Publications - 2022
Remote physiology practical: Viable alternative to in-person practical in health sciences education? |
| Tan Charmaine & Ivan Cherh Chiet Low |
| TAPS 2022, 7(2), 27-36 |
| Abstract |
| Practicals are core components of an undergraduate health sciences curriculum to promote experiential learning and motivation in students. With restrictions on traditional forms of face-to-face practicals during the COVID-19 pandemic, we designed and investigated the efficacy of remote practicals as a viable learning strategy in exercise physiology teaching. |
Magnetic field therapy enhances muscle mitochondrial bioenergetics and attenuates systemic ceramide levels following ACL reconstruction: Southeast Asian randomized-controlled pilot trial |
| Mary C. Stephenson, Lingaraj Krishna, Rina Malathi Pannir Selvan, Yee Kit Tai, Craig Jun Kit Wong, Jocelyn Naixin Yin, Shi-Jie Toh, Federico Torta, Alexander Triebl, Jürg Fröhlich, Christian Beyer, Jing Ze Li, Sara S. Tan, Chun-Kit Wong, Duraimurugan Chinnasamy, Leroy Sivappiragasam Pakkiri, Chester Lee Drum, Markus R. Wenk, John J. Totman, Alfredo Franco-Obregón |
| Journal of Orthopaedic Translation, Volume 35, 2022, Pages 99-112, ISSN 2214-031X, https://doi.org/10.1016/j.jot.2022.09.011 |
| Abstract |
| Metabolic disruption commonly follows Anterior Cruciate Ligament Reconstruction (ACLR) surgery. Brief exposure to low amplitude and frequency pulsed electromagnetic fields (PEMFs) has been shown to promote in vitro and in vivo murine myogeneses via the activation of a calcium–mitochondrial axis conferring systemic metabolic adaptations. This randomized-controlled pilot trial sought to detect local changes in muscle structure and function using MRI, and systemic changes in metabolism using plasma biomarker analyses resulting from ACLR, with or without accompanying PEMF therapy. |
Brief exposure to directionally-specific pulsed electromagnetic fields stimulates extracellular vesicle release and is antagonized by streptomycin: A potential regenerative medicine and food industry paradigm |
| Craig Jun Kit Wong, Yee Kit Tai, Jasmine Lye Yee Yap, Charlene Hui Hua Fong, Larry Sai Weng Loo, Marek Kukumberg, Jürg Fröhlich, Sitong Zhang, Jing Ze Li, Jiong-Wei Wang, Abdul JalilRufaihah, Alfredo Franco-Obregón |
| Biomaterials. 2022 Jul 6;287:121658. doi: 10.1016/j.biomaterials.2022.121658. |
| Abstract |
| Pulsing electromagnetic fields (PEMFs) have been shown to promote in vitro and in vivo myogeneses via mitohormetic survival adaptations of which secretome activation is a key component. A single 10-min exposure of donor myoblast cultures to 1.5 mT amplitude PEMFs produced a conditioned media (pCM) capable of enhancing the myogenesis of recipient cultures to a similar degree as direct magnetic exposure. Downwardly-directed magnetic fields produced greater secretome responses than upwardly-directed fields in adherent and fluid-suspended myoblasts. The suspension paradigm allowed for the rapid concentrating of secreted factors, particularly of extracellular vesicles. The brief conditioning of basal media from magnetically-stimulated myoblasts was capable of conferring myoblast survival to a greater degree than basal media supplemented with fetal bovine serum (5%). Downward-directed magnetic fields, applied directly to cells or in the form of pCM, upregulated the protein expression of TRPC channels, markers for cell cycle progression and myogenesis. Direct magnetic exposure produced mild oxidative stress, whereas pCM provision did not, providing a survival advantage on recipient cells. Streptomycin, a TRP channel antagonist, precluded the production of a myogenic pCM. We present a methodology employing a brief and non-invasive PEMF-exposure paradigm to effectively stimulate secretome production and release for commercial or clinical exploitation. |
Mapping genomic loci implicates genes and synaptic biology in schizophrenia |
| Vassily Trubetskoy, Antonio F. Pardiñas, Ting Qi, Georgia Panagiotaropoulou, Swapnil Awasthi, Tim B. Bigdeli, Julien Bryois, Chia-Yen Chen, Charlotte A. Dennison, Lynsey S. Hall, Max Lam, Kyoko Watanabe, Oleksandr Frei, Tian Ge, Janet C. Harwood, Frank Koopmans, Sigurdur Magnusson, Alexander L. Richards, Julia Sidorenko, Yang Wu, Jian Zeng, Jakob Grove, Minsoo Kim, Zhiqiang Li, Georgios Voloudakis, Wen Zhang, Mark Adams, Ingrid Agartz, Elizabeth G. Atkinson, Esben Agerbo, Mariam Al Eissa, Margot Albus, Madeline Alexander, Behrooz Z. Alizadeh, Köksal Alptekin, Thomas D. Als, Farooq Amin, Volker Arolt, Manuel Arrojo, Lavinia Athanasiu, Maria Helena Azevedo, Silviu A. Bacanu, Nicholas J. Bass, Martin Begemann, Richard A. Belliveau, Judit Bene, Beben Benyamin, Sarah E. Bergen, Giuseppe Blasi, Julio Bobes, Stefano Bonassi, Alice Braun, Rodrigo Affonseca Bressan, Evelyn J. Bromet, Richard Bruggeman, Peter F. Buckley, Randy L. Buckner, Jonas Bybjerg-Grauholm, Wiepke Cahn, Murray J. Cairns, Monica E. Calkins, Vaughan J. Carr, David Castle, Stanley V. Catts, Kimberley D. Chambert, Raymond C. K. Chan, Boris Chaumette, Wei Cheng, Eric F. C. Cheung, Siow Ann Chong, David Cohen, Angèle Consoli, Quirino Cordeiro, Javier Costas, Charles Curtis, Michael Davidson, Kenneth L. Davis, Lieuwe de Haan, Franziska Degenhardt, Lynn E. DeLisi, Ditte Demontis, Faith Dickerson, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Jubao Duan, Giuseppe Ducci, Frank Dudbridge, Johan G. Eriksson, Lourdes Fañanás, Stephen V. Faraone, Alessia Fiorentino, Andreas Forstner, Josef Frank, Nelson B. Freimer, Menachem Fromer, Alessandra Frustaci, Ary Gadelha, Giulio Genovese, Elliot S. Gershon, Marianna Giannitelli, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Javier González Peñas, Ana González-Pinto, Srihari Gopal, Jacob Gratten, Michael F. Green, Tiffany A. Greenwood, Olivier Guillin, Sinan Gülöksüz, Raquel E. Gur, Ruben C. Gur, Blanca Gutiérrez, Eric Hahn, Hakon Hakonarson, Vahram Haroutunian, Annette M. Hartmann, Carol Harvey, Caroline Hayward, Frans A. Henskens, Stefan Herms, Per Hoffmann, Daniel P. Howrigan, Masashi Ikeda, Conrad Iyegbe, Inge Joa, Antonio Julià, Anna K. Kähler, Tony Kam-Thong, Yoichiro Kamatani, Sena Karachanak-Yankova, Oussama Kebir, Matthew C. Keller, Brian J. Kelly, Andrey Khrunin, Sung-Wan Kim, Janis Klovins, Nikolay Kondratiev, Bettina Konte, Julia Kraft, Michiaki Kubo, Vaidutis Kučinskas, Zita Ausrele Kučinskiene, Agung Kusumawardhani, Hana Kuzelova-Ptackova, Stefano Landi, Laura C. Lazzeroni, Phil H. Lee, Sophie E. Legge, Douglas S. Lehrer, Rebecca Lencer, Bernard Lerer, Miaoxin Li, Jeffrey Lieberman, Gregory A. Light, Svetlana Limborska, Chih-Min Liu, Jouko Lönnqvist, Carmel M. Loughland, Jan Lubinski, Jurjen J. Luykx, Amy Lynham, Milan Macek Jr, Andrew Mackinnon, Patrik K. E. Magnusson, Brion S. Maher, Wolfgang Maier, Dolores Malaspina, Jacques Mallet, Stephen R. Marder, Sara Marsal, Alicia R. Martin, Lourdes Martorell, Manuel Mattheisen, Robert W. McCarley, Colm McDonald, John J. McGrath, Helena Medeiros, Sandra Meier, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Marina Mitjans, Espen Molden, Esther Molina, María Dolores Molto, Valeria Mondelli, Carmen Moreno, Christopher P. Morley, Gerard Muntané, Kieran C. Murphy, Inez Myin-Germeys, Igor Nenadić, Gerald Nestadt, Liene Nikitina-Zake, Cristiano Noto, Keith H. Nuechterlein, Niamh Louise O’Brien, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Vanessa Kiyomi Ota, Christos Pantelis, George N. Papadimitriou, Mara Parellada, Tiina Paunio, Renata Pellegrino, Sathish Periyasamy, Diana O. Perkins, Bruno Pfuhlmann, Olli Pietiläinen, Jonathan Pimm, David Porteous, John Powell, Diego Quattrone, Digby Quested, Allen D. Radant, Antonio Rampino, Mark H. Rapaport, Anna Rautanen, Abraham Reichenberg, Cheryl Roe, Joshua L. Roffman, Julian Roth, Matthias Rothermundt, Bart P. F. Rutten, Safaa Saker-Delye, Veikko Salomaa, Julio Sanjuan, Marcos Leite Santoro, Adam Savitz, Ulrich Schall, Rodney J. Scott, Larry J. Seidman, Sally Isabel Sharp, Jianxin Shi, Larry J. Siever, Engilbert Sigurdsson, Kang Sim, Nora Skarabis, Petr Slominsky, Hon-Cheong So, Janet L. Sobell, Erik Söderman, Helen J. Stain, Nils Eiel Steen, Agnes A. Steixner-Kumar, Elisabeth Stögmann, William S. Stone, Richard E. Straub, Fabian Streit, Eric Strengman, T. Scott Stroup, Mythily Subramaniam, Catherine A. Sugar, Jaana Suvisaari, Dragan M. Svrakic, Neal R. Swerdlow, Jin P. Szatkiewicz, Thi Minh Tam Ta, Atsushi Takahashi, Chikashi Terao, Florence Thibaut, Draga Toncheva, Paul A. Tooney, Silvia Torretta, Sarah Tosato, Gian Battista Tura, Bruce I. Turetsky, Alp Üçok, Arne Vaaler, Therese van Amelsvoort, Ruud van Winkel, Juha Veijola, John Waddington, Henrik Walter, Anna Waterreus, Bradley T. Webb, Mark Weiser, Nigel M. Williams, Stephanie H. Witt, Brandon K. Wormley, Jing Qin Wu, Zhida Xu, Robert Yolken, Clement C. Zai, Wei Zhou, Feng Zhu, Fritz Zimprich, Eşref Cem Atbaşoğlu, Muhammad Ayub, Christian Benner, Alessandro Bertolino, Donald W. Black, Nicholas J. Bray, Gerome Breen, Nancy G. Buccola, William F. Byerley, Wei J. Chen, C. Robert Cloninger, Benedicto Crespo-Facorro, Gary Donohoe, Robert Freedman, Cherrie Galletly, Michael J. Gandal, Massimo Gennarelli, David M. Hougaard, Hai-Gwo Hwu, Assen V. Jablensky, Steven A. McCarroll, Jennifer L. Moran, Ole Mors, Preben B. Mortensen, Bertram Müller-Myhsok, Amanda L. Neil, Merete Nordentoft, Michele T. Pato, Tracey L. Petryshen, Matti Pirinen, Ann E. Pulver, Thomas G. Schulze, Jeremy M. Silverman, Jordan W. Smoller, Eli A. Stahl, Debby W. Tsuang, Elisabet Vilella, Shi-Heng Wang, Shuhua Xu, Indonesia Schizophrenia Consortium, PsychENCODE, Psychosis Endophenotypes International Consortium, The SynGO Consortium, Rolf Adolfsson, Celso Arango, Bernhard T. Baune, Sintia Iole Belangero, Anders D. Børglum, David Braff, Elvira Bramon, Joseph D. Buxbaum, Dominique Campion, Jorge A. Cervilla, Sven Cichon, David A. Collier, Aiden Corvin, David Curtis, Marta Di Forti, Enrico Domenici, Hannelore Ehrenreich, Valentina Escott-Price, Tõnu Esko, Ayman H. Fanous, Anna Gareeva, Micha Gawlik, Pablo V. Gejman, Michael Gill, Stephen J. Glatt, Vera Golimbet, Kyung Sue Hong, Christina M. Hultman, Steven E. Hyman, Nakao Iwata, Erik G. Jönsson, René S. Kahn, James L. Kennedy, Elza Khusnutdinova, George Kirov, James A. Knowles, Marie-Odile Krebs, Claudine Laurent-Levinson, Jimmy Lee, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Dheeraj Malhotra, Andrew McIntosh, Andrew McQuillin, Paulo R. Menezes, Vera A. Morgan, Derek W. Morris, Bryan J. Mowry, Robin M. Murray, Vishwajit Nimgaonkar, Markus M. Nöthen, Roel A. Ophoff, Sara A. Paciga, Aarno Palotie, Carlos N. Pato, Shengying Qin, Marcella Rietschel, Brien P. Riley, Margarita Rivera, Dan Rujescu, Meram C. Saka, Alan R. Sanders, Sibylle G. Schwab, Alessandro Serretti, Pak C. Sham, Yongyong Shi, David St Clair, Hreinn Stefánsson, Kari Stefansson, Ming T. Tsuang, Jim van Os, Marquis P. Vawter, Daniel R. Weinberger, Thomas Werge, Dieter B. Wildenauer, Xin Yu, Weihua Yue, Peter A. Holmans, Andrew J. Pocklington, Panos Roussos, Evangelos Vassos, Matthijs Verhage, Peter M. Visscher, Jian Yang, Danielle Posthuma, Ole A. Andreassen, Kenneth S. Kendler, Michael J. Owen, Naomi R. Wray, Mark J. Daly, Hailiang Huang, Benjamin M. Neale, Patrick F. Sullivan, Stephan Ripke, James T. R. Walters, Michael C. O’Donovan & Schizophrenia Working Group of the Psychiatric Genomics Consortium |
| Nature. 2022 Apr 8. doi: 10.1038/s41586-022-04434-5. |
| Abstract |
| Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. |
Blocking CXCL1 signaling for hand, foot and mouth neuropathology |
| Justin Jang Hann Chu, John Jia En Chua |
| BioCentury Distillery Therapeutics. 2022 Apr 01. |
| Abstract |
| Blocking signaling via the chemokine CXCL1 could help treat neuropathological complications of hand, foot and mouth disease, which is caused by infection with human enterovirus A71. In a rat neuron cell culture model of hand foot and mouth disease, infection with enterovirus A71 induced axonal disintegration and apoptosis, and a screen for cytokines upregulated after infection identified CXCL1. In CSF samples from infected patients and mice, increased levels of CXCL1 were correlated with increased severity of neurological symptoms. In a mouse model of infection, intracranial injection of AZD5069, an inhibitor of the CXCL1 receptor CXCR2, extended survival and delayed symptom onset. |
PI3K/AKT Signaling Tips the Balance of Cytoskeletal Forces for Cancer Progression |
| Shuo Deng, Hin Chong Leong, Arpita Datta, Vennila Gopal, Alan Prem Kumar and Celestial T. Yap |
| Cancers 2022, 14(7), 1652. doi: 10.3390/cancers14071652. |
| Abstract |
| The PI3K/AKT signaling pathway plays essential roles in multiple cellular processes, which include cell growth, survival, metabolism, and motility. In response to internal and external stimuli, the PI3K/AKT signaling pathway co-opts other signaling pathways, cellular components, and cytoskeletal proteins to reshape individual cells. The cytoskeletal network comprises three main components, which are namely the microfilaments, microtubules, and intermediate filaments. Collectively, they are essential for many fundamental structures and cellular processes. In cancer, aberrant activation of the PI3K/AKT signaling cascade and alteration of cytoskeletal structures have been observed to be highly prevalent, and eventually contribute to many cancer hallmarks. Due to their critical roles in tumor progression, pharmacological agents targeting PI3K/AKT, along with cytoskeletal components, have been developed for better intervention strategies against cancer. In our review, we first discuss existing evidence in-depth and then build on recent advances to propose new directions for therapeutic intervention. |
The use of sun-shade on safe heat exposure limit on a sunny summer day: a modelling study in Japan |
| Hidenori Otani, Jason K W Lee |
| Int J Biometeorol. 2022 Jan 18. doi: 10.1007/s00484-021-02232-8. |
| Abstract |
| Sustainable methods are required to reduce the risks of thermal strain and heat-related illness without exacerbating greenhouse gas emissions. We investigated the effects of sun-shade use on safe heat exposure limit on a sunny summer day using historical climate data in Japan. We simulated a heat-acclimatised person standing at rest (metabolic heat production, 70 W·m-2) and during light work (100 W·m-2) on an asphalt pavement in the sun and sun-shade. Japan has three Köppen climate regions: tropical, temperate and cold. We analysed one city in the tropical region (24°N), three cities in the temperate region (31°N, 35°N and 39°N) and one city in the cold region (40°N). Hourly data were collected from 7 AM to 6 PM, June to September, from 2010 to 2019. The day with the longest daylight hours and the greatest solar radiation intensity was used for analysis. With sun-shade (a white polyester tarpaulin/awning), ambient temperature, global solar radiation and ground surface temperature were assumed to be 0.5°C, 45% and 6°C lower than in the sun, respectively. Sun-shade use eliminated the days with at least 1 hour exceeding safe heat exposure limit at rest in all cities. The same was observed for light work in the temperate and cold cities, although the tropical city had 2 days exceeding safe heat exposure limit during the decade. Sun-shade use on a sunny summer day can be an effective and sustainable method to reduce heat exposure hazard at rest and during light work in tropical, temperate and cold climate regions. |
PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production |
| Upadhyayula S Srinivas #, Norbert S C Tay #, Patrick Jaynes #, Akshaya Anbuselvan, Gokula K Ramachandran, Joanna D Wardyn, Michal M Hoppe, Phuong Mai Hoang, Yanfen Peng, Sherlly Lim, May Yin Lee, Praveen C Peethala, Omer An, Akshay Shendre, Bryce W Q Tan, Sherlyn Jemimah, Manikandan Lakshmanan, Longyu Hu, Rekha Jakhar, Karishma Sachaphibulkij, Lina H K Lim, Shazib Pervaiz, Karen Crasta, Henry Yang, Patrick Tan, Chao Liang, Lena Ho, Vartika Khanchandani, Dennis Kappei, Wei Peng Yong, David S P Tan, Matteo Bordi, Silvia Campello, Wai Leong Tam, Christian Frezza, Anand D Jeyasekharan |
| Oncogene. 2022 Mar 2. doi: 10.1038/s41388-022-02219-8. |
| Abstract |
| Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2/M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer. |
Educational dialogue on public perception of nuclear radiation |
| Varsha Hande, Karthik Prathaban, M. Prakash Hande |
| Int J Radiat Biol. 2022;98(2):158-172. doi: 10.1080/09553002.2022.2009147. |
| Abstract |
| Across the world, nuclear radiation and its effects on the population has been the topic of back-burner debates, given the strong emotional connotations involved. We believe that education is crucial for people to make informed decisions regarding nuclear energy. With a science-technology-society (STS) approach, a seminar-style educational module on Radiation and Society was formulated at Tembusu College, National University of Singapore (NUS) in 2015. This primarily aimed to equip students with the necessary analytical tools to assess evidence and thus, evaluate existing assumptions on radiation/nuclear power/nuclear energy, the effects on mankind and societal perception of radiation. |
Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection |
| Saravanan Gunaseelan, Mohammed Zacky Ariffin, Sanjay Khanna, Mong How Ooi, David Perera, Justin Jang Hann Chu, John Jia En Chua |
| Nat Commun. 2022 Feb 16;13(1):890. doi: 10.1038/s41467-022-28533-z. |
| Abstract |
| Hand, foot and mouth disease (HFMD) caused by Human Enterovirus A71 (HEVA71) infection is typically a benign infection. However, in minority of cases, children can develop severe neuropathology that culminate in fatality. Approximately 36.9% of HEVA71-related hospitalizations develop neurological complications, of which 10.5% are fatal. Yet, the mechanism by which HEVA71 induces these neurological deficits remain unclear. Here, we show that HEVA71-infected astrocytes release CXCL1 which supports viral replication in neurons by activating the CXCR2 receptor-associated ERK1/2 signaling pathway. Elevated CXCL1 levels correlates with disease severity in a HEVA71-infected mice model. In humans infected with HEVA71, high CXCL1 levels are only present in patients presenting neurological complications. CXCL1 release is specifically triggered by VP4 synthesis in HEVA71-infected astrocytes, which then acts via its receptor CXCR2 to enhance viral replication in neurons. Perturbing CXCL1 signaling or VP4 myristylation strongly attenuates viral replication. Treatment with AZD5069, a CXCL1-specific competitor, improves survival and lessens disease severity in infected animals. Collectively, these results highlight the CXCL1-CXCR2 signaling pathway as a potential target against HFMD neuropathogenesis. |
EHMT1 promotes tumor progression and maintains stemness by regulating ALDH1A1 expression in alveolar rhabdomyosarcoma |
| Alamelu Nachiyappan, Joshua Ling Jun Soon, Huey Jin Lim, Victor Km Lee, Reshma Taneja |
| J Pathol. 2022 Mar;256(3):349-362. doi: 10.1002/path.5848. |
| Abstract |
| Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with poor prognosis. Cancer stem cells (CSCs) are seeds for tumor relapse and metastasis. However, pathways that maintain stemness genes are not fully understood. Here, we report that the enzyme euchromatic histone lysine methyltransferase 1 (EHMT1) is expressed in primary and relapse ARMS tumors. EHMT1 suppression impaired motility and induced differentiation in ARMS cell lines and reduced tumor progression in a mouse xenograft model in vivo. RNA sequencing of EHMT1-depleted cells revealed downregulation of ALDH1A1 that is associated with CSCs. Consistent with this, inhibition of ALDH1A1 expression and activity mimicked EHMT1 depletion phenotypes and reduced tumorsphere formation. Mechanistically, we demonstrate that EHMT1 does not bind to the ALDH1A1 promoter but activates it by stabilizing C/EBPβ, a known regulator of ALDH1A1 expression. Our findings identify a role for EHMT1 in maintenance of stemness by regulating ALDH1A1 expression and suggest that targeting ALDH+ cells is a promising strategy in ARMS. |
Shape memory micro-anchors with magnetic guidance for precision micro-vascular deployment |
| Zhihua Li, Zijian Chen, Yanan Gao, Yi Xing, Yuping Zhou, Yucheng Luo, Weihong Xu, Zhengchang Chen, Xu Gao, Kapish Gupta, Karthic Anbalakan, Lei Chen, Chuang Liu, Jian Kong, Hwa Liang Leo, Chengzhi Hu, Hanry Yu, Qiongyu Guo |
| Biomaterials. 2022 Feb 22;283:121426. doi: 10.1016/j.biomaterials.2022.121426. |
| Abstract |
| Transcatheter medical micro-devices through circulatory system show great potential for therapy but lack strategies to stably anchor them at the desired site in vascularized tissues to take actions. Here a shape memory functionalized biodegradable magnetic micro-anchor (SM2A) is developed to achieve magnetic guided endovascular localization through precisely controlled shape transformation. The SM2A comprises anisotropic polylactide-based microparticle embedded with superparamagnetic Fe3O4 nanoparticles, exhibiting thermally activated tunable shape recovery modes at a body-friendly temperature range to accomplished an efficient endovascular anchoring effect in both decellularized liver organ and rabbit ear embolization models. The SM2A can be anchored at the target micro-vessel, exhibiting a controlled radial expansion of the vessel wall yielding with estimated stresses of 7-26 kPa in contact stress and 38-218 kPa in von Mises stress. The SM2A is a promising platform to incorporate diagnostic or therapeutic agents for precision deployment and in-situ action. |
E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity |
| Jeehyun Yoon, Oleg V. Grinchuk, Roberto Tirado-Magallanes, Zhen Kai Ngian, Emmy Xue Yun Tay, You Heng Chuah, Bernice Woon Li Lee, Jia Feng, Karen Carmelina Crasta, Chin Tong Ong, Touati Benoukraf & Derrick Sek Tong Ong |
| Cell Death & Differentiation. 2022 January 2022. DOI: 10.1038/s41418-021-00926-5. |
| Abstract |
| The histone variant H2AZ is overexpressed in diverse cancer types where it facilitates the accessibility of transcriptional regulators to the promoters of cell cycle genes. However, the molecular basis for its dysregulation in cancer remains unknown. Here, we report that glioblastomas (GBM) and glioma stem cells (GSCs) preferentially overexpress H2AZ for their proliferation, stemness and tumorigenicity. Chromatin accessibility analysis of H2AZ2 depleted GSC revealed that E2F1 occupies the enhancer region within H2AZ2 gene promoter, thereby activating H2AZ2 transcription. Exploration of other H2AZ2 transcriptional activators using a customized “anti-H2AZ2” query signature for connectivity map analysis identified STAT3. Co-targeting E2F and STAT3 synergistically reduced the levels of H2AZ, histone 3 lysine 27 acetylation (H3K27ac) and cell cycle gene transcription, indicating that E2F1 and STAT3 synergize to activate H2AZ gene transcription in GSCs. Remarkably, an E2F/STAT3 inhibitor combination durably suppresses GSC tumorigenicity in an orthotopic GBM xenograft model. In glioma patients, high STAT3 signaling is associated with high E2F1 and H2AZ2 expression. Thus, GBM has uniquely opted the use of E2F1- and STAT3-containing “enhanceosomes” that integrate multiple signaling pathways to achieve H2AZ gene activation, supporting a translational path for the E2F/STAT3 inhibitor combination to be applied in GBM treatment. |
The importance of fasciculation and elongation protein zeta-1 in neural circuit establishment and neurological disorders |
| Rafhanah Banu Bte Abdul Razar, Yinghua Qu, Saravanan Gunaseelan, John Jia En Chua |
| Neural Regen Res. 2022 Jun;17(6):1165-1171. DOI: 10.4103/1673-5374.327327. |
| Abstract |
| The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly. These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions. Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders. Supporting this notion, efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation, maturation, synaptogenesis and synaptic function. Fasciculation and elongation protein zeta-1, a Kinesin-1 adapter, has emerged as a key central player involved in many of these processes. Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment. Furthermore, it acts downstream of guidance cue pathways to regulate axo-dendritic development. Significantly, perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system. Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders. Moreover, altered phosphorylation of the protein contributes to neurodegenerative disorders. Together, these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance. |
Educational dialogue on public perception of nuclear radiation |
| Varsha Hande, Karthik Prathaban & M. Prakash Hande |
| International Journal of Radiation Biology, in press. DOI: 10.1080/09553002.2022.2009147 |
| Abstract |
| Across the world, nuclear radiation and its effects on the population has been the topic of back-burner debates, given the strong emotional connotations involved. We believe that education is crucial for people to make informed decisions regarding nuclear energy. With a science-technology-society (STS) approach, a seminar-style educational module on Radiation and Society was formulated at Tembusu College, National University of Singapore (NUS) in 2015. This primarily aimed to equip students with the necessary analytical tools to assess evidence and thus, evaluate existing assumptions on radiation/nuclear power/nuclear energy, the effects on mankind and societal perception of radiation. |