K Channel Subconductance Levels Result from Heteromeric Pore Conformations

Voltage-gated K channels assemble from four identical subunits symmetrically arranged around a central permeation pathway. Each subunit harbors a voltage-sensing domain. The sigmoidal nature of the activation kinetics suggests that multiple sensors need to undergo a conformational change before the channel can open. Following activation, individual K channels alternate stochastically between two main permeation states, open and closed. This binary character of single channel behavior suggests the presence of a structure in the permeation pathway that can exist in only two conformations. However, single channel analysis of drk1 (Kv2.1) K channels demonstrated the existence of four additional, intermediate conductance levels. These short-lived subconductance levels are visited when the channel gate moves between the closed and fully open state. We have proposed that these sublevels arise from transient heteromeric pore conformations, in which some, but not all, subunits are in the “open” state. A minimal model based on this hypothesis relates specific subconductance states with the number of activated subunits (Chapman et al., 1997). To stringently test this hypothesis, we constructed a tandem dimer that links two K channel subunits with different activation thresholds. Activation of this dimer by strong depolarizations resulted in the characteristic binary open–close behavior. However, depolarizations to membrane potentials in between the activation thresholds of the two parents elicited highly unusual single channel gating, displaying frequent visits to two subconductance levels. The voltage dependence and kinetics of the small and large sublevels associate them with the activation of one and two subunits, respectively. The data therefore support the hypothesis that subconductance levels result from heteromeric pore conformations. In this model, both sensor movement and channel opening have a subunit basis and these processes are allosterically coupled

Controls on the 87Sr/86Sr ratios of carbonates in the Garhwal Himalaya, Headwaters of the Ganges

The episodic variation of the seawater 87Sr/86Sr ratio has been attributed to either variations in the Sr flux or the Sr-isotopic composition of the riverine-dissolved load derived from weathering of the continental crust. The discovery that Himalayan rivers are characterized by high concentrations of dissolved Sr concentrations with high 87Sr/86Sr ratios has raised the possibility that collisional orogens play a critical role in moderating the variations in seawater 87Sr/86Sr ratios. Here we describe Himalayan carbonates and calc-silicates from Garhwal, the headwaters of the Ganges, with extreme 87Sr/86Sr ratios (>1.0). Elevated Sr-isotope ratios result from exchange with Rb-rich silicate material during both Himalayan and pre-Himalayan metamorphic episodes, and the carbonates contribute a significant fraction to the Ganges 87Sr flux. Particularly elevated 87Sr/86Sr ratios are found in calc-silicates from the Deoban Formation of the Lesser Himalaya. A detailed traverse of shales and calc-silicates from this unit confirms that carbonate horizons have increased 87Sr/86Sr ratios as a result of isotopic exchange over length scales of 1030 cm. We conclude that metamorphism of carbonates may cause elevation of their 87Sr/86Sr ratios and that uplift of metamorphosed carbonates may be a consequence of collisional orogens, which contributes to the elevation of seawater 87Sr/86Sr ratios

On the nature of the short duration GRB 050906

The definitive version is available at www.blackwell-synergy.com. Copyright Blackwell Publishing DOI : 10.1111/j.1365-2966.2007.11953.xPeer reviewe

Transcriptional regulation of the urokinase receptor (u-PAR) - A central molecule of invasion and metastasis

The phenomenon of tumor-associated proteolysis has been acknowledged as a decisive step in the progression of cancer. This short review focuses on the urokinase receptor (u-PAR), a central molecule involved in tumor-associated invasion and metastasis, and summarizes the transcriptional regulation of u-PAR. The urokinase receptor (u-PAR) is a heavily glycosylated cell surface protein and binds the serine protease urokinase specifically and with high affinity. It consists of three similar cysteine-rich repeats and is anchored to the cell membrane via a GPI-anchor. The u-PAR gene comprises 7 exons and is located on chromosome 19q13. Transcriptional activation of the u-PAR promoter region can be induced by binding of transcription factors (Sp1, AP-1, AP-2, NF-kappaB). One current study gives an example for transcriptional downregulation of u-PAR through a PEA3/ets transcriptional silencing element. Knowledge of the molecular regulation of this molecule in tumor cells could be very important for diagnosis and therapy in the near future

A scoping review of use of wearable devices to evaluate outcomes in survivors of critical illness

Objective: Wearable devices using new technology may be a cost-effective method to assess functional outcomes in survivors of critical illness. Our primary objective was to review the extent to which wearable devices such as smartphones, pedometers, accelerometers and global positioning systems have been used to evaluate outcomes in survivors of an intensive care unit admission. Design: We included studies of patients surviving an ICU admission and which measured outcomes using wearable devices. We performed a scoping review of studies found by searching the CINAHL, Embase, MEDLINE and PubMed databases. Results: The seven studies we identifi ed were published in or after 2012 and were predominantly descriptive (n = 6) with one randomised controlled trial. All studies described outcomes in cohorts of relatively few participants (range, 11–51 participants). Duration to follow-up was mostly short, at a median time of 3 months after ICU discharge (range, in-hospital to 27 years). All studies used accelerometers to monitor patient movement: physical activity (n = 5), sleep quality (n = 1), and infant movement (n = 1). The accelerometers were bi-axial (n = 3), uni-axial (n = 2) combined uni-axial (n = 1) and tri-axial (n = 1). Common outcomes evaluated were the number of participants walking for < 30 min/day, mean daily step count and walking speed. Conclusions: Wearable devices have infrequently been used to measure physical activity in survivors of critical illness and all identifi ed studies were published recently, which suggests that the use of wearable devices for research may be increasing. To date, only accelerometry has been reported, and the wide variation in methodologies used and the outcomes measured limits synthesis of these data.Samuel Gluck, Lee-anne S Chapple, Marianne J Chapman, Theodore J Iwashyna and Adam M Dean

Manganese-enhanced magnetic resonance imaging depicts brain activity in models of acute and chronic pain: a new window to study experimental spontaneous pain?

Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10 µg/50 µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1 mg/50 µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7 T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72 mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5 g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats

Reduced models for ETG transport in the pedestal

This paper reports on the development of reduced models for electron temperature gradient (ETG) driven transport in the pedestal. Model development is enabled by a set of 61 nonlinear gyrokinetic simulations with input parameters taken from the pedestals in a broad range of experimental scenarios. The simulation data has been consolidated in a new database for gyrokinetic simulation data, the Multiscale Gyrokinetic Database (MGKDB), facilitating the analysis. The modeling approach may be considered a generalization of the standard quasilinear mixing length procedure. The parameter η, the ratio of the density to temperature gradient scale length, emerges as the key parameter for formulating an effective saturation rule. With a single order-unity fitting coefficient, the model achieves an RMS error of 15%. A similar model for ETG particle flux is also described. We also present simple algebraic expressions for the transport informed by an algorithm for symbolic regression.</p

Being relevant: Practical guidance for early career researchers interested in solving conservation problems

AbstractIn a human-altered world where biodiversity is in decline and conservation problems abound, there is a dire need to ensure that the next generation of conservation scientists have the knowledge, skills, and training to address these problems. So called “early career researchers” (ECRs) in conservation science have many challenges before them and it is clear that the status quo must change to bridge the knowledge–action divide. Here we identify thirteen practical strategies that ECRs can employ to become more relevant. In this context, “relevance” refers to the ability to contribute to solving conservation problems through engagement with practitioners, policy makers, and stakeholders. Conservation and career strategies outlined in this article include the following: thinking ‘big picture’ during conservation projects; embracing various forms of knowledge; maintaining positive relationships with locals familiar with the conservation issue; accepting failure as a viable (and potentially valuable) outcome; daring to be creative; embracing citizen science; incorporating interdisciplinarity; promoting and practicing pro-environmental behaviours; understanding financial aspects of conservation; forming collaboration from the onset of a project; accepting the limits of technology; ongoing and effective networking; and finally, maintaining a positive outlook by focusing on and sharing conservation success stories. These strategies move beyond the generic and highlight the importance of continuing to have an open mind throughout the entire conservation process, from establishing one’s self as an asset to embracing collaboration and interdisciplinary work, and striving to push for professional and personal connections that strengthen personal career objectives

Negatively Charged Excitons and Photoluminescence in Asymmetric Quantum Well

We study photoluminescence (PL) of charged excitons ($X^-$) in narrow asymmetric quantum wells in high magnetic fields B. The binding of all $X^-$ states strongly depends on the separation $\delta$ of electron and hole layers. The most sensitive is the ``bright'' singlet, whose binding energy decreases quickly with increasing $\delta$ even at relatively small B. As a result, the value of B at which the singlet--triplet crossing occurs in the $X^-$ spectrum also depends on $\delta$ and decreases from 35 T in a symmetric 10 nm GaAs well to 16 T for $\delta=0.5$ nm. Since the critical values of $\delta$ at which different $X^-$ states unbind are surprisingly small compared to the well width, the observation of strongly bound $X^-$ states in an experimental PL spectrum implies virtually no layer displacement in the sample. This casts doubt on the interpretation of PL spectra of heterojunctions in terms of $X^-$ recombination

The average submillimetre properties of Lyman α blobs at z = 3

Ly α blobs (LABs) offer insight into the complex interface between galaxies and their circumgalactic medium. Whilst some LABs have been found to contain luminous star-forming galaxies and active galactic nuclei that could potentially power the Ly α emission, others appear not to be associated with obvious luminous galaxy counterparts. It has been speculated that LABs may be powered by cold gas streaming on to a central galaxy, providing an opportunity to directly observe the ‘cold accretion’ mode of galaxy growth. Star-forming galaxies in LABs could be dust obscured and therefore detectable only at longer wavelengths. We stack deep Submillimetre Common User Bolometer Array 2 (SCUBA-2) observations of the Small Selected Area 22h field to determine the average 850 μm flux density of 34 LABs. We measure S850 = 0.6 ± 0.2 mJy for all LABs, but stacking the LABs by size indicates that only the largest third (area ≥1794 kpc2) have a mean detection, at 4.5σ, with S850 = 1.4 ± 0.3 mJy. Only two LABs (1 and 18) have individual SCUBA-2 >3.5σ detections at a depth of 1.1 mJy beam−1. We consider two possible mechanisms for powering the LABs and find that central star formation is likely to dominate the emission of Ly α, with cold accretion playing a secondary role