Nucleoporin Mediated Nuclear Positioning and Silencing of HMR

The organization of chromatin domains in the nucleus is an important factor in gene regulation. In eukaryotic nuclei, transcriptionally silenced chromatin clusters at the nuclear periphery while transcriptionally poised chromatin resides in the nuclear interior. Recent studies suggest that nuclear pore proteins (NUPs) recruit loci to nuclear pores to aid in insulation of genes from silencing and during gene activation. We investigated the role of NUPs at a native yeast insulator and show that while NUPs localize to the native tDNA insulator adjacent to the silenced HMR domain, loss of pore proteins does not compromise insulation. Surprisingly we find that NUPs contribute to silencing at HMR and are able to restore silencing to a silencing-defective HMR allele when tethered to the locus. We show that the perinuclear positioning of heterochromatin is important for the NUP-mediated silencing effect and find that loss of NUPs result in decreased localization of HMR to the nuclear periphery. We also show that loss of telomeric tethering pathways does not eliminate NUP localization to HMR, suggesting that NUPs may mediate an independent pathway for HMR association with the nuclear periphery. We propose that localization of NUPs to the tDNA insulator at HMR helps maintain the intranuclear position of the silent locus, which in turn contributes to the fidelity of silencing at HMR

Evaluation of tumor ischemia in response to an indole-based vascular disrupting agent using BLI and (19)F MRI.

Vascular disrupting agents (VDAs) have been proposed as an effective broad spectrum approach to cancer therapy, by inducing ischemia leading to hypoxia and cell death. A novel VDA (OXi8007) was recently reported to show rapid acute selective shutdown of tumor vasculature based on color-Doppler ultrasound. We have now expanded investigations to noninvasively assess perfusion and hypoxiation of orthotopic human MDA-MB-231/luc breast tumor xenografts following the administration of OXi8007 based on dynamic bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). BLI showed significantly lower signal four hours after the administration of OXi8007, which was very similar to the response to combretastatin A-4P (CA4P), but the effect lasted considerably longer, with the BLI signal remaining depressed at 72 hrs. Meanwhile, control tumors exhibited minimal change. Oximetry used (19)F MRI of the reporter molecule hexafluorobenzene and FREDOM (Fluorocarbon Relaxometry using Echo Planar Imaging for Dynamic Oxygen Mapping) to assess pO2 distributions during air and oxygen breathing. pO2 decreased significantly upon the administration of OXi8007 during oxygen breathing (from 122 ± 64 to 34 ± 20 Torr), with further decrease upon switching the gas to air (pO2 = 17 ± 9 Torr). pO2 maps indicated intra-tumor heterogeneity in response to OXi8007, though ultimately all tumor regions became hypoxic. Both BLI and FREDOM showed the efficacy of OXi8007. The pO2 changes measured by FREDOM may be crucial for future study of combined therapy

Architecture Of The Magmatic System In The Main Ethiopian Rift

The Main Ethiopian Rift represents a young continental rift with an associated large volume of magmatism that forms one of the major Large Igneous Provinces. Plio-Quaternary magmatic activity is located in the Main Ethiopian Rift. Transitional to peralkaline mafic and felsic magmatic products dominate the volcanism which is related to complex variation in the crustal structure across the rift. Clinopyroxene, olivine and plagioclase are liquidus phases in the transitional and alkaline mafic magmas. Here we used the ability of clinopyroxene to record variations of P, T and fO2 to reconstruct the host-rocks geological history. Transitional and alkaline basalts and basaltic trachyandesite (with MgO>7 wt.%) from across the MER have augitic phenocrysts as liquidus phase. Euhedral centrimetric megacrysts of similar composition are sometime associated with alkaline rift basalts. Clinopyroxene geobarometry performed combining X-ray diffraction with mineral chemistry points to a complex polybaric plumbing system active since 7.5-3.7 My. MER clinopyroxene crystallize in a wide pressure range from the lower crust (ca. 10 kbar) up to middle crust (ca. 4 kbar) in the plumbing system beneath Debre Zeyit Fault Zone and the Wonji Fault Belt. The continuous polybaric MER clinopyroxene crystallization from lower to middle crust can be explained by a plumbing system composed of a complex of dykes and sills where magmas rise, stall and crystallize