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Mark sansom

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https://www.readbyqxmd.com/read/29038439/analysis-of-nkx3-1-cre-driven-erk5-deletion-reveals-a-profound-spinal-deformity-which-is-linked-to-increased-osteoclast-activity
#1
Carolyn J Loveridge, Rob J van 't Hof, Gemma Charlesworth, Ayala King, Ee Hong Tan, Lorraine Rose, Anna Daroszewska, Amanda Prior, Imran Ahmad, Michelle Welsh, Ernest J Mui, Catriona Ford, Mark Salji, Owen Sansom, Karen Blyth, Hing Y Leung
Extracellular signal-regulated protein kinase 5 (ERK5) has been implicated during development and carcinogenesis. Nkx3.1-mediated Cre expression is a useful strategy to genetically manipulate the mouse prostate. While grossly normal at birth, we observed an unexpected phenotype of spinal protrusion in Nkx3.1:Cre;Erk5 (fl/fl) (Erk5 (fl/fl)) mice by ~6-8 weeks of age. X-ray, histological and micro CT (µCT) analyses showed that 100% of male and female Erk5 (fl/fl) mice had a severely deformed curved thoracic spine, with an associated loss of trabecular bone volume...
October 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29034329/comparative-metabolomics-of-mycoplasma-bovis-and-mycoplasma-gallisepticum-reveals-fundamental-differences-in-active-metabolic-pathways-and-suggests-novel-gene-annotations
#2
Y Masukagami, D P De Souza, S Dayalan, C Bowen, S O'Callaghan, K Kouremenos, B Nijagal, D Tull, K A Tivendale, P F Markham, M J McConville, G F Browning, F M Sansom
Mycoplasmas are simple, but successful parasites that have the smallest genome of any free-living cell and are thought to have a highly streamlined cellular metabolism. Here, we have undertaken a detailed metabolomic analysis of two species, Mycoplasma bovis and Mycoplasma gallisepticum, which cause economically important diseases in cattle and poultry, respectively. Untargeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses of mycoplasma metabolite extracts revealed significant differences in the steady-state levels of many metabolites in central carbon metabolism, while (13)C stable isotope labeling studies revealed marked differences in carbon source utilization...
September 2017: MSystems
https://www.readbyqxmd.com/read/28961531/peptide-surfactant-interactions-a-combined-spectroscopic-and-molecular-dynamics-simulation-approach
#3
Guillaume Roussel, Yves Caudano, André Matagne, Mark S Sansom, Eric A Perpète, Catherine Michaux
In the present contribution, we report a combined spectroscopic and computational approach aiming to unravel at atomic resolution the effect of the anionic SDS detergent on the structure of two model peptides, the α-helix TrpCage and the β-stranded TrpZip. A detailed characterization of the specific amino acids involved is performed. Monomeric (single molecules) and micellar SDS species differently interact with the α-helix and β-stranded peptides, emphasizing the different mechanisms occurring below and above the critical aggregation concentration (CAC)...
September 21, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/28923939/asymmetric-mechanosensitivity-in-a-eukaryotic-ion-channel
#4
Michael V Clausen, Viwan Jarerattanachat, Elisabeth P Carpenter, Mark S P Sansom, Stephen J Tucker
Living organisms perceive and respond to a diverse range of mechanical stimuli. A variety of mechanosensitive ion channels have evolved to facilitate these responses, but the molecular mechanisms underlying their exquisite sensitivity to different forces within the membrane remains unclear. TREK-2 is a mammalian two-pore domain (K2P) K(+) channel important for mechanosensation, and recent studies have shown how increased membrane tension favors a more expanded conformation of the channel within the membrane...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28827388/correction-a-cd80-biased-ctla4-ig-fusion-protein-with-superior-in-vivo-efficacy-by-simultaneous-engineering-of-affinity-selectivity-stability-and-fcrn-binding
#5
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
No abstract text is available yet for this article.
September 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28818576/the-effect-of-mutations-in-the-lid-region-of-thermomyces-lanuginosus-lipase-on-interactions-with-triglyceride-surfaces-a-multi-scale-simulation-study
#6
Nathalie Willems, Mickäel Lelimousin, Jakob Skjold-Jorgensen, Allan Svendsen, Mark S P Sansom
Lipases naturally function at the interface formed between amphiphilic molecules and the aqueous environment. Thermomyces lanuginosus lipase (TLL) is a well-characterised lipase, known to exhibit interfacial activation during which a lid region covering the active site becomes displaced upon interaction with an interface. In this study, we investigate the effect the amino acid sequence of the lid region on interfacial binding and lid dynamics of TLL. Three TLL variants were investigated, a wild-type variant, a variant containing an esterase lid region (Esterase), and a Hybrid variant, containing both wild-type lid residues and esterase lid residues...
August 14, 2017: Chemistry and Physics of Lipids
https://www.readbyqxmd.com/read/28778113/educational-and-vocational-goal-disruption-in-adolescent-and-young-adult-cancer-survivors
#7
Janine Vetsch, Claire E Wakefield, Brittany C McGill, Richard J Cohn, Sarah J Ellis, Natalie Stefanic, Susan M Sawyer, Brad Zebrack, Ursula M Sansom-Daly
OBJECTIVE: Cancer in adolescents and young adults (AYAs) can interrupt important developmental milestones. Absence from school and time lost from work, together with the physical impacts of treatment on energy and cognition, can disrupt educational and vocational goals. The purpose of this paper is to report on AYA cancer survivors' experiences of reintegration into school and/or work and to describe perceived changes in their educational and vocational goals. METHODS: AYAs recruited from seven hospitals in Australia, aged 15-26years and ≤24months post-treatment, were interviewed using the Psychosocial Adjustment to Illness Scale (PAIS)...
August 4, 2017: Psycho-oncology
https://www.readbyqxmd.com/read/28723241/the-effects-of-stretch-activation-on-ionic-selectivity-of-the-trek-2-k2p-k-channel
#8
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...
September 3, 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
#9
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
#10
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
#11
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
#12
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...
October 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
#13
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
#14
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
#15
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
#16
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
#17
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...
July 4, 2017: Channels
https://www.readbyqxmd.com/read/28317903/stability-and-dynamics-of-membrane-spanning-dna-nanopores
#18
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
#19
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
#20
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
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