The charybdotoxin receptor of a Shaker K+ channel: peptide and channel residues mediating molecular recognition.

Charybdotoxin (CTX) is a peptide of known structure that inhibits Shaker K+ channels by a pore-blocking mechanism. Point mutagenesis of all 30 solvent-exposed residues identified the part of the CTX molecular surface making contact with the receptor in the K+ channel. All close-contact residues are clustered in a well-defined interaction surface; the shape of this surface implies that the outer opening of the Shaker channel conduction pore abruptly widens to a 25 x 35 A plateau. A mutagenic scan of the S5-S6 linker sequence of the Shaker K+ channel identified those channel residues influencing CTX binding affinity. The Shaker residues making the strongest contribution to toxin binding are located close to the pore-lining sequence, and more distant residues on both sides of this region influence CTX binding weakly, probably by an electrostatic mechanism. Complementary mutagenesis of both CTX and Shaker suggests that Shaker-F425 contacts a specific area near T8 and T9 on the CTX molecular surface. This contact point constrains Shaker-F425 to be located at a 20 A radial distance from the pore axis and 10-15 A above the "floor" of the CTX receptor

Weight management: a comparison of existing dietary approaches in a work-site setting

<b>OBJECTIVES:</b> (1) To compare the effectiveness a 2512 kJ (600 kcal) daily energy deficit diet (ED) with a 6279 kJ (1500 kcal) generalized low-calorie diet (GLC) over a 24 week period (12 weeks weight loss plus 12 weeks weight maintenance). (2) To determine if the inclusion of lean red meat at least five times per week as part of a slimming diet is compatible with weight loss in comparison with a diet that excludes lean red meat. DESIGN: Randomized controlled trial. <b>SETTING:</b> Large petrochemical work-site. <b>PARTICIPANTS:</b> One-hundred and twenty-two men aged between 18 and 55 y. <b>MAIN OUTCOME MEASURES:</b> Weight loss and maintenance of weight loss. <b>INTERVENTION:</b> Eligible volunteers were randomized to one of the four diet=meat combinations (ED meat, ED no meat, GLC meat, GLC no meat). One-third of subjects in each diet/meat combination were randomized to an initial control period prior to receiving dietary advice. All subjects attended for review every 2 weeks during the weight loss period. For the 12 week structured weight maintenance phase, individualized energy prescriptions were re-calculated for the ED group as 1.4 (activity factor)x basal metabolic rate. Healthy eating advice was reviewed with subjects in the GLC group. All subjects were contacted by electronic mail at 2 week intervals and anthropometric and dietary information requested. <b>RESULTS:</b> No difference was evident between diet groups in mean weight loss at 12 weeks (4.3 (s.d. 3.4) kg ED group vs 5.0 (s.d. 3.5) kg GLC group, P=0.34). Mean weight loss was closer to the intended weight loss in the 2512 kJ (600 kcal) ED group. The dropout rate was also lower than the GLC group. The inclusion of lean red meat in the diet on at least five occasions per week did not impair weight loss. Mean weight gain following 12 weeks weight maintenance was þ1.1 (s.d. 1.8) kg, P<0.0001. No differences were found between groups. <b>CONCLUSIONS:</b> This study has shown that the individualized 2512 kJ (600 kcal) ED approach was no more effective in terms of weight loss than the 6279 kJ (1500 kcal) GLC approach. However the ED approach might be considered preferable as compliance was better with this less demanding prescription. In terms of weight loss the elimination of red meat from the diet is unnecessary. The weight maintenance intervention was designed as a low-input approach, however weight regain was significant and weight maintenance strategies require further development

The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page

Solar wind interaction with comet 67P: impacts of corotating interaction regions

International audienceWe present observations from the Rosetta Plasma Consortium of the effects of stormy solar wind on comet 67P/Churyumov-Gerasimenko. Four corotating interaction regions (CIRs), where the first event has possibly merged with a coronal mass ejection, are traced from Earth via Mars (using Mars Express and Mars Atmosphere and Volatile EvolutioN mission) to comet 67P from October to December 2014. When the comet is 3.1–2.7 AU from the Sun and the neutral outgassing rate ∼1025–1026 s−1, the CIRs significantly influence the cometary plasma environment at altitudes down to 10–30 km. The ionospheric low-energy (∼5 eV) plasma density increases significantly in all events, by a factor of >2 in events 1 and 2 but less in events 3 and 4. The spacecraft potential drops below −20 V upon impact when the flux of electrons increases. The increased density is likely caused by compression of the plasma environment, increased particle impact ionization, and possibly charge exchange processes and acceleration of mass-loaded plasma back to the comet ionosphere. During all events, the fluxes of suprathermal (∼10–100 eV) electrons increase significantly, suggesting that the heating mechanism of these electrons is coupled to the solar wind energy input. At impact the magnetic field strength in the coma increases by a factor of 2–5 as more interplanetary magnetic field piles up around the comet. During two CIR impact events, we observe possible plasma boundaries forming, or moving past Rosetta, as the strong solar wind compresses the cometary plasma environment. We also discuss the possibility of seeing some signatures of the ionospheric response to tail disconnection events

Analytical method for perturbed frozen orbit around an Asteroid in highly inhomogeneous gravitational fields : A first approach

This article provides a method for nding initial conditions for perturbed frozen orbits around inhomogeneous fast rotating asteroids. These orbits can be used as reference trajectories in missions that require close inspection of any rigid body. The generalized perturbative procedure followed exploits the analytical methods of relegation of the argument of node and Delaunay normalisation to arbitrary order. These analytical methods are extremely powerful but highly computational. The gravitational potential of the heterogeneous body is rstly stated, in polar-nodal coordinates, which takes into account the coecients of the spherical harmonics up to an arbitrary order. Through the relegation of the argument of node and the Delaunay normalization, a series of canonical transformations of coordinates is found, which reduces the Hamiltonian describing the system to a integrable, two degrees of freedom Hamiltonian plus a truncated reminder of higher order. Setting eccentricity, argument of pericenter and inclination of the orbit of the truncated system to be constant, initial conditions are found, which evolve into frozen orbits for the truncated system. Using the same initial conditions yields perturbed frozen orbits for the full system, whose perturbation decreases with the consideration of arbitrary homologic equations in the relegation and normalization procedures. Such procedure can be automated for the first homologic equation up to the consideration of any arbitrary number of spherical harmonics coefficients. The project has been developed in collaboration with the European Space Agency (ESA)

The environmental impact of climate change adaptation on land use and water quality

Encouraging adaptation is an essential aspect of the policy response to climate change1. Adaptation seeks to reduce the harmful consequences and harness any beneficial opportunities arising from the changing climate. However, given that human activities are the main cause of environmental transformations worldwide2, it follows that adaptation itself also has the potential to generate further pressures, creating new threats for both local and global ecosystems. From this perspective, policies designed to encourage adaptation may conflict with regulation aimed at preserving or enhancing environmental quality. This aspect of adaptation has received relatively little consideration in either policy design or academic debate. To highlight this issue, we analyse the trade-offs between two fundamental ecosystem services that will be impacted by climate change: provisioning services derived from agriculture and regulating services in the form of freshwater quality. Results indicate that climate adaptation in the farming sector will generate fundamental changes in river water quality. In some areas, policies that encourage adaptation are expected to be in conflict with existing regulations aimed at improving freshwater ecosystems. These findings illustrate the importance of anticipating the wider impacts of human adaptation to climate change when designing environmental policies

Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

Objective: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and investigate factors which increase diagnostic yield. Design: Retrospective analysis of data from two prospective cohort studies. Setting: Fetal medicine centres in the UK and USA. Population: Fetuses with increased NT ≥3.5mm at 11-14 weeks’ gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal WES studies (n = 213). Methods: We grouped cases based on (i) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (ii) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. Main Outcome Measures: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. Results: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. Conclusions: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis