1,720,962 research outputs found
Transmembrane Helix Straightening and Buckling Underlies Activation of Mechanosensitive and Thermosensitive K-2P Channels
No full textMechanical and thermal activation of ion channels is central to touch,
thermosensation, and pain. The TRAAK/TREK K-2P potassium channel
subfamily produces background currents that alter neuronal excitability
in response to pressure, temperature, signaling lipids, and anesthetics.
How such diverse stimuli control channel function is unclear. Here we
report structures of K(2P)4.1 (TRAAK) bearing C-type gate-activating
mutations that reveal a tilting and straightening of the M4 inner
transmembrane helix and a buckling of the M2 transmembrane helix. These
conformational changes move M4 in a direction opposite to that in
classical potassium channel activation mechanisms and open a passage
lateral to the pore that faces the lipid bilayer inner leaflet.
Together, our findings uncover a unique aspect of K-2P modulation,
indicate a means for how the K-2P C-terminal cytoplasmic domain affects
the C-type gate which lies similar to 40 angstrom away, and suggest how
lipids and bilayer inner leaflet deformations may gate the channel
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Structural characterization of the C-terminal domains in the p53 protein family
Full text linkThe identification of many homologs and paralogs of the most famous tumor suppressor, p53, has expanded its role from tumor suppression to epidermal development, neuronal development, and protection of germ cells. Of all the members in the p53 protein family, the DNA binding domain (DBD) is the most conserved domain. In contrast, the C-terminal region is diverse in sequence and composition of protein domains that include the oligomerization domain (OD), the sterile alpha motif (SAM) domain, and the transcription inhibitory domain (TID). While the function of each domain has been delineated, the SAM domain is the least functionally characterized, yet it is conserved between vertebrate and invertebrate p53. Furthermore, mutations of this domain in p63, a homolog of p53, cause defects in epidermal development in human.The diversity of the C-terminus is most apparent in two p53 like proteins in C. elegans (CEP-1) and Drosophila (Dmp53). Neither of these proteins have any domains in the C-terminus found in other p53 protein family members, yet the DBD in both proteins recognize the DNA consensus motif in vitro. Interestingly, CEP-1 and Dmp53 could only elicit an apoptotic response, but not both cell cycle arrest and apoptosis like in human. The variation of the C-terminal end by each member of the p53 protein family may account for the discrepancy between identical in vitro DNA specificity, and distinct promoter specificity in vivo. By using bioinformatics and structural determination by nuclear magnetic resonance, the domain architecture of the C-termini of CEP-1 and Dmp53 was revealed. In CEP-1, an OD and a SAM domain were identified, in which the stability of the OD depends on its interaction with the SAM domain, thus suggesting an early function for the SAM domain. In Dmp53, the OD displays an unconventional fold that requires an additional helix to stabilize the OD. Structural and biochemical investigations into the human SAM domain in p63 also reveal that the SAM domain has interactions with the OD. Mutations in the SAM domain may disrupt this interaction and cause a change in the conformation of p63 that results in its abnormal function
K(2P)2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site
Full text linkPolymodal thermo- and mechanosensitive two-pore domain potassium (K-2P)
channels of the TREK1 subfamily generate `leak' currents that regulate
neuronal excitability, respond to lipids, temperature and mechanical
stretch, and influence pain, temperature perception and anaesthetic
responses(1-3). These dimeric voltage-gated ion channel (VGIC)
superfamily members have a unique topology comprising two pore-forming
regions per subunit(4-6). In contrast to other potassium channels, K-2P
channels use a selectivity filter `C-type' gate(7-10) as the principal
gating site. Despite recent advances(3,11,12), poor pharmacological
profiles of K2P channels limit mechanistic and biological studies. Here
we describe a class of small-molecule TREK activators that directly
stimulate the C-type gate by acting as molecular wedges that restrict
interdomain interface movement behind the selectivity filter. Structures
of K(2P)2.1 (also known as TREK-1) alone and with two selective K(2P)2.1
(TREK-1) and K(2P)10.1 (TREK-2) activators-an N-aryl-sulfonamide, ML335,
and a thiophene-carboxamide, ML402-define a cryptic binding pocket
unlike other ion channel small-molecule binding sites and, together with
functional studies, identify a cation-p interaction that controls
selectivity. Together, our data reveal a druggable K-2P site that
stabilizes the C-type gate `leak mode' and provide direct evidence for
K-2P selectivity filter gating
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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