Crystallographic Analyses of Ion Channels: Lessons and Challenges

Membrane proteins fascinate at many levels, from their central functional roles in transport, energy transduction, and signal transduction processes to structural questions concerning how they fold and operate in the exotic environments of the membrane bilayer and the water-bilayer interface and to methodological issues associated with studying membrane proteins either in situ or extracted from the membrane. This interplay is beautifully exemplified by ion channels, a collection of integral membrane proteins that mediate the transmembrane passage of ions down their electrochemical potential gradient (for general reviews, see Refs. 1 and 2). Ion channels are key elements of signaling and sensing pathways, including nerve cell conduction, hormone response, and mechanosensation. The characteristic properties of ion channels reflect their conductance, ion selectivity, and gating. Ion channels are often specific for a particular type of ion (such as potassium or chloride) or a class of ions (such as anions) and are typically regulated by conformational switching of the protein structure between "open" and "closed" states. This conformational switching may be gated in response to changes in membrane potential, ligand binding, or application of mechanical forces. Detailed functional characterizations of channels and their gating mechanisms have been achieved, reflecting exquisite methodological advances such as patch clamp methods that can monitor the activities of individual channels (3). Until recently, corresponding information about the three-dimensional structures of channels was not available, reflecting difficulties in obtaining sufficient quantities of membrane proteins for crystallization trials. Happily, this situation has started to change with the structure determinations of the Streptomyces lividans K+ channel (KcsA (4)) and the Mycobacterium tuberculosis mechanosensitive channel (MscL (5)). A variety of reviews (6-12) have appeared recently that discuss functional implications of these channel structures. This review discusses these developments from a complementary perspective, by considering the implications of these structures from within the larger framework of membrane protein structure and function. Because of space restrictions, this review necessarily emphasizes membrane proteins that are composed primarily of alpha-helical bundles, such as KcsA and MscL, rather than beta-barrel proteins, such as porins, typically found in bacterial outer membranes

A pilot randomised controlled trial of metacognitive therapy for prolonged grief

Objectives: Prolonged grief disorder is associated with significant distress and impairment and thus efforts to improve treatments are essential. The present pilot study tested the efficacy and feasibility of group Metacognitive Grief Therapy (MCGT) designed specifically for prolonged grief symptomatology to reduce the psychological distress and impaired function resulting from bereavement. Design/participants: Twenty-two bereaved adult participants with prolonged grief symptomatology were randomised to a wait-list control (n=10) or an intervention condition (n=12) with a 3-month and 6-month follow-up. The wait-list control group was offered treatment after the post-test assessment. Intervention: Participants attended six group MCGT sessions that ran for 2 hours per week. Outcome measures: A primary outcome measure of prolonged grief symptomatology and secondary outcome measures of depression, anxiety, rumination, metacognitive beliefs and quality of life were taken pretreatment and post-treatment for both groups and at the 3-month and 6-month follow-up for the intervention group. A Generalised Linear Mixed Model was used to assess treatment efficacy. Results: Post-treatment intent-to-treat analyses showed MCGT reduced prolonged grief symptomatology (Cohen's d=1.7), depression (d=1.3), anxiety (d=0.8), stress (d=1.0), rumination (d=0.9) and increased quality of life (d=0.6), and these effects were maintained at the 3-month and 6-month follow-ups. No prepost between-group differences were found in metacognitive beliefs. However, a large significant effect was identified at the 3-month and 6-month follow-ups (d=1.0). Conclusion: The results show promise for the utility of group MCGT for reducing psychological distress and promoting quality of life. Additionally, the results underscore the need for a full randomised controlled trial of group MCGT, which may be an important addition to the treatment armamentarium available to support people with prolonged grief

ColloCaid: A real-time tool to help academic writers with English collocations”

Writing is a cognitively challenging activity that can benefit from lexicographic support. Academic writing in English presents a particular challenge, given the extent of use of English for this purpose. The ColloCaid tool, currently under development, responds to this challenge. It is intended to assist academic English writers by providing collocation suggestions, as well as alerting writers to unconventional collocational choices as they write. The underlying collocational data are based on a carefully curated set of about 500 collocational bases (nouns, verbs, and adjectives) characteristic of academic English, and their collocates with illustrative examples. These data have been derived from state-of-the-art corpora of academic English and academic vocabulary lists. The manual curation by expert lexicographers and reliance on specifically Academic English textual resources are what distinguishes ColloCaid from existing collocational resources. A further characteristic of ColloCaid is its strong emphasis on usability. The tool draws on dictionary-user research, findings in information visualization, as well as usability testing specific to ColloCaid in order to find an optimal amount of collocation prompts, and the best way to present them to the user

BATSE Observations of Gamma-Ray Burst Spectra. IV. Time-Resolved High-Energy Spectroscopy

We report on the temporal behavior of the high-energy power law continuum component of gamma-ray burst spectra with data obtained by the Burst and Transient Source Experiment. We have selected 126 high fluence and high flux bursts from the beginning of the mission up until the present. Much of the data were obtained with the Large Area Detectors, which have nearly all-sky coverage, excellent sensitivity over two decades of energy and moderate energy resolution, ideal for continuum spectra studies of a large sample of bursts at high time resolution. At least 8 spectra from each burst were fitted with a spectral form that consisted of a low-energy power law, a spectral break at middle energies and a high-energy continuum. In most bursts (122), the high-energy continuum was consistent with a power law. The evolution of the fitted high-energy power-law index over the selected spectra for each burst is inconsistent with a constant for 34% of the total sample. The sample distribution of the average value for the index from each burst is fairly narrow, centered on -2.12. A linear trend in time is ruled out for only 20% of the bursts, with hard-to-soft evolution dominating the sample (100 events). The distribution for the total change in the power-law index over the duration of a burst peaks at the value -0.37, and is characterized by a median absolute deviation of 0.39, arguing that a single physical process is involved. We present analyses of the correlation of the power-law index with time, burst intensity and low-energy time evolution. In general, we confirm the general hard-to-soft spectral evolution observed in the low-energy component of the continuum, while presenting evidence that this evolution is different in nature from that of the rest of the continuum.Comment: 30 pages, with 2 tables and 9 figures To appear in The Astrophysical Journal, April 1, 199

Developing a writing assistant to help EAP writers with collocations in real time

Corpora have given rise to a wide range of lexicographic resources aimed at helping novice users of academic English with their writing. This includes academic vocabulary lists, a variety of textbooks, and even a bespoke academic English dictionary. However, writers may not be familiar with these resources or may not be sufficiently aware of the lexical shortcomings of their emerging texts to trigger the need to use such help in the first place. Moreover, writers who have to stop writing to look up a word can be distracted from getting their ideas down on paper. The ColloCaid project aims to address this problem by integrating information on collocation with text editors. In this paper, we share the research underpinning the initial development of ColloCaid by detailing the rationale of (1) the lexicographic database we are compiling to support novice EAP users’ collocation needs and (2) the preliminary visualisation decisions taken to present information on collocation to EAP users without disrupting their writing. We conclude the paper by outlining the next steps in the research