Properties of Transient K+ Currents and Underlying Single K+ Channels in Rat Olfactory Receptor Neurons

The transient potassium current, I(K)(t), of enzymatically dissociated rat olfactory receptor neurons was studied using patch-clamp techniques. Upon depolarization from negative holding potentials, I(K)(t) activated rapidly and then inactivated with a time course described by the sum of two exponential components with time constants of 22.4 and 143 ms. Single-channel analysis revealed a further small component with a time constant of several seconds. Steady-state inactivation was complete at -20 mV and completely removed at -80 mV (midpoint -45 mV). Activation was significant at -40 mV and appeared to reach a maximum conductance at +40 mV (midpoint -13 mV). Deactivation was described by the sum of two voltage-dependent exponential components. Recovery from inactivation was extraordinarily slow (50 s at -100 mV) and the underlying processes appeared complex. I(K)(t) was reduced by 4-aminopyridine and tetraethylammonium applied externally. Increasing the external K+ concentration ([K+]o) from 5 to 25 mM partially removed I(K)(t) inactivation, usually without affecting activation kinetics. The elevated [K+]o also hyperpolarized the steady-state inactivation curve by 9 mV and significantly depolarized the voltage dependence of activation. Single transient K+ channels, with conductances of 17 and 26 pS, were observed in excised patches and often appeared to be localized into large clusters. These channels were similar to I(K)(t) in their kinetic, pharmacological, and voltage-dependent properties and their inactivation was also subject to modulation by [K+]o. The properties of I(K)(t) imply a role in action potential repolarization and suggest it may also be important in modulating spike parameters during neuronal burst firing. A simple method is also presented to correct for errors in the measurement of whole-cell resistance (R(o)) that can result when patch-clamping very small cells. The analysis revealed a mean corrected R(o) of 26 G-OMEGA for these cells

Continuous Variable Quantum State Sharing via Quantum Disentanglement

Quantum state sharing is a protocol where perfect reconstruction of quantum states is achieved with incomplete or partial information in a multi-partite quantum networks. Quantum state sharing allows for secure communication in a quantum network where partial information is lost or acquired by malicious parties. This protocol utilizes entanglement for the secret state distribution, and a class of "quantum disentangling" protocols for the state reconstruction. We demonstrate a quantum state sharing protocol in which a tripartite entangled state is used to encode and distribute a secret state to three players. Any two of these players can collaborate to reconstruct the secret state, whilst individual players obtain no information. We investigate a number of quantum disentangling processes and experimentally demonstrate quantum state reconstruction using two of these protocols. We experimentally measure a fidelity, averaged over all reconstruction permutations, of F = 0.73. A result achievable only by using quantum resources.Comment: Published, Phys. Rev. A 71, 033814 (2005) (7 figures, 11 pages

Degradation of a quantum directional reference frame as a random walk

We investigate if the degradation of a quantum directional reference frame through repeated use can be modeled as a classical direction undergoing a random walk on a sphere. We demonstrate that the behaviour of the fidelity for a degrading quantum directional reference frame, defined as the average probability of correctly determining the orientation of a test system, can be fit precisely using such a model. Physically, the mechanism for the random walk is the uncontrollable back-action on the reference frame due to its use in a measurement of the direction of another system. However, we find that the magnitude of the step size of this random walk is not given by our classical model and must be determined from the full quantum description.Comment: 5 pages, no figures. Comments are welcome. v2: several changes to clarify the key results. v3: journal reference added, acknowledgements and references update

Relationship between outdoor temperature and cardiovascular disease risk factors in older people.

Background Previous studies demonstrated that lower outdoor temperatures increase the levels of established cardiovascular disease risk factors, such as blood pressure and lipids. Whether or not low temperatures increase novel cardiovascular disease risk factors levels is not well studied. The aim was to investigate associations of outdoor temperature with a comprehensive range of established and novel cardiovascular disease risk factors in two large Northern European studies of older adults, in whom cardiovascular disease risk is increased. Design and methods Data came from the British Regional Heart Study (4252 men aged 60-79 years) and the Prospective Study of Pravastatin in the Elderly at Risk (5804 men and women aged 70-82 years). Associations between outdoor temperature and cardiovascular disease risk factors were quantified in each study and then pooled using a random effects model. Results With a 5℃ lower mean temperature, total cholesterol was 0.04 mmol/l (95% confidence interval (CI) 0.02-0.07) higher, low density lipoprotein cholesterol was 0.02 mmol/l (95% CI 0.01-0.05) higher and SBP was 1.12 mm Hg (95% CI 0.60-1.64) higher. Among novel cardiovascular disease risk factors, C-reactive protein was 3.3% (95% CI 1.0-5.6%) higher, interleukin-6 was 2.7% (95% CI 1.1-4.3%) higher, and vitamin D was 11.2% (95% CI 1.0-20.4%) lower. Conclusions Lower outdoor temperature was associated with adverse effects on cholesterol, blood pressure, circulating inflammatory markers, and vitamin D in two older populations. Public health approaches to protect the elderly against low temperatures could help in reducing the levels of several cardiovascular disease risk factors

A rainfall model for drought risk analysis in south-east UK

Drought risk assessment ideally requires long-term rainfall records especially where inter-annual droughts are of potential concern, and spatially consistent estimates of rainfall to support regional and inter-regional scale assessments. This paper addresses these challenges by developing a spatially consistent stochastic model of monthly rainfall for south-east UK. Conditioned on 50 gauged sites, the model infills the historic record from 1855-2011 in both space and time, and extends the record by synthesising droughts which are consistent with the observed rainfall statistics. The long record length allows more insight into the variability of rainfall and potentially a stronger basis for risk assessment than is generally possible. It is shown that, although localised biases exist in both space and time, the model results are generally consistent with the observed record including for a range of inter-annual droughts and spatial statistics. Simulations show that some of the most severe inter-annual droughts on the record may recur, despite a trend towards generally wetter winters

Combinations of β-lactam or aminoglycoside antibiotics with plectasin are synergistic against methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and the latter can be difficult to treat. The traditional strategy of novel therapeutic drug development inevitably leads to emergence of resistant strains, rendering the new drugs ineffective. Therefore, rejuvenating the therapeutic potentials of existing antibiotics offers an attractive novel strategy. Plectasin, a defensin antimicrobial peptide, potentiates the activities of other antibiotics such as β-lactams, aminoglycosides and glycopeptides against MSSA and MRSA. We performed in vitro and in vivo investigations to test against genetically diverse clinical isolates of MSSA (n = 101) and MRSA (n = 115). Minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The effects of combining plectasin with β-lactams, aminoglycosides and glycopeptides were examined using the chequerboard method and time kill curves. A murine neutropenic thigh model and a murine peritoneal infection model were used to test the effect of combination in vivo. Determined by factional inhibitory concentration index (FICI), plectasin in combination with aminoglycosides (gentamicin, neomycin or amikacin) displayed synergistic effects in 76-78% of MSSA and MRSA. A similar synergistic response was observed when plectasin was combined with β-lactams (penicillin, amoxicillin or flucloxacillin) in 87-89% of MSSA and MRSA. Interestingly, no such interaction was observed when plectasin was paired with vancomycin. Time kill analysis also demonstrated significant synergistic activities when plectasin was combined with amoxicillin, gentamicin or neomycin. In the murine models, plectasin at doses as low as 8 mg/kg augmented the activities of amoxicillin and gentamicin in successful treatment of MSSA and MRSA infections. We demonstrated that plectasin strongly rejuvenates the therapeutic potencies of existing antibiotics in vitro and in vivo. This is a novel strategy that can have major clinical implications in our fight against bacterial infections

Accessibility Validation with RAVEN

ABSTRACT Testing is, for most, a necessary evil in the software life cycle. One very important form of testing is the evaluation of software products according to mandated criteria or guidelines such as those that specify level of accessibility. Such evaluations can be quite tedious, especially if they must be done manually and applied consistently to each and every component of an application. The use of assistive technologies like screen readers to demonstrate the compliance of a software product to a set of regulations is time-consuming, error-prone, and expensive. Validation tools that can perform such evaluations are becoming more popular as integrated development environments become more sophisticated but, in the area of accessibility validation, they are sorely lacking if not nonexistent. This paper introduces the IBM Rule-based Accessibility Validation Environment, an Eclipse-based tool for inspecting and validating Java rich-client GUIs for accessibility using non-invasive, semi-to fullyautomatic, rule-based validation and inspection

Effects of Hydrogen Peroxide on Wound Healing in Mice in Relation to Oxidative Damage

10.1371/journal.pone.0049215PLoS ONE711

Homo-PROTACs:bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for 'proteolysis-targeting chimeras'). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation

The ‘Biophilic Organization’: An Integrative Metaphor for Corporate Sustainability

This paper proposes a new organizational metaphor, the ‘Biophilic Organization’, which aims to counter the bio-cultural disconnection of many organizations despite their espoused commitment to sustainability. This conceptual research draws on multiple disciplines such as evolutionary psychology and architecture to not only develop a diverse bio-cultural connection but to show how this connection tackles sustainability, in a holistic and systemic sense. Moreover, the paper takes an integrative view of sustainability, which effectively means that it embraces the different emergent tensions. Three specific tensions are explored: efficiency versus resilience, organizational versus personal agendas and isomorphism versus institutional change. In order to illustrate how the Biophilic Organization could potentially provide a synthesis strategy for such tensions, healthcare examples are drawn from the emerging fields of Biophilic Design in Singapore and Generative Design in the U.S.A. Finally, an example is provided which highlights how a Taoist cultural context has impacted on a business leader in China, to illustrative the significance of a transcendent belief system to such a bio-cultural narrative