Oxygen ion energization by waves in the high altitude cusp and mantle

We present a comparative study of low frequency electric field spectral densities and temperatures observed by the Cluster spacecraft in the high altitude cusp/mantle region. We compare the relation between the O+ temperature and wave intensity at the oxygen gyrofrequency at each measurement point and find a clear correlation. The trend of the correlation agrees with the predictions by both an asymptotic mean-particle theory and a test-particle approach. The perpendicular to parallel temperature ratio is also consistent with the predictions of the asymptotic mean-particle theory. At times the perpendicular temperature is significantly higher than predicted by the models. A simple study of the evolution of the particle distributions (conics) at these altitudes indicates that enhanced perpendicular temperatures would be observed over many RE after heating ceases. Therefore, sporadic intense heating is the likely explanation for cases with high temperature and comparably low wave activity. We observe waves of sufficient amplitude to explain the highest observed temperatures, while the theory in general overestimates the temperature associated with the highest observed wave activity, indicating that such high wave activity is very sporadic

CAPN2-responsive mesoporous silica nanoparticles: a promising nanocarrier for targeted therapy of pancreatic cancer

Pancreatic adenocarcinoma (PDAC) is highly resistant to conventional chemotherapeutic interventions, resulting in exceptionally low survival rates. The limited efficacy can in part be attributed to dose limitations and treatment cessation urged by toxicity of currently used chemotherapy. The advent of targeted delivery strategies has kindled hope for circumventing off-target toxicity. We have previously reported a PDAC-specific mesoporous silica nanoparticle (MSN) containing a protease linker responsive to ADAM9, a PDAC-enriched extracellularly deposited protease. Upon loading with paclitaxel these ADAM9-MSNs reduced side effects both in vitro and in vivo, however, disappointing antitumor efficacy was observed in vivo. Here, we propose that an efficient uptake of MSNs by tumor cells might underlie the lack of antitumor efficacy of MSNs functionalized with linker responsive to extracellular proteases. Harnessing this premise to improve antitumor efficacy, we performed an in silico analysis to identify PDAC-enriched intracellular proteases. We report the identification of BACE2, CAPN2 and DPP3 as PDAC enriched intracellular proteases, and report the synthesis of BACE2-, CAPN2- and DPP3- responsive MSNs. Extensive preclinical assessments revealed that paclitaxel-loaded CAPN2- and DPP3-MSNs exhibit high PDAC specificity in vitro as opposed to free paclitaxel. The administration of paclitaxel-loaded CAPN2- and DPP3-MSNs in vivo confirmed the reduction of leukopenia and induced no organ damage. Promisingly, in two mouse models CAPN2-MSNs reduced tumor growth at least as efficiently as free paclitaxel. Taken together, our results pose CAPN2-MSNs as a promising nanocarrier for the targeted delivery of chemotherapeutics in PDAC.Supramolecular & Biomaterials Chemistr

Preclinical assessment of ADAM9-responsive mesoporous silica nanoparticles for the treatment of pancreatic cancer

Supramolecular & Biomaterials Chemistr

The GCC repeat length in the 5'UTR of MRP1 gene is polymorphic: a functional characterization of its relevance for cystic fibrosis

BACKGROUND: Among the members of the ATP binding cassette transporter superfamily, MRPs share the closest homology with the CFTR protein, which is defective in CF disease. MRP1 has been proposed as a potential modifier gene and/or as novel target for pharmacotherapy of CF to explain the clinical benefits observed in some CF patients treated with the macrolide AZM. The 5'UTR of the MRP1 gene contains a GCC triplet repeat that could represent a polymorphic site and affect the activity of the promoter. METHODS: The MRP1 5' flanking region was amplified by PCR from 36 CF patients and 100 non-CF subjects and the number of GCC triplets of each allele was determined by sequence and electrophoretic analysis. We performed gene reporter studies in CF airway epithelial cells 16HBE14o-AS3, in basal conditions and in the presence of AZM. RESULTS: We found that the GCC repeat is polymorphic, ranging from 7 to 14 triplets either in CF or in non-CF subjects. Our data are preliminary and have to be confirmed on a larger population of CF subjects. The transcriptional activity of the proximal MRP1 5' regulatory region revealed no statistically significant correlations between the number of repeats and treatment with AZM. CONCLUSION: We identified a novel polymorphism in the 5'UTR of MRP1 gene that provides multiple alleles in a gene relevant for multidrug resistance as well as for CF, determining that this region is transcriptionally active and that this activity does not appear to be influenced by AZM treatment

Imaging Poliovirus Entry in Live Cells

Viruses initiate infection by transferring their genetic material across a cellular membrane and into the appropriate compartment of the cell. The mechanisms by which animal viruses, especially nonenveloped viruses, deliver their genomes are only poorly understood. This is due in part to technical difficulties involved in direct visualization of viral gene delivery and to uncertainties in distinguishing productive and nonproductive pathways caused by the high particle-to–plaque forming unit ratio of most animal viruses. Here, we combine an imaging assay that simultaneously tracks the viral capsid and genome in live cells with an infectivity-based assay for RNA release to characterize the early events in the poliovirus (PV) infection. Effects on RNA genome delivery from inhibitors of cell trafficking pathways were probed systematically by both methods. Surprisingly, we observe that genome release by PV is highly efficient and rapid, and thus does not limit the overall infectivity or the infection rate. The results define a pathway in which PV binds to receptors on the cell surface and enters the cell by a clathrin-, caveolin-, flotillin-, and microtubule-independent, but tyrosine kinase- and actin-dependent, endocytic mechanism. Immediately after the internalization of the virus particle, genome release takes place from vesicles or tightly sealed membrane invaginations located within 100–200 nm of the plasma membrane. These results settle a long-lasting debate of whether PV directly breaks the plasma membrane barrier or relies on endocytosis to deliver its genome into the cell. We expect this imaging assay to be broadly applicable to the investigation of entry mechanisms for nonenveloped viruses

Review of Environmental Monitoring by Means of Radio Waves in the Polar Regions: From Atmosphere to Geospace

The Antarctic and Arctic regions are Earth's open windows to outer space. They provide unique opportunities for investigating the troposphere–thermosphere–ionosphere–plasmasphere system at high latitudes, which is not as well understood as the mid- and low-latitude regions mainly due to the paucity of experimental observations. In addition, different neutral and ionised atmospheric layers at high latitudes are much more variable compared to lower latitudes, and their variability is due to mechanisms not yet fully understood. Fortunately, in this new millennium the observing infrastructure in Antarctica and the Arctic has been growing, thus providing scientists with new opportunities to advance our knowledge on the polar atmosphere and geospace. This review shows that it is of paramount importance to perform integrated, multi-disciplinary research, making use of long-term multi-instrument observations combined with ad hoc measurement campaigns to improve our capability of investigating atmospheric dynamics in the polar regions from the troposphere up to the plasmasphere, as well as the coupling between atmospheric layers. Starting from the state of the art of understanding the polar atmosphere, our survey outlines the roadmap for enhancing scientific investigation of its physical mechanisms and dynamics through the full exploitation of the available infrastructures for radio-based environmental monitoring