On spin-rotation contribution to nuclear spin conversion in C_{3v}-symmetry molecules. Application to CH_3F

The symmetrized contribution of E-type spin-rotation interaction to conversion between spin modifications of E- and A_1-types in molecules with C_{3v}-symmetry is considered. Using the high-J descending of collisional broadening for accidental rotational resonances between these spin modifications, it was possible to co-ordinate the theoretical description of the conversion with (updated) experimental data for two carbon-substituted isotopes of fluoromethane. As a result, both E-type spin-rotation constants are obtained. They are roughly one and a half times more than the corresponding constants for (deutero)methane.Comment: 13 pages with single-spacing, REVTeX, no figures, accepted for publication in <J. Phys. B

Activation of WNT/beta-Catenin Signaling Enhances Pancreatic Cancer Development and the Malignant Potential Via Up-regulation of Cyr61

Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding beta-cateninS37A and WNT1 stimulated the progression of premalignant pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-beta-cateninS37A or RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P \u3c .05). Ectopic expression of active beta-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the beta-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/beta-catenin signaling pathway in pancreatic cancer cells. Nuclear beta-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear beta-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P \u3c .01). Knockdown of CYR61 in a beta-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/beta-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61

The helicases DinG, Rep and UvrD cooperate to promote replication across transcription units in vivo

How living cells deal with head-on collisions of the replication and transcription complexes has been debated for a long time. Even in the widely studied model bacteria Escherichia coli, the enzymes that take care of such collisions are still unknown. We report here that in vivo, the DinG, Rep and UvrD helicases are essential for efficient replication across highly transcribed regions. We show that when rRNA operons (rrn) are inverted to face replication, the viability of the dinG mutant is affected and over-expression of RNase H rescues the growth defect, showing that DinG acts in vivo to remove R-loops. In addition, DinG, Rep and UvrD exert a common function, which requires the presence of two of these three helicases. After replication blockage by an inverted rrn, Rep in conjunction with DinG or UvrD removes RNA polymerase, a task that is fulfilled in its absence by the SOS-induced DinG and UvrD helicases. Finally, Rep and UvrD also act at inverted sequences other than rrn, and promote replication through highly transcribed regions in wild-type E. coli

ECOG-ACRIN (E4805) Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients with Metastatic Renal Cell Carcinoma

Background—Aflibercept is a recombinantly-produced fusion protein that has potent anti-VEGF activity. We tested whether aflibercept has clinical activity in clear cell renal cell carcinoma (ccRCC). The recommended Phase 2 dose was 4 mg/kg but several patients treated at 1 mg/kg demonstrated prolonged progression-free survival (PFS). We therefore tested both doses in a parallel group randomized trial. Methods—Eligible patients (pts) had histologically confirmed advanced or metastatic ccRCC and previous treatments including prior exposure to a VEGF RTKI. Patients received aflibercept (either 1 mg/kg or 4 mg/kg) day 1 of a 14-day cycle until progression. Patients randomized to 1 mg/kg could crossover to 4 mg/kg at progression. The primary endpoint was proportion alive and progression-free at 8 weeks. A Simon 2-stage design was used for each arm with 33 and 24 eligible pts/arm enrolled in stages 1 and 2. Results—94 pts were enrolled, 59 and 35 to 4 mg and 1 mg doses, respectively. 72% had 1 prior tx most commonly sunitinib. 16 eligible pts crossed over at progression to the 4 mg dose. Most common adverse events were hypertension, proteinuria, and fatigue. Only 4 pts reported Grade 4 or higher toxicity. With 36/59 (61%) pts PFS at 8 wks, the 4-mg/kg dose met protocol specified efficacy criteria. Conclusions—Aflibercept is active in previously treated ccRCC and may be worthy of further study

Stress Field Interactions Between Overlapping Shield Volcanoes : Borehole Breakout Evidence From the Island of Hawai'i, USA

Acknowledgments: This PTA2 borehole investigation was funded by the International Continental Scientific Drilling Program (ICDP) and by VMAPP (Volcanic Margin Petroleum Prospectivity) project (VBPR/DougalEARTH/TGS) in collaboration with the Humu'ula Groundwater Research Project. D. A. J. and S. P. are partly funded through a Norwegian Research Council Centres of Excellence project (project number 223272, CEED). We thank Marco Groh for the logging operations. We thank two anonymous reviewers for the comments and suggestions. We are particularly grateful to the Associate Editor Mike Poland for his valuable comments and his critical review that greatly improved the manuscript.Peer reviewedPublisher PD

Aviation effects on already-existing cirrus clouds.

Determining the effects of the formation of contrails within natural cirrus clouds has proven to be challenging. Quantifying any such effects is necessary if we are to properly account for the influence of aviation on climate. Here we quantify the effect of aircraft on the optical thickness of already-existing cirrus clouds by matching actual aircraft flight tracks to satellite lidar measurements. We show that there is a systematic, statistically significant increase in normalized cirrus cloud optical thickness inside mid-latitude flight tracks compared with adjacent areas immediately outside the tracks

Exploiting Ligand-Protein Conjugates to Monitor Ligand-Receptor Interactions

We introduce three assays for analyzing ligand-receptor interactions based on the specific conjugation of ligands to SNAP-tag fusion proteins. Conjugation of ligands to different SNAP-tag fusions permits the validation of suspected interactions in cell extracts and fixed cells as well as the establishment of high-throughput assays. The different assays allow the analysis of strong and weak interactions. Conversion of ligands into SNAP-tag substrates thus provides access to a powerful toolbox for the analysis of their interactions with proteins