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REVIEW
Kirill S Korshunov, Laura J Blakemore, Paul Q Trombley
In the central nervous system, dopamine is well-known as the neuromodulator that is involved with regulating reward, addiction, motivation, and fine motor control. Yet, decades of findings are revealing another crucial function of dopamine: modulating sensory systems. Dopamine is endogenous to subsets of neurons in the retina and olfactory bulb (OB), where it sharpens sensory processing of visual and olfactory information. For example, dopamine modulation allows the neural circuity in the retina to transition from processing dim light to daylight and the neural circuity in the OB to regulate odor discrimination and detection...
2020: Frontiers in Cellular Neuroscience
#22
JOURNAL ARTICLE
S Ahmed, L Foulkes, J T Leung, C Griffin, A Sakhardande, M Bennett, D L Dunning, K Griffiths, J Parker, W Kuyken, J M G Williams, T Dalgleish, S J Blakemore
INTRODUCTION: Adolescents are particularly susceptible to social influence and previous studies have shown that this susceptibility decreases with age. The current study used a cross-sectional experimental paradigm to investigate the effect of age and puberty on susceptibility to both prosocial and antisocial influence. METHODS: Participants (N = 520) aged 11-18 from London and Cambridge (United Kingdom) rated how likely they would be to engage in a prosocial (e...
October 2020: Journal of Adolescence
#23
JOURNAL ARTICLE
Thomas D Downes, S Paul Jones, Hanna F Klein, Mary C Wheldon, Masakazu Atobe, Paul S Bond, James D Firth, Ngai S Chan, Laura Waddelove, Roderick E Hubbard, David C Blakemore, Claudia De Fusco, Stephen D Roughley, Lewis R Vidler, Maria Ann Whatton, Alison J-A Woolford, Gail L Wrigley, Peter O'Brien
Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1...
July 22, 2020: Chemistry: a European Journal
#24
JOURNAL ARTICLE
Kirill S Korshunov, Laura J Blakemore, Richard Bertram, Paul Q Trombley
The mammalian olfactory bulb (OB) has a vast population of dopamine (DA) neurons, whose function is to increase odor discrimination through mostly inhibitory synaptic mechanisms. However, it is not well understood whether there is more than one neuronal type of OB DA neuron, how these neurons respond to different stimuli, and the ionic mechanisms behind those responses. In this study, we used a transgenic rat line (hTH-GFP) to identify fluorescent OB DA neurons for recording via whole-cell electrophysiology...
2020: Frontiers in Cellular Neuroscience
#25
JOURNAL ARTICLE
Genome-Wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.
Chen Li, Svetlana Stoma, Luca A Lotta, Sophie Warner, Eva Albrecht, Alessandra Allione, Pascal P Arp, Linda Broer, Jessica L Buxton, Alexessander Da Silva Couto Alves, Joris Deelen, Iryna O Fedko, Scott D Gordon, Tao Jiang, Robert Karlsson, Nicola Kerrison, Taylor K Loe, Massimo Mangino, Yuri Milaneschi, Benjamin Miraglio, Natalia Pervjakova, Alessia Russo, Ida Surakka, Ashley van der Spek, Josine E Verhoeven, Najaf Amin, Marian Beekman, Alexandra I Blakemore, Federico Canzian, Stephen E Hamby, Jouke-Jan Hottenga, Peter D Jones, Pekka Jousilahti, Reedik Mägi, Sarah E Medland, Grant W Montgomery, Dale R Nyholt, Markus Perola, Kirsi H Pietiläinen, Veikko Salomaa, Elina Sillanpää, H Eka Suchiman, Diana van Heemst, Gonneke Willemsen, Antonio Agudo, Heiner Boeing, Dorret I Boomsma, Maria-Dolores Chirlaque, Guy Fagherazzi, Pietro Ferrari, Paul Franks, Christian Gieger, Johan Gunnar Eriksson, Marc Gunter, Sara Hägg, Iiris Hovatta, Liher Imaz, Jaakko Kaprio, Rudolf Kaaks, Timothy Key, Vittorio Krogh, Nicholas G Martin, Olle Melander, Andres Metspalu, Concha Moreno, N Charlotte Onland-Moret, Peter Nilsson, Ken K Ong, Kim Overvad, Domenico Palli, Salvatore Panico, Nancy L Pedersen, Brenda W J H Penninx, J Ramón Quirós, Marjo Riitta Jarvelin, Miguel Rodríguez-Barranco, Robert A Scott, Gianluca Severi, P Eline Slagboom, Tim D Spector, Anne Tjonneland, Antonia Trichopoulou, Rosario Tumino, André G Uitterlinden, Yvonne T van der Schouw, Cornelia M van Duijn, Elisabete Weiderpass, Eros Lazzerini Denchi, Giuseppe Matullo, Adam S Butterworth, John Danesh, Nilesh J Samani, Nicholas J Wareham, Christopher P Nelson, Claudia Langenberg, Veryan Codd
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci...
February 20, 2020: American Journal of Human Genetics
#26
JOURNAL ARTICLE
L J Knoll, A Gaule, A Lazari, E A K Jacobs, S J Blakemore
Studies have shown that adolescents are more likely than adults to take risks in the presence of peers than when alone, and that young adolescents' risk perception is more influenced by other teenagers than by adults. The current fMRI study investigated the effect of social influence on risk perception in female adolescents (aged 12-14) and adults (aged 23-29). Participants rated the riskiness of everyday situations and were then informed about the (alleged) risk ratings of a social influence group (teenagers or adults), before rating each situation again...
June 2020: Social Neuroscience
#27
RANDOMIZED CONTROLLED TRIAL
Stuart J Blakemore, Ruth Clifford, Helen Parker, Pavlos Antoniou, Ewa Stec-Dziedzic, Marta Larrayoz, Zadie Davis, Latha Kadalyayil, Andrew Colins, Pauline Robbe, Dimitris Vavoulis, Jade Forster, Louise Carr, Ricardo Morilla, Monica Else, Dean Bryant, Helen McCarthy, Renata J Walewska, Andrew J Steele, Jacqueline Chan, Graham Speight, Tanja Stankovic, Mark S Cragg, Daniel Catovsky, David G Oscier, Matthew J J Rose-Zerilli, Anna Schuh, Jonathan C Strefford
Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1)...
July 2020: Leukemia
#28
JOURNAL ARTICLE
J Murphy, T Uttamlal, K A Schmidtke, I Vlaev, D Taylor, M Ahmad, S Alsters, P Purkayastha, S Scholtz, R Ramezani, A R Ahmed, H Chahal, A Darzi, A I F Blakemore
BACKGROUND: Within the United Kingdom's National Health System (NHS), patients suffering from obesity may be provided with bariatric surgery. After receiving surgery many of these patients require further support to continue to lose more weight or to maintain a healthy weight. Remotely monitoring such patients' physical activity and other health-related variables could provide healthworkers with a more 'ecologically valid' picture of these patients' behaviours to then provide more personalised support...
February 3, 2020: BMC Medical Informatics and Decision Making
#29
JOURNAL ARTICLE
Alexessander Couto Alves, N Maneka G De Silva, Ville Karhunen, Ulla Sovio, Shikta Das, H Rob Taal, Nicole M Warrington, Alexandra M Lewin, Marika Kaakinen, Diana L Cousminer, Elisabeth Thiering, Nicholas J Timpson, Tom A Bond, Estelle Lowry, Christopher D Brown, Xavier Estivill, Virpi Lindi, Jonathan P Bradfield, Frank Geller, Doug Speed, Lachlan J M Coin, Marie Loh, Sheila J Barton, Lawrence J Beilin, Hans Bisgaard, Klaus Bønnelykke, Rohia Alili, Ida J Hatoum, Katharina Schramm, Rufus Cartwright, Marie-Aline Charles, Vincenzo Salerno, Karine Clément, Annique A J Claringbould, Cornelia M van Duijn, Elena Moltchanova, Johan G Eriksson, Cathy Elks, Bjarke Feenstra, Claudia Flexeder, Stephen Franks, Timothy M Frayling, Rachel M Freathy, Paul Elliott, Elisabeth Widén, Hakon Hakonarson, Andrew T Hattersley, Alina Rodriguez, Marco Banterle, Joachim Heinrich, Barbara Heude, John W Holloway, Albert Hofman, Elina Hyppönen, Hazel Inskip, Lee M Kaplan, Asa K Hedman, Esa Läärä, Holger Prokisch, Harald Grallert, Timo A Lakka, Debbie A Lawlor, Mads Melbye, Tarunveer S Ahluwalia, Marcella Marinelli, Iona Y Millwood, Lyle J Palmer, Craig E Pennell, John R Perry, Susan M Ring, Markku J Savolainen, Fernando Rivadeneira, Marie Standl, Jordi Sunyer, Carla M T Tiesler, Andre G Uitterlinden, William Schierding, Justin M O'Sullivan, Inga Prokopenko, Karl-Heinz Herzig, George Davey Smith, Paul O'Reilly, Janine F Felix, Jessica L Buxton, Alexandra I F Blakemore, Ken K Ong, Vincent W V Jaddoe, Struan F A Grant, Sylvain Sebert, Mark I McCarthy, Marjo-Riitta Järvelin
Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health...
September 2019: Science Advances
#30
JOURNAL ARTICLE
Yang Zhang, Gerd Bobe, Johana S Revel, Richard R Rodrigues, Thomas J Sharpton, Mary L Fantacone, Kareem Raslan, Cristobal L Miranda, Malcolm B Lowry, Paul R Blakemore, Andrey Morgun, Natalia Shulzhenko, Claudia S Maier, Jan F Stevens, Adrian F Gombart
SCOPE: Two hydrogenated xanthohumol (XN) derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a diet-induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation. METHODS AND RESULTS: To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN...
January 2020: Molecular Nutrition & Food Research
#31
JOURNAL ARTICLE
A modified AUGIS Delphi process to establish research priorities in bariatric and metabolic surgery.
Michael S J Wilson, Stephen Knight, Peter Vaughan-Shaw, Alex I Blakemore, Mary O'Kane, Christopher Boyle, Peter Small, Kamal Mahawar
Delphi methodology may be utilized to develop consensus opinion among a group of experts. The aim of our study was to use a modified Delphi process to determine the future research priorities among bariatric and metabolic healthcare professionals in the United Kingdom. Members of the Association of Upper Gastrointestinal Surgeons and the British Obesity and Metabolic Surgery Society were invited to submit individual research questions via an online survey (phase I). Two rounds of prioritization by multidisciplinary expert healthcare professionals (phase II and III) were completed to determine a final list of high-priority research questions...
October 24, 2019: Clinical Obesity
#32
JOURNAL ARTICLE
Christina J Ge, Rosa M Polan, Kristin W Baranano, Irina Burd, Ahmet A Baschat, Karin J Blakemore, Edward S Ahn, Eric B Jelin, Angie C Jelin
Objectives: We sought to characterize patterns of in utero dilation in isolated severe fetal ventriculomegaly (ISVM) and investigate their value in predicting obstetrical and postnatal outcomes. Methods: This is a retrospective cohort study. ISVM was defined as a sonographic cerebral ventricle atrial with width ≥15 mm in the absence of additional cerebral or other anatomic anomalies. The aim of this study was to characterize two ISVM groups using a receiver operator curve to evaluate the rate of ventricular progression versus need for ventriculoperitoneal (VP) shunt postnatally...
October 16, 2019: Journal of Maternal-fetal & Neonatal Medicine
#33
JOURNAL ARTICLE
J L Andrews, L Foulkes, C Griffin, S J Blakemore
In the current study, we were interested in whether adolescents show a preference for social stimuli compared with non-social stimuli in the context of academic diligence, that is, the ability to expend effort on tedious tasks that have long-term benefits. Forty-five female adolescents (aged 11-17) and 46 female adults (aged 23-33) carried out an adapted version of the Academic Diligence Task (ADT). We created two variations of the ADT: a social ADT and non-social ADT. Individuals were required to freely split their time between an easy, boring arithmetic task and looking at a show-reel of photographs of people (in the social ADT) or landscapes (in the non-social ADT)...
September 2019: Royal Society Open Science
#34
JOURNAL ARTICLE
Evangelos Evangelou, He Gao, Congying Chu, Georgios Ntritsos, Paul Blakeley, Andrew R Butts, Raha Pazoki, Hideaki Suzuki, Fotios Koskeridis, Andrianos M Yiorkas, Ibrahim Karaman, Joshua Elliott, Qiang Luo, Stefanie Aeschbacher, Traci M Bartz, Sebastian E Baumeister, Peter S Braund, Michael R Brown, Jennifer A Brody, Toni-Kim Clarke, Niki Dimou, Jessica D Faul, Georg Homuth, Anne U Jackson, Katherine A Kentistou, Peter K Joshi, Rozenn N Lemaitre, Penelope A Lind, Leo-Pekka Lyytikäinen, Massimo Mangino, Yuri Milaneschi, Christopher P Nelson, Ilja M Nolte, Mia-Maria Perälä, Ozren Polasek, David Porteous, Scott M Ratliff, Jennifer A Smith, Alena Stančáková, Alexander Teumer, Samuli Tuominen, Sébastien Thériault, Jagadish Vangipurapu, John B Whitfield, Alexis Wood, Jie Yao, Bing Yu, Wei Zhao, Dan E Arking, Juha Auvinen, Chunyu Liu, Minna Männikkö, Lorenz Risch, Jerome I Rotter, Harold Snieder, Juha Veijola, Alexandra I Blakemore, Michael Boehnke, Harry Campbell, David Conen, Johan G Eriksson, Hans J Grabe, Xiuqing Guo, Pim van der Harst, Catharina A Hartman, Caroline Hayward, Andrew C Heath, Marjo-Riitta Jarvelin, Mika Kähönen, Sharon L R Kardia, Michael Kühne, Johanna Kuusisto, Markku Laakso, Jari Lahti, Terho Lehtimäki, Andrew M McIntosh, Karen L Mohlke, Alanna C Morrison, Nicholas G Martin, Albertine J Oldehinkel, Brenda W J H Penninx, Bruce M Psaty, Olli T Raitakari, Igor Rudan, Nilesh J Samani, Laura J Scott, Tim D Spector, Niek Verweij, David R Weir, James F Wilson, Daniel Levy, Ioanna Tzoulaki, Jimmy D Bell, Paul M Matthews, Adrian Rothenfluh, Sylvane Desrivières, Gunter Schumann, Paul Elliott
Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1 ) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies...
September 2019: Nature Human Behaviour
#35
JOURNAL ARTICLE
Laura J Blakemore, Paul Q Trombley
The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediates most fast excitatory transmission. Glutamate binding to AMPA receptors (AMPARs) causes most AMPARs to rapidly and completely desensitize, and their desensitization kinetics influence synaptic timing. Thus, factors that alter AMPAR desensitization influence synaptic transmission. Synaptically released zinc is such a factor. Zinc is a neuromodulator with effects on amino acid receptors and synaptic transmission in many brain regions, including the olfactory bulb (OB)...
May 10, 2019: Neuroscience
#36
JOURNAL ARTICLE
Alan D Brown, Sharan K Bagal, Paul Blackwell, David C Blakemore, Bruce Brown, Peter J Bungay, Martin Corless, James Crawforth, David Fengas, David R Fenwick, Victoria Gray, Mark Kemp, Wolfgang Klute, Laia Malet Sanz, Duncan Miller, Yoshihisa Murata, C Elizabeth Payne, Sarah Skerratt, Edward B Stevens, Joseph S Warmus
The voltage gated sodium channel NaV 1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV 1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
January 1, 2019: Bioorganic & Medicinal Chemistry
#37
JOURNAL ARTICLE
Delia Fuhrmann, Susanne Schweizer, Jovita Leung, Cait Griffin, Sarah-Jayne Blakemore
Academic diligence is the ability to regulate behavior in the service of goals, and a predictor of educational attainment. Here we combined behavioral, structural MRI, functional MRI and connectivity data to investigate the neurocognitive correlates of diligence. We assessed whether individual differences in diligence are related to the interplay between frontal control and striatal reward systems, as predicted by the dual-systems hypothesis of adolescent development. We obtained behavioral measures of diligence from 40 adolescent girls (aged 14-15 years) using the Academic Diligence Task...
August 27, 2018: Cognitive Neuroscience
#38
JOURNAL ARTICLE
Sharan K Bagal, Mark Andrews, Bruce M Bechle, Jianwei Bian, James Bilsland, David C Blakemore, John F Braganza, Peter J Bungay, Matthew S Corbett, Ciaran N Cronin, Jingrong Jean Cui, Rebecca Dias, Neil J Flanagan, Samantha E Greasley, Rachel Grimley, Kim James, Eric Johnson, Linda Kitching, Michelle L Kraus, Indrawan McAlpine, Asako Nagata, Sacha Ninkovic, Kiyoyuki Omoto, Stephanie Scales, Sarah E Skerratt, Jianmin Sun, Michelle Tran-Dubé, Gareth J Waldron, Fen Wang, Joseph S Warmus
Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability...
August 9, 2018: Journal of Medicinal Chemistry
#39
JOURNAL ARTICLE
Eytan M Stein, Guillermo Garcia-Manero, David A Rizzieri, Raoul Tibes, Jesus G Berdeja, Michael R Savona, Mojca Jongen-Lavrenic, Jessica K Altman, Blythe Thomson, Stephen J Blakemore, Scott R Daigle, Nigel J Waters, A Benjamin Suttle, Alicia Clawson, Roy Pollock, Andrei Krivtsov, Scott A Armstrong, Jorge DiMartino, Eric Hedrick, Bob Löwenberg, Martin S Tallman
Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia ( MLL ) gene rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m2 per day by continuous intravenous infusion in 28-day cycles...
June 14, 2018: Blood
#40
JOURNAL ARTICLE
Sharan K Bagal, Kiyoyuki Omoto, David C Blakemore, Peter J Bungay, James G Bilsland, Philip J Clarke, Matthew S Corbett, Ciaran N Cronin, J Jean Cui, Rebecca Dias, Neil J Flanagan, Samantha E Greasley, Rachel Grimley, Eric Johnson, David Fengas, Linda Kitching, Michelle L Kraus, Indrawan McAlpine, Asako Nagata, Gareth J Waldron, Joseph S Warmus
Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach...
May 3, 2018: Journal of Medicinal Chemistry
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