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https://www.readbyqxmd.com/read/28723241/the-effects-of-stretch-activation-on-ionic-selectivity-of-the-trek-2-k2p-k-channel
#1
Ehsan Nematian-Ardestani, Viwan Jarerattanachat, Prafulla Aryal, Mark S P Sansom, Stephen J Tucker
The TREK-2 (KCNK10) K2P potassium channel can be regulated by variety of polymodal stimuli including pressure. In a recent study, we demonstrated that this mechanosensitive K(+) channel responds to changes in membrane tension by undergoing a major structural change from its 'down' state to the more expanded 'up' state conformation. These changes are mostly restricted to the lower part of the protein within the bilayer, but are allosterically coupled to the primary gating mechanism located within the selectivity filter...
July 19, 2017: Channels
https://www.readbyqxmd.com/read/28720589/dynamic-role-of-the-tether-helix-in-pip2-dependent-gating-of-a-g-protein-gated-potassium-channel
#2
Emre Lacin, Prafulla Aryal, Ian W Glaaser, Karthik Bodhinathan, Eric Tsai, Nidaa Marsh, Stephen J Tucker, Mark S P Sansom, Paul A Slesinger
G protein-gated inwardly rectifying potassium (GIRK) channels control neuronal excitability in the brain and are implicated in several different neurological diseases. The anionic phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) is an essential cofactor for GIRK channel gating, but the precise mechanism by which PIP2 opens GIRK channels remains poorly understood. Previous structural studies have revealed several highly conserved, positively charged residues in the "tether helix" (C-linker) that interact with the negatively charged PIP2 However, these crystal structures of neuronal GIRK channels in complex with PIP2 provide only snapshots of PIP2's interaction with the channel and thus lack details about the gating transitions triggered by PIP2 binding...
July 18, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28673959/pharmacists-perceptions-of-their-emerging-general-practice-roles-in-uk-primary-care-a-qualitative-interview-study
#3
Jo Butterworth, Anna Sansom, Laura Sims, Mark Healey, Ellie Kingsland, John Campbell
BACKGROUND: UK general practice is experiencing a workload crisis. Pharmacists are the third largest healthcare profession in the UK; however, their skills are a currently underutilised and potentially highly valuable resource for primary health care. This study forms part of the evaluation of an innovative training programme for pharmacists who are interested in extended roles in primary care, advocated by a UK collaborative '10-point GP workforce action plan'. AIM: To explore pharmacists' perceptions of primary care roles including the potential for greater integration of their profession into general practice...
July 3, 2017: British Journal of General Practice: the Journal of the Royal College of General Practitioners
https://www.readbyqxmd.com/read/28659641/lgr5-joins-the-club-of-gastric-stem-cell-markers-in-the-corpus
#4
Toby J Phesse, Owen J Sansom
Several markers of gastric stem cells have been identified in recent years. Now a study demonstrates that Lgr5 marks a population of reserve stem cells located at the base of the corpus glands of the gastric epithelium, and that these cells can also act as a cell-of-origin for gastric tumorigenesis.
June 29, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28622298/tgf%C3%AE-pathway-limits-dedifferentiation-following-wnt-and-mapk-pathway-activation-to-suppress-intestinal-tumourigenesis
#5
Patrizia Cammareri, David F Vincent, Michael C Hodder, Rachel A Ridgway, Claudio Murgia, Max Nobis, Andrew D Campbell, Julia Varga, David J Huels, Chithra Subramani, Katie L H Prescott, Colin Nixon, Ann Hedley, Simon T Barry, Florian R Greten, Gareth J Inman, Owen J Sansom
Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis...
June 16, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28515147/increased-t-cell-infiltration-elicited-by-erk5-deletion-in-a-pten-deficient-mouse-model-of-prostate-carcinogenesis
#6
Carolyn J Loveridge, Ernest J Mui, Rachana Patel, Ee Hong Tan, Imran Ahmad, Michelle Welsh, Julie Galbraith, Ann Hedley, Colin Nixon, Karen Blyth, Owen Sansom, Hing Y Leung
Prostate cancer does not appear to respond to immune checkpoint therapies where T-cell infiltration may be a key limiting factor. Here, we report evidence that ablating the growth regulatory kinase Erk5 can increase T-cell infiltration in an established Pten-deficient mouse model of human prostate cancer. Mice that were doubly mutant in prostate tissue for Pten and Erk5 (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared with control Pten-mutant mice, the latter of which exhibited increased Erk5 mRNA expression...
June 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28453537/an-efficient-and-robust-mri-guided-radiotherapy-planning-approach-for-targeting-abdominal-organs-and-tumours-in-the-mouse
#7
Veerle Kersemans, John S Beech, Stuart Gilchrist, Paul Kinchesh, Philip D Allen, James Thompson, Ana L Gomes, Zenobia D'Costa, Luke Bird, Iain D C Tullis, Robert G Newman, Aurelien Corroyer-Dulmont, Nadia Falzone, Abul Azad, Katherine A Vallis, Owen J Sansom, Ruth J Muschel, Borivoj Vojnovic, Mark A Hill, Emmanouil Fokas, Sean C Smart
INTRODUCTION: Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. METHODS: A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI...
2017: PloS One
https://www.readbyqxmd.com/read/28392258/bilayer-mediated-structural-transitions-control-mechanosensitivity-of-the-trek-2-k2p-channel
#8
Prafulla Aryal, Viwan Jarerattanachat, Michael V Clausen, Marcus Schewe, Conor McClenaghan, Liam Argent, Linus J Conrad, Yin Y Dong, Ashley C W Pike, Elisabeth P Carpenter, Thomas Baukrowitz, Mark S P Sansom, Stephen J Tucker
The mechanosensitive two-pore domain (K2P) K(+) channels (TREK-1, TREK-2, and TRAAK) are important for mechanical and thermal nociception. However, the mechanisms underlying their gating by membrane stretch remain controversial. Here we use molecular dynamics simulations to examine their behavior in a lipid bilayer. We show that TREK-2 moves from the "down" to "up" conformation in direct response to membrane stretch, and examine the role of the transmembrane pressure profile in this process. Furthermore, we show how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28381539/transient-tissue-priming-via-rock-inhibition-uncouples-pancreatic-cancer-progression-sensitivity-to-chemotherapy-and-metastasis
#9
Claire Vennin, Venessa T Chin, Sean C Warren, Morghan C Lucas, David Herrmann, Astrid Magenau, Pauline Melenec, Stacey N Walters, Gonzalo Del Monte-Nieto, James R W Conway, Max Nobis, Amr H Allam, Rachael A McCloy, Nicola Currey, Mark Pinese, Alice Boulghourjian, Anaiis Zaratzian, Arne A S Adam, Celine Heu, Adnan M Nagrial, Angela Chou, Angela Steinmann, Alison Drury, Danielle Froio, Marc Giry-Laterriere, Nathanial L E Harris, Tri Phan, Rohit Jain, Wolfgang Weninger, Ewan J McGhee, Renee Whan, Amber L Johns, Jaswinder S Samra, Lorraine Chantrill, Anthony J Gill, Maija Kohonen-Corish, Richard P Harvey, Andrew V Biankin, T R Jeffry Evans, Kurt I Anderson, Shane T Grey, Christopher J Ormandy, David Gallego-Ortega, Yingxiao Wang, Michael S Samuel, Owen J Sansom, Andrew Burgess, Thomas R Cox, Jennifer P Morton, Marina Pajic, Paul Timpson
The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy...
April 5, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28319451/a-best-example-of-channel-structure-annotation-by-molecular-simulation
#10
Shanlin Rao, Gianni Klesse, Phillip J Stansfeld, Stephen J Tucker, Mark S P Sansom
An increasing number of ion channel structures are being determined. This generates a need for computational tools to enable functional annotation of channel structures. However, several studies of ion channel and model pores have indicated that the physical dimensions of a pore are not always a reliable indicator of its conductive status. This is due to the unusual behavior of water within nano-confined spaces, resulting in a phenomenon referred to as "hydrophobic gating". We have recently demonstrated how simulating the behavior of water within an ion channel pore can be used to predict its conductive status...
March 20, 2017: Channels
https://www.readbyqxmd.com/read/28317903/stability-and-dynamics-of-membrane-spanning-dna-nanopores
#11
Vishal Maingi, Jonathan R Burns, Jaakko J Uusitalo, Stefan Howorka, Siewert J Marrink, Mark S P Sansom
Recently developed DNA-based analogues of membrane proteins have advanced synthetic biology. A fundamental question is how hydrophilic nanostructures reside in the hydrophobic environment of the membrane. Here, we use multiscale molecular dynamics (MD) simulations to explore the structure, stability and dynamics of an archetypical DNA nanotube inserted via a ring of membrane anchors into a phospholipid bilayer. Coarse-grained MD reveals that the lipids reorganize locally to interact closely with the membrane-spanning section of the DNA tube...
March 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28165704/biomimetic-phospholipid-membrane-organization-on-graphene-and-graphene-oxide-surfaces-a-molecular-dynamics-simulation-study
#12
Nathalie Willems, Ainhoa Urtizberea, Andrea F Verre, Maria Iliut, Mickael Lelimousin, Michael Hirtz, Aravind Vijayaraghavan, Mark S P Sansom
Supported phospholipid membrane patches stabilized on graphene surfaces have shown potential in sensor device functionalization, including biosensors and biocatalysis. Lipid dip-pen nanolithography (L-DPN) is a method useful in generating supported membrane structures that maintain lipid functionality, such as exhibiting specific interactions with protein molecules. Here, we have integrated L-DPN, atomic force microscopy, and coarse-grained molecular dynamics simulation methods to characterize the molecular properties of supported lipid membranes (SLMs) on graphene and graphene oxide supports...
February 28, 2017: ACS Nano
https://www.readbyqxmd.com/read/28141923/voltage-gating-of-a-biomimetic-nanopore-electrowetting-of-a-hydrophobic-barrier
#13
Jemma L Trick, Chen Song, E Jayne Wallace, Mark S P Sansom
It is desirable that nanopores that are components of biosensors are gated, i.e., capable of controllable switching between closed (impermeable) and open (permeable) states. A central hydrophobic barrier within a nanopore may act as a voltage-dependent gate via electrowetting, i.e., changes in nanopore surface wettability by application of an electric field. We use "computational electrophysiology" simulations to demonstrate and characterize electrowetting of a biomimetic nanopore containing a hydrophobic gate...
February 6, 2017: ACS Nano
https://www.readbyqxmd.com/read/28116358/dynamic-interactions-between-a-membrane-binding-protein-and-lipids-induce-fluctuating-diffusivity
#14
Eiji Yamamoto, Takuma Akimoto, Antreas C Kalli, Kenji Yasuoka, Mark S P Sansom
Pleckstrin homology (PH) domains are membrane-binding lipid recognition proteins that interact with phosphatidylinositol phosphate (PIP) molecules in eukaryotic cell membranes. Diffusion of PH domains plays a critical role in biological reactions on membrane surfaces. Although diffusivity can be estimated by long-time measurements, it lacks information on the short-time diffusive nature. We reveal two diffusive properties of a PH domain bound to the surface of a PIP-containing membrane using molecular dynamics simulations...
January 2017: Science Advances
https://www.readbyqxmd.com/read/28068080/effect-of-the-southeast-asian-ovalocytosis-deletion-on-the-conformational-dynamics-of-signal-anchor-transmembrane-segment-1-of-red-cell-anion-exchanger-1-ae1-band-3-or-slc4a1
#15
Philip W Fowler, Mark S P Sansom, Reinhart A F Reithmeier
The first transmembrane (TM1) helix in the red cell anion exchanger (AE1, Band 3, or SLC4A1) acts as an internal signal anchor that binds the signal recognition particle and directs the nascent polypeptide chain to the endoplasmic reticulum (ER) membrane where it moves from the translocon laterally into the lipid bilayer. The sequence N-terminal to TM1 forms an amphipathic helix that lies at the membrane interface and is connected to TM1 by a bend at Pro403. Southeast Asian ovalocytosis (SAO) is a red cell abnormality caused by a nine-amino acid deletion (Ala400-Ala408) at the N-terminus of TM1...
February 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/28052056/genome-wide-in-vivo-screen-identifies-novel-host-regulators-of-metastatic-colonization
#16
Louise van der Weyden, Mark J Arends, Andrew D Campbell, Tobias Bald, Hannah Wardle-Jones, Nicola Griggs, Martin Del Castillo Velasco-Herrera, Thomas Tüting, Owen J Sansom, Natasha A Karp, Simon Clare, Diane Gleeson, Edward Ryder, Antonella Galli, Elizabeth Tuck, Emma L Cambridge, Thierry Voet, Iain C Macaulay, Kim Wong, Sarah Spiegel, Anneliese O Speak, David J Adams
Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment ('host', which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth ('colonization') being critical in determining metastatic outcome...
January 12, 2017: Nature
https://www.readbyqxmd.com/read/27993564/interfacial-activation-of-m37-lipase-a-multi-scale-simulation-study
#17
Nathalie Willems, Mickaël Lelimousin, Heidi Koldsø, Mark S P Sansom
Lipases are enzymes of biotechnological importance that function at the interface formed between hydrophobic and aqueous environments. Hydrophobic interfaces can induce structural transitions in lipases that result in an increase in enzyme activity, although the detailed mechanism of this process is currently not well understood for many lipases. Here, we present a multi-scale molecular dynamics simulation study of how different interfaces affect the conformational dynamics of the psychrophilic lipase M37. Our simulations show that M37 lipase is able to interact both with anionic lipid bilayers and with triglyceride surfaces...
March 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27974389/structure-and-lipid-binding-properties-of-the-kindlin-3-pleckstrin-homology-domain
#18
Tao Ni, Antreas C Kalli, Fiona B Naughton, Luke A Yates, Omar Naneh, Mirijam Kozorog, Gregor Anderluh, Mark S P Sansom, Robert J C Gilbert
Kindlins co-activate integrins alongside talin. They possess, like talin, a FERM domain (4.1-erythrin-radixin-moiesin domain) comprising F0-F3 subdomains, but with a pleckstrin homology (PH) domain inserted in the F2 subdomain that enables membrane association. We present the crystal structure of murine kindlin-3 PH domain determined at a resolution of 2.23 Å and characterise its lipid binding using biophysical and computational approaches. Molecular dynamics simulations suggest flexibility in the PH domain loops connecting β-strands forming the putative phosphatidylinositol phosphate (PtdInsP)-binding site...
February 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/27917824/on-the-interpretation-of-reflectivity-data-from-lipid-bilayers-in-terms-of-molecular-dynamics-models
#19
Arwel V Hughes, Fillip Ciesielski, Antreas C Kalli, Luke A Clifton, Timothy R Charlton, Mark S P Sansom, John R P Webster
Neutron and X-ray reflectivity of model membranes is increasingly used as a tool for the study of membrane structures and dynamics. As the systems under study become more complex, and as long, all-atom molecular-dynamics (MD) simulations of membranes become more available, there is increasing interest in the use of MD simulations in the analysis of reflectometry data from membranes. In order to perform this, it is necessary to produce a model of the complete interface, including not only the MD-derived structure of the membrane, but also the supporting substrate and any other interfacial layers that may be present...
December 1, 2016: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/27881707/a-cd80-biased-ctla4-ig-fusion-protein-with-superior-in-vivo-efficacy-by-simultaneous-engineering-of-affinity-selectivity-stability-and-fcrn-binding
#20
Julie Douthwaite, Jacques Moisan, Cyril Privezentzev, Blagoje Soskic, Shereen Sabbah, Suzanne Cohen, Andie Collinson, Elizabeth England, Catherine Huntington, Ben Kemp, Li Zhuang, Suzanne Hudak, D Gareth Rees, Debbie Goldberg, Chris Barton, Linda Chang, Inna Vainshtein, Meina Liang, Laurie Iciek, Philip Ambery, Mark Peakman, Tristan J Vaughan, Tim I M Tree, David M Sansom, Michael A Bowen, Ralph R Minter, Lutz Jermutus
Affinity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic profiles could yield improved therapies with the potential of higher efficacy and greater convenience to patients. In this study, to our knowledge, we have, for the first time, used in vitro evolution to simultaneously optimize CTLA4 affinity and stability. We selected for improved binding to both ligands, CD80 and CD86, and screened as dimeric Fc fusions directly in functional assays to identify variants with stronger suppression of in vitro T cell activation...
January 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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