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Holman pathway

Nathan Mellor, Leah R Band, Aleš Pěnčík, Ondřej Novák, Afaf Rashed, Tara Holman, Michael H Wilson, Ute Voß, Anthony Bishopp, John R King, Karin Ljung, Malcolm J Bennett, Markus R Owen
The hormone auxin is a key regulator of plant growth and development, and great progress has been made understanding auxin transport and signaling. Here, we show that auxin metabolism and homeostasis are also regulated in a complex manner. The principal auxin degradation pathways in Arabidopsis include oxidation by Arabidopsis thaliana gene DIOXYGENASE FOR AUXIN OXIDATION 1/2 (AtDAO1/2) and conjugation by Gretchen Hagen3s (GH3s). Metabolic profiling of dao1-1 root tissues revealed a 50% decrease in the oxidation product 2-oxoindole-3-acetic acid (oxIAA) and increases in the conjugated forms indole-3-acetic acid aspartic acid (IAA-Asp) and indole-3-acetic acid glutamic acid (IAA-Glu) of 438- and 240-fold, respectively, whereas auxin remains close to the WT...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Stephen W Holman, Dean E Hammond, Deborah M Simpson, John Waters, Jane L Hurst, Robert J Beynon
Protein turnover represents an important mechanism in the functioning of cells, with deregulated synthesis and degradation of proteins implicated in many diseased states. Therefore, proteomics strategies to measure turnover rates with high confidence are of vital importance to understanding many biological processes. In this study, the more widely used approach of non-targeted precursor ion signal intensity (MS1) quantification is compared with selected reaction monitoring (SRM), a data acquisition strategy that records data for specific peptides, to determine if improved quantitative data would be obtained using a targeted quantification approach...
October 28, 2016: Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences
Kevin M Elias, Megan M Emori, Thomas Westerling, Henry Long, Anna Budina-Kolomets, Fugen Li, Emily MacDuffie, Michelle R Davis, Alexander Holman, Brian Lawney, Matthew L Freedman, John Quackenbush, Myles Brown, Ronny Drapkin
Regulation of lineage-restricted transcription factors has been shown to influence malignant transformation in several types of cancer. Whether similar mechanisms are involved in ovarian cancer pathogenesis is unknown. PAX8 is a nuclear transcription factor that controls the embryologic development of the Müllerian system, including the fallopian tubes. Recent studies have shown that fallopian tube secretory epithelial cells (FTSECs) give rise to the most common form of ovarian cancer, high-grade serous ovarian carcinomas (HGSOCs)...
August 18, 2016: JCI Insight
Jennifer Yeung, Benjamin E Tourdot, Reheman Adili, Abigail R Green, Cody J Freedman, Pilar Fernandez-Perez, Johnny Yu, Theodore R Holman, Michael Holinstat
OBJECTIVE: Dietary supplementation with polyunsaturated fatty acids has been widely used for primary and secondary prevention of cardiovascular disease in individuals at risk; however, the cardioprotective benefits of polyunsaturated fatty acids remain controversial because of lack of mechanistic and in vivo evidence. We present direct evidence that an omega-6 polyunsaturated fatty acid, dihomo-γ-linolenic acid (DGLA), exhibits in vivo cardioprotection through 12-lipoxygenase (12-LOX) oxidation of DGLA to its reduced oxidized lipid form, 12(S)-hydroxy-8Z,10E,14Z-eicosatrienoic acid (12(S)-HETrE), inhibiting platelet activation and thrombosis...
October 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
S E Legge, M L Hamshere, S Ripke, A F Pardinas, J I Goldstein, E Rees, A L Richards, G Leonenko, L F Jorskog, K D Chambert, D A Collier, G Genovese, I Giegling, P Holmans, A Jonasdottir, G Kirov, S A McCarroll, J H MacCabe, K Mantripragada, J L Moran, B M Neale, H Stefansson, D Rujescu, M J Daly, P F Sullivan, M J Owen, M C O'Donovan, J T R Walters
The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses...
July 12, 2016: Molecular Psychiatry
Uttio Roy Chowdhury, Kimberly B Viker, Kristen L Stoltz, Bradley H Holman, Michael P Fautsch, Peter I Dosa
ATP-sensitive potassium (KATP) channel openers have emerged as potential therapeutics for the treatment of glaucoma, lowering intraocular pressure (IOP) in animal models and cultured human anterior segments. We have prepared water-soluble phosphate and dipeptide derivatives of the KATP channel opener cromakalim and evaluated their IOP lowering capabilities in vivo. In general, the phosphate derivatives proved to be more chemically robust and efficacious at lowering IOP with once daily dosing in a normotensive mouse model...
July 14, 2016: Journal of Medicinal Chemistry
James Rc Miller, Kitty K Lo, Ralph Andre, Davina J Hensman Moss, Ulrike Träger, Timothy C Stone, Lesley Jones, Peter Holmans, Vincent Plagnol, Sarah J Tabrizi
Innate immune activation beyond the central nervous system is emerging as a vital component of the pathogenesis of neurodegeneration. Huntington's disease is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The systemic innate immune system is thought to act as a modifier of disease progression; however, the molecular mechanisms remain only partially understood. Here we use RNA sequencing to perform whole transcriptome analysis of primary monocytes from thirty manifest Huntington's disease patients and thirty-three control subjects, cultured with and without a proinflammatory stimulus...
May 11, 2016: Human Molecular Genetics
Conceição Bettencourt, Davina Hensman-Moss, Michael Flower, Sarah Wiethoff, Alexis Brice, Cyril Goizet, Giovanni Stevanin, Georgios Koutsis, Georgia Karadima, Marios Panas, Petra Yescas-Gómez, Lizbeth Esmeralda García-Velázquez, María Elisa Alonso-Vilatela, Manuela Lima, Mafalda Raposo, Bryan Traynor, Mary Sweeney, Nicholas Wood, Paola Giunti, Alexandra Durr, Peter Holmans, Henry Houlden, Sarah J Tabrizi, Lesley Jones
OBJECTIVE: The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome-wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases...
June 2016: Annals of Neurology
Antonia Klein, Eva Schultner, Helena Lowak, Lukas Schrader, Jürgen Heinze, Luke Holman, Jan Oettler
The major transition to eusociality required the evolution of a switch to canalize development into either a reproductive or a helper, the nature of which is currently unknown. Following predictions from the 'theory of facilitated variation', we identify sex differentiation pathways as promising candidates because of their pre-adaptation to regulating development of complex phenotypes. We show that conserved core genes, including the juvenile hormone-sensitive master sex differentiation gene doublesex (dsx) and a krüppel homolog 2 (kr-h2) with putative regulatory function, exhibit both sex and morph-specific expression across life stages in the ant Cardiocondyla obscurior...
March 2016: PLoS Genetics
Tarjinder Singh, Mitja I Kurki, David Curtis, Shaun M Purcell, Lucy Crooks, Jeremy McRae, Jaana Suvisaari, Himanshu Chheda, Douglas Blackwood, Gerome Breen, Olli Pietiläinen, Sebastian S Gerety, Muhammad Ayub, Moira Blyth, Trevor Cole, David Collier, Eve L Coomber, Nick Craddock, Mark J Daly, John Danesh, Marta DiForti, Alison Foster, Nelson B Freimer, Daniel Geschwind, Mandy Johnstone, Shelagh Joss, Georg Kirov, Jarmo Körkkö, Outi Kuismin, Peter Holmans, Christina M Hultman, Conrad Iyegbe, Jouko Lönnqvist, Minna Männikkö, Steve A McCarroll, Peter McGuffin, Andrew M McIntosh, Andrew McQuillin, Jukka S Moilanen, Carmel Moore, Robin M Murray, Ruth Newbury-Ecob, Willem Ouwehand, Tiina Paunio, Elena Prigmore, Elliott Rees, David Roberts, Jennifer Sambrook, Pamela Sklar, David St Clair, Juha Veijola, James T R Walters, Hywel Williams, Patrick F Sullivan, Matthew E Hurles, Michael C O'Donovan, Aarno Palotie, Michael J Owen, Jeffrey C Barrett
By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties...
April 2016: Nature Neuroscience
Saravanan S Karuppagounder, Ishraq Alim, Soah J Khim, Megan W Bourassa, Sama F Sleiman, Roseleen John, Cyrille C Thinnes, Tzu-Lan Yeh, Marina Demetriades, Sandra Neitemeier, Dana Cruz, Irina Gazaryan, David W Killilea, Lewis Morgenstern, Guohua Xi, Richard F Keep, Timothy Schallert, Ryan V Tappero, Jian Zhong, Sunghee Cho, Frederick R Maxfield, Theodore R Holman, Carsten Culmsee, Guo-Hua Fong, Yijing Su, Guo-li Ming, Hongjun Song, John W Cave, Christopher J Schofield, Frederick Colbourne, Giovanni Coppola, Rajiv R Ratan
Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH...
March 2, 2016: Science Translational Medicine
David L Tabb, Xia Wang, Steven A Carr, Karl R Clauser, Philipp Mertins, Matthew C Chambers, Jerry D Holman, Jing Wang, Bing Zhang, Lisa J Zimmerman, Xian Chen, Harsha P Gunawardena, Sherri R Davies, Matthew J C Ellis, Shunqiang Li, R Reid Townsend, Emily S Boja, Karen A Ketchum, Christopher R Kinsinger, Mehdi Mesri, Henry Rodriguez, Tao Liu, Sangtae Kim, Jason E McDermott, Samuel H Payne, Vladislav A Petyuk, Karin D Rodland, Richard D Smith, Feng Yang, Daniel W Chan, Bai Zhang, Hui Zhang, Zhen Zhang, Jian-Ying Zhou, Daniel C Liebler
The NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) employed a pair of reference xenograft proteomes for initial platform validation and ongoing quality control of its data collection for The Cancer Genome Atlas (TCGA) tumors. These two xenografts, representing basal and luminal-B human breast cancer, were fractionated and analyzed on six mass spectrometers in a total of 46 replicates divided between iTRAQ and label-free technologies, spanning a total of 1095 LC-MS/MS experiments. These data represent a unique opportunity to evaluate the stability of proteomic differentiation by mass spectrometry over many months of time for individual instruments or across instruments running dissimilar workflows...
March 4, 2016: Journal of Proteome Research
A Thapar, J Martin, E Mick, A Arias Vásquez, K Langley, S W Scherer, R Schachar, J Crosbie, N Williams, B Franke, J Elia, J Glessner, H Hakonarson, M J Owen, S V Faraone, M C O'Donovan, P Holmans
A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders...
September 2016: Molecular Psychiatry
Assunta De Rienzo, Michael A Archer, Beow Y Yeap, Nhien Dao, Daniele Sciaranghella, Antonios C Sideris, Yifan Zheng, Alexander G Holman, Yaoyu E Wang, Paola S Dal Cin, Jonathan A Fletcher, Renee Rubio, Larry Croft, John Quackenbush, Peter E Sugarbaker, Kiara J Munir, Jesse R Battilana, Corinne E Gustafson, Lucian R Chirieac, Soo Meng Ching, James Wong, Liang Chung Tay, Stephen Rudd, Robert Hercus, David J Sugarbaker, William G Richards, Raphael Bueno
Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM...
January 15, 2016: Cancer Research
Uttio Roy Chowdhury, Cindy K Bahler, Bradley H Holman, Peter I Dosa, Michael P Fautsch
Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Unfortunately, all current therapeutics used to treat elevated IOP and glaucoma have significant and sometimes irreversible side effects necessitating the development of novel compounds. We evaluated the IOP lowering ability of the broad spectrum KATP channel opener cromakalim. Cultured human anterior segments when treated with 2 μM cromakalim showed a decrease in pressure (19...
2015: PloS One
J Chakedis, R French, M Babicky, D Jaquish, H Howard, E Mose, R Lam, P Holman, J Miyamoto, Z Walterscheid, A M Lowy
The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations in MST1R are rare, alternative splice variants have been previously reported in epithelial cancers. We report the discovery of a novel RON isoform discovered in human pancreatic cancer. Partial splicing of exons 5 and 6 (P5P6) produces a RON isoform that lacks the first extracellular immunoglobulin-plexin-transcription domain. The splice variant is detected in 73% of xenografts derived from pancreatic adenocarcinoma patients and 71% of pancreatic cancer cell lines...
June 23, 2016: Oncogene
Franziska Bender, Maria Gorbati, Marta Carus Cadavieco, Natalia Denisova, Xiaojie Gao, Constance Holman, Tatiana Korotkova, Alexey Ponomarenko
Hippocampal theta oscillations support encoding of an animal's position during spatial navigation, yet longstanding questions about their impact on locomotion remain unanswered. Combining optogenetic control of hippocampal theta oscillations with electrophysiological recordings in mice, we show that hippocampal theta oscillations regulate locomotion. In particular, we demonstrate that their regularity underlies more stable and slower running speeds during exploration. More regular theta oscillations are accompanied by more regular theta-rhythmic spiking output of pyramidal cells...
2015: Nature Communications
R S Metcalfe, F Koumanov, J S Ruffino, K A Stokes, G D Holman, D Thompson, N B J Vollaard
PURPOSE: We have previously shown that 6 weeks of reduced-exertion high-intensity interval training (REHIT) improves VO2max in sedentary men and women and insulin sensitivity in men. Here, we present two studies examining the acute physiological and molecular responses to REHIT. METHODS: In Study 1, five men and six women (age: 26 ± 7 year, BMI: 23 ± 3 kg m(-2), VO2max: 51 ± 11 ml kg(-1) min(-1)) performed a single 10-min REHIT cycling session (60 W and two 20-s 'all-out' sprints), with vastus lateralis biopsies taken before and 0, 30, and 180 min post-exercise for analysis of glycogen content, phosphorylation of AMPK, p38 MAPK and ACC, and gene expression of PGC1α and GLUT4...
November 2015: European Journal of Applied Physiology
Seong-Su Han, Van S Tompkins, Dong-Ju Son, Sangwoo Han, Hwakyung Yun, Natalie L Kamberos, Casey L Dehoedt, Chunyan Gu, Carol Holman, Guido Tricot, Fenghuang Zhan, Siegfried Janz
BACKGROUND: Comparative genetic and biological studies on malignant tumor counterparts in human beings and laboratory mice may be powerful gene discovery tools for blood cancers, including neoplasms of mature B-lymphocytes and plasma cells such as Burkitt lymphoma (BL) and multiple myeloma (MM). METHODS: We used EMSA to detect constitutive NF-κB/STAT3 activity in BL- and MM-like neoplasms that spontaneously developed in single-transgenic IL6 (interleukin-6) or MYC (c-Myc) mice, or in double-transgenic IL6MYC mice...
2015: Experimental Hematology & Oncology
Sarah A Tersey, Esther Bolanis, Theodore R Holman, David J Maloney, Jerry L Nadler, Raghavendra G Mirmira
The insulin producing islet β-cells have increasingly gained attention for their role in the pathogeneses of virtually all forms of diabetes. Dysfunction, de-differentiation, and/or death of β-cells are pivotal features in the transition from normoglycemia to hyperglycemia in both animal models of metabolic disease and humans. In both type 1 and type 2 diabetes, inflammation appears to be a central cause of β-cell derangements, and molecular pathways that modulate inflammation or the inflammatory response are felt to be prime targets of future diabetes therapy...
June 2015: Molecular Endocrinology
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