGIC telescopes host the MAGIC-SII system (Stellar Intensity Interferometer), implemented to investigate the feasibility and potential of this technique on IACTs. After the first successful measurements in 2019, the system was upgraded and now features a real-time, dead-time-free, 4-channel, GPU-based correlator. These hardware modifications allow seamless transitions between MAGIC’s standard very-high-energy gamma-ray observations and optical interferometry measurements within seconds. We establish the feasibility and potential of employing IACTs as competitive optical Intensity Interferometers with minimal hardware adjustments. The measurement of a total of 22 stellar diameters are reported, 9 corresponding to reference stars with previous comparable measurements, and 13 with no prior measurements. A prospective implementation involving telescopes from the forthcoming Cherenkov Telescope Array Observatory’s Northern hemisphere array, such as the first prototype of its Large-Sized Telescopes, LST-1, is technically viable. This integration would significantly enhance the sensitivity of the current system and broaden the UV-plane coverage. This advancement would enable the system to achieve competitive sensitivity with the current generation of long-baseline optical interferometers over blue wavelengths