identifying allosteric networks to fight antibiotics resistance

The rise of multi-drug resistance in bacterial pathogens is one of the grand challenges facing medical science. A major concern is the speed of development of β-lactamase-mediated resistance in Gram-negative species, thus putting at risk the efficacy of the most recently approved antibiotics and inhibitors, including carbapenems and avibactam, respectively. New strategies to overcome resistance are urgently required, which will ultimately be facilitated by a deeper understanding of the mechanisms that regulate the function of β-lactamases such as the Klebsiella Pneumoniae carbapenemases (KPCs). Using enhanced sampling computational methods together with site-directed mutagenesis, we report the identification of two “hydrophobic networks” in the KPC-2 enzyme, the integrity of which has been found to be essential for protein stability and corresponding resistance. Present throughout the structure, these networks are responsible for the structural integrity and allosteric signaling. Disruption of the networks leads to a loss of the KPC-2 mediated resistance phenotype, resulting in restored susceptibility to different classes of β-lactam antibiotics including carbapenems and cephalosporins. The ”hydrophobic networks” were found to be highly conserved among class-A β-lactamases, which implies their suitability for exploitation as a potential target for therapeutic intervention

Timing of detachment faulting in the Bullfrog Hills and Bare Mountain area, southwest Nevada: Inferences from 40Ar/39Ar, K-Ar, U-Pb and fission track thermochronology

Crustal extension in the Bullfrog Hills and Bare Mountain area of southwest Nevada is associated with movement along a regional detachment fault. Normal faulting in the upper plate and rapid cooling (denudation) of the lower plate were coeval with Miocene silicic volcanism and with west-northwest transport along the detachment fault. A west-northwest progression of tilting along upper plate normal faults is indicated by ages of the volcanic rocks in relation to angular unconformities. Near the breakaway, tilting in the upper plate occurred between 12.7 and 11.6 Ma, continued less strongly past 10.7 Ma, and was over by 8.2 Ma. Ten to 20 km west of the breakaway, tilting occurred between 10.7 and 10.33 Ma, continued less strongly after 10.33 Ma, and was over by 8.1 Ma. The cooling histories of the lower plate metamorphic rocks were determined by thermochronologic dating methods: K-Ar and Ar-40/(39)A on muscovite, biotite, and hornblende, Ar-40/(39)A on K-feldspar, U-Pb on apatite, zircon, and sphene, and fission track on apatite, zircon, and sphene. Lower plate rocks 10 km west of the breakaway cooled slowly from Early Cretaceous lower-amphibolite facies conditions through 350+/-50 degrees to 300+/-50 degrees C between 57 and 38 Ma, then cooled rapidly from 205+/-50 degrees to 120+/-5O degrees C between 12.6+/-1.6 and 11.1+/-1.9 Ma. Lower plate rocks 20 km west of the breakaway cooled slowly from Early Cretaceous upper-amphibolite facies conditions through 500+/-50 degrees C at 78-67 Ma, passed through 350+/-50 degrees to 300+/-50 degrees C between 16.3+/-0.4 and 10.5+/-0.3 Ma, then cooled rapidly from 285+/-50 degrees to 120+/-50 degrees C between 10.2 and 8.6 Ma. Upper plate tilting and rapid cooling (denudation) of the lower plate occurred simultaneously in the respective areas. The early slow-cooling part of the lower plate thermal histories was probably related to erosion at the Earth's surface, which stripped off about 9 km of material in 50 to 100 m.y. The results indicate an initial fault dip greater than or equal to 30 degrees and a 12 mm yr(-1) west-northwest migration of the locus of rapid tilting in the upper plate

Neutron reflection study of the adsorption of the phosphate surfactant NaDEHP onto alumina from water.

The adsorption of a phosphorus analogue of the surfactant AOT, sodium bis(2-ethylhexyl) phosphate (NaDEHP), at the water/alumina interface is described. The material is found to adsorb as an essentially water-free bilayer from neutron reflection measurements. This is similar to the behavior of AOT under comparable conditions, although AOT forms a thicker, more hydrated layer. The NaDEHP shows rather little variation with added salt, but a small thickening of the layer on increasing the pH, in contrast to the behavior of AOT.We thank BP plc and EPSRC for financial support for this work as well as the ISIS and ILL staff and scientists for the allocation of beam time and technical assistance with NR measurements. We also appreciate Chris Sporikou at Department of Chemistry, University of Cambridge, for help with the surfactant synthesis.This is the final version of the article. It first appeared at http://dx.doi.org/10.1021/la504837

Theoretical Criteria for Scattering Dark States in Nanostructured Particles

Nanostructures with multiple resonances can exhibit a suppressed or even completely eliminated scattering of light, called a scattering dark state. We describe this phenomenon with a general treatment of light scattering from a multiresonant nanostructure that is spherical or nonspherical but subwavelength in size. With multiple resonances in the same channel (i.e., same angular momentum and polarization), coherent interference always leads to scattering dark states in the low-absorption limit, regardless of the system details. The coupling between resonances is inevitable and can be interpreted as arising from far-field or near-field. This is a realization of coupled-resonator-induced transparency in the context of light scattering, which is related to but different from Fano resonances. Explicit examples are given to illustrate these concepts.Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Contract W911NF-13-D-0001)National Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (Grant DMR-0819762

Life cycle assessment of a renewable energy system with hydrogen-battery storage for a remote off-grid community

Remote areas usually do not have access to electricity from the national grid. The energy demand is often covered by diesel generators, resulting in high operating costs and significant environmental impacts. With reference to the case study of Ginostra (a village on a small island in the south of Italy), this paper analyses the environmental sustainability of an innovative solution based on Renewable Energy Sources (RES) integrated with a hybrid hydrogen-battery energy storage system. A comparative Life Cycle Assessment (LCA) has been carried out to evaluate if and to what extent the RES-based system could bring environmental improvements compared to the current diesel-based configuration. The results show that the impact of the RES-based system is less than 10% of that of the current diesel-based solution for almost all impact categories (climate change, ozone depletion, photochemical ozone formation, acidification, marine and terrestrial eutrophication and fossil resource use). The renewable solution has slightly higher values only for the following indicators: use of mineral and metal resources, water use and freshwater eutrophication. The climate change category accounts for 0.197 kg CO2 eq./kWh in the renewable scenario and 1.73 kg CO2 eq./kWh in the diesel-based scenario, which corresponds to a reduction in GHG emissions of 89%. By shifting to the RES-based solution, about 6570 t of CO2 equivalent can be saved in 25 years (lifetime of the plant). In conclusion, the hydrogen-battery system could provide a sustainable and reliable alternative for power supply in remote areas

The physiological responses of cacao to the environment and the implications for climate change resilience. A review

Cacao (Theobroma cacao L.) is a tropical perennial crop which is of great economic importance to the confectionary industry and to the economies of many countries of the humid tropics where it is grown. Some recent studies have suggested climate change could severely impact cacao production in West Africa. It is essential to incorporate our understanding of the physiology and genetic variation within cacao germplasm when discussing the implications of climate change on cacao productivity and developing strategies for climate resilience in cacao production. Here we review the current research on the physiological responses of cacao to various climate factors. Our main findings are 1) water limitation causes significant yield reduction in cacao but genotypic variation in sensitivity is evident, 2) in the field cacao experiences higher temperatures than is often reported in the literature, 3) the complexity of the cacao/ shade tree interaction can lead to contradictory results, 4) elevated CO2 may alleviate some negative effects of climate change 5) implementation of mitigation strategies can help reduce environmental stress, 6) significant gaps in the research need addressing to accelerate the development of climate resilience. Harnessing the significant genetic variation apparent within cacao germplasm is essential to develop modern varieties capable of high yields in non-optimal conditions. Mitigation strategies will also be essential but to use shading to best effect shade tree selection is crucial to avoid resource competition. Cacao is often described as being sensitive to climate change but genetic variation, adaptive responses, appropriate mitigation strategies and interactive climate effects should all be considered when predicting the future of cacao production. Incorporating these physiological responses to various environmental conditions and developing a deeper understanding of the processes underlying these responses will help to accelerate the development of a more resource use efficient tree ensuring sustainable production into the future