Pisces IV submersible observations in the epicentral region of the 1929 Grand Banks earthquake

The PISCES IVsubmersible was used to investigate the upper continental slope around 44 ON, 56 W, near the epicentre of the 1929 Grand Banks earthquake. Four dives in water depths of 800-2000 m were undertaken to observe speci3c features identijied with the SeaMARC I sidescan system in 1983. Two dives were made in the head of Eastern Valley where pebbly mudstones ofprobable Pleistocene age were recognized outcropping on the seafloor. Constructional features of cobbles and boulders, derived by exhumation and reworking of the pebbly mudstone, were also observed. These include gravel/sand bedforms (transverse waves) on the valley floor. Slope failure features in semiconsolidated mudstone were recognized on two dives onto the St. Pierre slope. Exposures in these mudstones are rapidly eroded by intense burrowing by benthic organisms

Harnessing autophagy to overcome mitogen‐activated protein kinase kinase inhibitor‐induced resistance in metastatic melanoma

Background Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogen‐activated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance. Objectives To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy. Methods Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinib‐induced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinib‐resistant melanoma cell survival and invasion, respectively. Results CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAF‐mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271‐expressing subpopulations. Trametinib‐induced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271‐expressing melanoma subpopulations with RNA interference and small‐molecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents – including Δ9‐tetrahydrocannabinol and Vps34 – reduced survival of MEKi‐resistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi‐resistant cells in an in vivo zebrafish xenograft. Conclusions These results highlight a novel mechanism of MEKi‐induced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drug‐resistant melanoma cells to the cytotoxic effects of MEKi

Tunable fishnet metamaterials infiltrated by liquid crystals

We analyze numerically the optical response and effective macroscopic parameters of fishnet metamaterials infiltrated with a nematic liquid crystal. We show that even a small amount of liquid crystal can provide tuning of the structures due to reorientation of the liquid crystal director. This enables switchable optical metamaterials, where the refractive index can be switched from positive to negative by an external field. This tuning is primarily determined by the shift of the cut-off wavelength of the holes, with only a small influence due to the change in plasmon dispersio

How the Proximal Pocket May Influence the Enantiospecificities of Chloroperoxidase-Catalyzed Epoxidations of Olefins

Chloroperoxidase-catalyzed enantiospecific epoxidations of olefins are of significant biotechnological interest. Typical enantiomeric excesses are in the range of 66%–97% and translate into free energy differences on the order of 1 kcal/mol. These differences are generally attributed to the effect of the distal pocket. In this paper, we show that the influence of the proximal pocket on the electron transfer mechanism in the rate-limiting event may be just as significant for a quantitatively accurate account of the experimentally-measured enantiospecificities