Enantioselective silyl protection of alcohols catalysed by an amino-acid-based small molecule

Reliable, selective and environmentally friendly chemical transformations are crucial to the development of new therapeutics and the design of novel materials. Chiral catalysts that can be easily prepared and used to obtain organic molecules of high enantiomeric purity are critical to modern chemical synthesis. The development of protecting groups that shield reactive functionalities has also proved indispensable in the preparation of complex biologically active molecules. Here we present a chiral catalyst that promotes the enantioselective protection of a secondary alcohol as one of the most commonly used protected forms of an alcohol: a silyl ether. The catalyst is a small, simple molecule that can be prepared in three steps from commercial materials without the need for rigorously controlled conditions. Enantioselective silylations are performed with commercial silyl chlorides and produce yields of up to 96 per cent at an enantiomeric ratio of up to 98:2. Chiral catalysts for selective formation of commonly used protecting groups such as silyl ethers should significantly enhance the ability of chemical synthesis to deliver, in a more practical and efficient manner, important organic molecules.     

Catestatin, an endogenous Chromogranin A-derived peptide, inhibits in vitro growth of Plasmodium falciparum

Catestatin, an endogenous peptide derived from bovine chromogranin A, and its active domain cateslytin display powerful antimicrobial activities. We have tested the activities of catestatin and other related peptides on the growth of Plasmodium falciparum in vitro. Catestatin inhibits growth of the chloroquine-sensitive strain of P. falciparum 3D7, exhibiting 88% inhibition at 20 μM. A similar partial inhibition of parasite growth was observed for the chloroquine-resistant strain, 7G8 (64%,) and the multidrug-resistant strain, W2 (62%). In the presence of parasite-specific lactate dehydrogenase, a specific protein–protein interaction between catestatin and plasmepsin II precursor was demonstrated. In addition, catestatin partially inhibited the parasite-specific proteases plasmepsin in vitro. A specific interaction between catestatin and plasmepsins II and IV from P. falciparum and plasmepsin IV from the three remaining species of Plasmodium known to infect man was observed, suggesting a catestatin-induced reduction in availability of nutrients for protein synthesis in the parasite.     

Single-spin addressing in an atomic Mott insulator

Ultracold atoms in optical lattices provide a versatile tool with which to investigate fundamental properties of quantum many-body systems. In particular, the high degree of control of experimental parameters has allowed the study of many interesting phenomena, such as quantum phase transitions and quantum spin dynamics. Here we demonstrate how such control can be implemented at the most fundamental level of a single spin at a specific site of an optical lattice. Using a tightly focused laser beam together with a microwave field, we were able to flip the spin of individual atoms in a Mott insulator with sub-diffraction-limited resolution, well below the lattice spacing. The Mott insulator provided us with a large two-dimensional array of perfectly arranged atoms, in which we created arbitrary spin patterns by sequentially addressing selected lattice sites after freezing out the atom distribution. We directly monitored the tunnelling quantum dynamics of single atoms in the lattice prepared along a single line, and observed that our addressing scheme leaves the atoms in the motional ground state. The results should enable studies of entropy transport and the quantum dynamics of spin impurities, the implementation of novel cooling schemes, and the engineering of quantum many-body phases and various quantum information processing applications.     

Single mimivirus particles intercepted and imaged with an X-ray laser

X-ray lasers offer new capabilities in understanding the structure of biological systems, complex materials and matter under extreme conditions. Very short and extremely bright, coherent X-ray pulses can be used to outrun key damage processes and obtain a single diffraction pattern from a large macromolecule, a virus or a cell before the sample explodes and turns into plasma. The continuous diffraction pattern of non-crystalline objects permits oversampling and direct phase retrieval. Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source. Calculations indicate that the energy deposited into the virus by the pulse heated the particle to over 100,000?K after the pulse had left the sample. The reconstructed exit wavefront (image) yielded 32-nm full-period resolution in a single exposure and showed no measurable damage. The reconstruction indicates inhomogeneous arrangement of dense material inside the virion. We expect that significantly higher resolutions will be achieved in such experiments with shorter and brighter photon pulses focused to a smaller area. The resolution in such experiments can be further extended for samples available in multiple identical copies.     

Dispersal characteristics of the yucca weevil ( Scyphophorus yuccae ) in a flowering field of Yucca whipplei

Dispersal characteristics were measured for a population of yucca weevils ( Scyphophorus yuccae ) in a plot consisting of flowering and nonflowering Yucca whipplei . We compared weevil dispersal to yucca distribution, pheonolgy, and caudex temperature. We also compared weevil movement to wind patterns and time of day. Captured weevils were marked and released into both flowering and nonflowering home plants in the field. Distance traveled, weevil flight direction, and target plant characteristics were recorded. We found that yucca weevils moved only between 1600 h on the release day and 0600 h of the following day. We recorded movement from both nonflowering and old flowering (> 1/2 stalk had reached anthesis) yuccas to new flowering (> 1/2 stalk pre-anthesis) yuccas. The pattern of weevil movement did not match the pattern of flowering yuccas in the field. Yucca weevils moved a mean distance of 33 ± 8 m. Caudex temperature appeared to be important to maintain a population of weevils on a plant. Wind direction was the best predictor of weevil dispersal direction. Weevils consistently moved into the wind, suggesting that they are active fliers. Dispersal characteristics of the yucca weevil have implications for the evolution of the semelparous flowering strategy of Y. whipplei and S. yuccae life history.     

Post-breeding season movements of Columbia spotted frogs ( Rana luteiventris ) in northeastern Oregon

Movements of Columbia spotted frogs ( Rana luteiventris ) were determined after breeding to provide managers with information on habitat requirements. We radio-tagged 47 adults and observed movements occurring with 22 frogs. Eleven frogs remained in breeding ponds, and 11 moved to other ponds or river stretches during spring and summer 1998. Distances frogs traveled to other water bodies ranged from 15 to 560 m. Movements appeared to be influenced by availability of habitat and aquatic conditions. Eleven of 16 frogs located within 100 m of other permanent water sources moved, while no frogs at an isolated breeding pond moved. Frogs moved to river stretches in July where water temperatures averaged 5.6 ° C cooler than ponds. Knowledge of Columbia spotted frog movements and habitat use in summer enables land managers to make decisions on activities that affect aquatic sites, vegetation, and stream structures that may influence frog populations.     

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ～600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.