Investigation of hydrophobic moment and hydrophobicity properties for transmembrane α-helices

Integral membrane proteins are the primary targets of novel drugs but are largely without solved structures. As a consequence, hydrophobic moment plot methodology is often used to identify putative transmembrane α-helices of integral membrane proteins, based on their local maximum mean hydrophobic moment (<μH>) and the corresponding mean hydrophobicity (<H>). To calculate these properties, the methodology identifies an optimal eleven residue window (L = 11), assuming an amino acid angular frequency, θ, fixed at 100°. Using a data set of 403 transmembrane α-helix forming sequences, the relationship between <μH> and <H>, and the effect of varying of L and / or θ on this relationship, was investigated. Confidence intervals for correlations between <μH> and <H> are established. It is shown, using bootstrapping procedures that the strongest statistically significant correlations exist for small windows where 7 ≤ L ≤ 16. Monte Carlo analysis suggests that this correlation is dependent upon amino acid residue primary structure, implying biological function and indicating that smaller values of L give better characterisation of transmembrane sequences using <μH>. However, varying window size can also lead to different regions within a given sequence being identified as the optimal window for structure / function predictions. Furthermore, it is shown that optimal periodicity varies with window size; the optimum, based on <μH> over the range of window sizes, (7 ≤ L ≤ 16), was at θ = 102° for the transmembrane α-helix data set

Scaling laws and dynamics of bubble coalescence

The coalescence of bubbles and drops plays a central role in nature and industry. During coalescence, two bubbles or drops touch and merge into one as the neck connecting them grows from microscopic to macroscopic scales. The hydrodynamic singularity that arises when two bubbles or drops have just touched and the flows that ensue have been studied thoroughly when two drops coalesce in a dynamically passive outer fluid. In this paper, the coalescence of two identical and initially spherical bubbles, which are idealized as voids, that are surrounded by an incompressible Newtonian liquid is analyzed by numerical simulation. This problem has recently been studied (a) experimentally using high-speed imaging and (b) by asymptotic analysis in which the dynamics is analyzed by determining the growth of a hole in the thin liquid sheet separating the two bubbles. In the latter, advantage is taken of the fact that the flow in the thin sheet of non-constant thickness is governed by a set of one-dimensional, radial extensional flow equations. While these studies agree on the power law scaling of the variation of the minimum neck radius with time, they disagree with respect to the numerical value of the prefactors in the scaling laws. In order to reconcile these differences and also provide insights into the dynamics that are difficult to probe by either of the aforementioned approaches, simulations are used to access both earlier times than it has been possible in the experiments and also later times when asymptotic analysis is no longer applicable. Early times and extremely small length scales are attained in the new simulations through the use of a truncated domain approach. Furthermore, it is shown by direct numerical simulations in which the flow within the bubbles is also determined along with the flow exterior to them that idealizing the bubbles as passive voids has virtually no effect on the scaling laws relating minimum neck radius and time.This research was sponsored by the Petroleum Research Fund of the American Chemical Society, the Basic Energy Sciences Program of the United States Department of Energy, and the Engineering and Physical Sciences Research Council

Hospital case volume and outcomes for proximal femoral fractures in the USA: an observational study

Objective: To explore whether older adults with isolated hip fractures benefit from treatment in high-volume hospitals. Design: Population-based observational study. Setting: All acute hospitals in California, USA. Participants: All individuals aged >65 that underwent an operation for an isolated hip fracture in California between 2007 and 2011. Patients transferred between hospitals were excluded. Primary and secondary outcomes: Quality indicators (time to surgery) and patient outcomes (length of stay, in-hospital mortality, unplanned 30-day re-admission, and selected complications). Results: 91,401 individuals satisfied the inclusion criteria. Time to operation and length of stay were significantly prolonged in low volume hospitals, by 1.96 (95% CI 1.20-2.73) and 0.70 (0.38-1.03) days respectively. However, there were no differences in clinical outcomes, including in-hospital mortality, 30-day re-admission, and rates of pneumonia, pressure ulcers, and venous thromboembolism. Conclusion: These data suggest that there is no patient safety imperative to limit hip fracture care to high-volume hospitals

Low-temperature muon spin rotation studies of the monopole charges and currents in Y doped Ho2Ti2O7

In the ground state of Ho2Ti2O7 spin ice, the disorder of the magnetic moments follows the same rules as the proton disorder in water ice. Excitations take the form of magnetic monopoles that interact via a magnetic Coulomb interaction. Muon spin rotation has been used to probe the low-temperature magnetic behaviour in single crystal Ho2−xYxTi2O7 (x = 0, 0.1, 1, 1.6 and 2). At very low temperatures, a linear field dependence for the relaxation rate of the muon precession λ(B), that in some previous experiments on Dy2Ti2O7 spin ice has been associated with monopole currents, is observed in samples with x = 0, and 0.1. A signal from the magnetic fields penetrating into the silver sample plate due to the magnetization of the crystals is observed for all the samples containing Ho allowing us to study the unusual magnetic dynamics of Y doped spin ice

Cognitive loading affects motor awareness and movement kinematics but not locomotor trajectories during goal-directed walking in a virtual reality environment.

The primary purpose of this study was to investigate the effects of cognitive loading on movement kinematics and trajectory formation during goal-directed walking in a virtual reality (VR) environment. The secondary objective was to measure how participants corrected their trajectories for perturbed feedback and how participants' awareness of such perturbations changed under cognitive loading. We asked 14 healthy young adults to walk towards four different target locations in a VR environment while their movements were tracked and played back in real-time on a large projection screen. In 75% of all trials we introduced angular deviations of ±5° to ±30° between the veridical walking trajectory and the visual feedback. Participants performed a second experimental block under cognitive load (serial-7 subtraction, counter-balanced across participants). We measured walking kinematics (joint-angles, velocity profiles) and motor performance (end-point-compensation, trajectory-deviations). Motor awareness was determined by asking participants to rate the veracity of the feedback after every trial. In-line with previous findings in natural settings, participants displayed stereotypical walking trajectories in a VR environment. Our results extend these findings as they demonstrate that taxing cognitive resources did not affect trajectory formation and deviations although it interfered with the participants' movement kinematics, in particular walking velocity. Additionally, we report that motor awareness was selectively impaired by the secondary task in trials with high perceptual uncertainty. Compared with data on eye and arm movements our findings lend support to the hypothesis that the central nervous system (CNS) uses common mechanisms to govern goal-directed movements, including locomotion. We discuss our results with respect to the use of VR methods in gait control and rehabilitation

Towards high-speed optical quantum memories

Quantum memories, capable of controllably storing and releasing a photon, are a crucial component for quantum computers and quantum communications. So far, quantum memories have operated with bandwidths that limit data rates to MHz. Here we report the coherent storage and retrieval of sub-nanosecond low intensity light pulses with spectral bandwidths exceeding 1 GHz in cesium vapor. The novel memory interaction takes place via a far off-resonant two-photon transition in which the memory bandwidth is dynamically generated by a strong control field. This allows for an increase in data rates by a factor of almost 1000 compared to existing quantum memories. The memory works with a total efficiency of 15% and its coherence is demonstrated by directly interfering the stored and retrieved pulses. Coherence times in hot atomic vapors are on the order of microsecond - the expected storage time limit for this memory.Comment: 13 pages, 5 figure

A measure of individual role in collective dynamics

Identifying key players in collective dynamics remains a challenge in several research fields, from the efficient dissemination of ideas to drug target discovery in biomedical problems. The difficulty lies at several levels: how to single out the role of individual elements in such intermingled systems, or which is the best way to quantify their importance. Centrality measures describe a node's importance by its position in a network. The key issue obviated is that the contribution of a node to the collective behavior is not uniquely determined by the structure of the system but it is a result of the interplay between dynamics and network structure. We show that dynamical influence measures explicitly how strongly a node's dynamical state affects collective behavior. For critical spreading, dynamical influence targets nodes according to their spreading capabilities. For diffusive processes it quantifies how efficiently real systems may be controlled by manipulating a single node.Comment: accepted for publication in Scientific Report

Effects of beta-alanine supplementation on brain homocarnosine/carnosine signal and cognitive function: an exploratory study

Objectives: Two independent studies were conducted to examine the effects of 28 d of beta-alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2). Methods: In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sex-matched omnivores undertook a brain 1H-MRS exam at baseline and after beta-alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion. Results: In Study 1, there were no within-group effects of beta-alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P0.05) of beta-alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise. Conclusion: 28 d of beta-alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/ carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists

Disposition of Federally Owned Surpluses

PDZ domains are scaffolding modules in protein-protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to-ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to-ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein-protein interactions

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate