593 results on '"Haggarty P"'
Search Results
2. Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency
- Author
-
Tesla, Rachel, Guhl, Charlotte, Werthmann, Gordon C., Dixon, Danielle, Cenik, Basar, Addepalli, Yesu, Liang, Jue, Fass, Daniel M., Rosenthal, Zachary, Haggarty, Stephen J., Williams, Noelle S., Posner, Bruce A., Ready, Joseph M., and Herz, Joachim
- Published
- 2024
- Full Text
- View/download PDF
3. Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia
- Author
-
Rosenthal, Zachary C., Fass, Daniel M., Payne, N. Connor, She, Angela, Patnaik, Debasis, Hennig, Krista M., Tesla, Rachel, Werthmann, Gordon C., Guhl, Charlotte, Reis, Surya A., Wang, Xiaoyu, Chen, Yueting, Placzek, Michael, Williams, Noelle S., Hooker, Jacob, Herz, Joachim, Mazitschek, Ralph, and Haggarty, Stephen J.
- Published
- 2024
- Full Text
- View/download PDF
4. Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency
- Author
-
Rachel Tesla, Charlotte Guhl, Gordon C. Werthmann, Danielle Dixon, Basar Cenik, Yesu Addepalli, Jue Liang, Daniel M. Fass, Zachary Rosenthal, Stephen J. Haggarty, Noelle S. Williams, Bruce A. Posner, Joseph M. Ready, and Joachim Herz
- Subjects
Science - Abstract
Abstract Heterozygous loss-of-function mutations in the GRN gene are a major cause of hereditary frontotemporal dementia. The mechanisms linking frontotemporal dementia pathogenesis to progranulin deficiency are not well understood, and there is currently no treatment. Our strategy to prevent the onset and progression of frontotemporal dementia in patients with GRN mutations is to utilize small molecule positive regulators of GRN expression to boost progranulin levels from the remaining functional GRN allele, thus restoring progranulin levels back to normal within the brain. This work describes a series of blood-brain-barrier-penetrant small molecules which significantly increase progranulin protein levels in human cellular models, correct progranulin protein deficiency in Grn +/− mouse brains, and reverse lysosomal proteome aberrations, a phenotypic hallmark of frontotemporal dementia, more efficiently than the previously described small molecule suberoylanilide hydroxamic acid. These molecules will allow further elucidation of the cellular functions of progranulin and its role in frontotemporal dementia and will also serve as lead structures for further drug development.
- Published
- 2024
- Full Text
- View/download PDF
5. Few-shot meta-learning applied to whole brain activity maps improves systems neuropharmacology and drug discovery
- Author
-
Xuan Luo, Yanyun Ding, Yi Cao, Zhen Liu, Wenchong Zhang, Shangzhi Zeng, Shuk Han Cheng, Honglin Li, Stephen J. Haggarty, Xin Wang, Jin Zhang, and Peng Shi
- Subjects
Biological sciences ,Natural sciences ,Neuroscience ,Pharmacology ,Systems neuroscience ,Science - Abstract
Summary: In this study, we present an approach to neuropharmacological research by integrating few-shot meta-learning algorithms with brain activity mapping (BAMing) to enhance the discovery of central nervous system (CNS) therapeutics. By utilizing patterns from previously validated CNS drugs, our approach facilitates the rapid identification and prediction of potential drug candidates from limited datasets, thereby accelerating the drug discovery process. The application of few-shot meta-learning algorithms allows us to adeptly navigate the challenges of limited sample sizes prevalent in neuropharmacology. The study reveals that our meta-learning-based convolutional neural network (Meta-CNN) models demonstrate enhanced stability and improved prediction accuracy over traditional machine-learning methods. Moreover, our BAM library proves instrumental in classifying CNS drugs and aiding in pharmaceutical repurposing and repositioning. Overall, this research not only demonstrates the effectiveness in overcoming data limitations but also highlights the significant potential of combining BAM with advanced meta-learning techniques in CNS drug discovery.
- Published
- 2024
- Full Text
- View/download PDF
6. Automatic detection of unidentified fish sounds: a comparison of traditional machine learning with deep learning
- Author
-
Xavier Mouy, Stephanie K. Archer, Stan Dosso, Sarah Dudas, Philina English, Colin Foord, William Halliday, Francis Juanes, Darienne Lancaster, Sofie Van Parijs, and Dana Haggarty
- Subjects
passive acoustics ,random forest ,convolutional neural networks ,British Columbia ,Florida ,Geophysics. Cosmic physics ,QC801-809 ,Meteorology. Climatology ,QC851-999 - Abstract
Many species of fishes around the world are soniferous. The types of sounds fishes produce vary among species and regions but consist typically of low-frequency (
- Published
- 2024
- Full Text
- View/download PDF
7. Lack of effect of methamphetamine on reward-related brain activity in healthy adults
- Author
-
Haggarty, Connor J., Glazer, James E., Nusslock, Robin, Lee, Royce, and de Wit, Harriet
- Published
- 2024
- Full Text
- View/download PDF
8. Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated Ca2+ entry and accelerated differentiation
- Author
-
Hewitt, Tristen, Alural, Begüm, Tilak, Manali, Wang, Jennifer, Becke, Natalina, Chartley, Ellis, Perreault, Melissa, Haggarty, Stephen J., Sheridan, Steven D., Perlis, Roy H., Jones, Nina, Mellios, Nikolaos, and Lalonde, Jasmin
- Published
- 2023
- Full Text
- View/download PDF
9. Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia
- Author
-
Zachary C. Rosenthal, Daniel M. Fass, N. Connor Payne, Angela She, Debasis Patnaik, Krista M. Hennig, Rachel Tesla, Gordon C. Werthmann, Charlotte Guhl, Surya A. Reis, Xiaoyu Wang, Yueting Chen, Michael Placzek, Noelle S. Williams, Jacob Hooker, Joachim Herz, Ralph Mazitschek, and Stephen J. Haggarty
- Subjects
Medicine ,Science - Abstract
Abstract Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells. In terms of potential for disease modification, we show BETi treatment effectively restores PGRN levels in neural cells with a GRN mutation known to cause PGRN haploinsufficiency and FTD. We demonstrate that BETi can rapidly and durably enhance PGRN in neural progenitor cells (NPCs) in a manner dependent upon BET protein expression, suggesting a gain-of-function mechanism. We further describe a CNS-optimized BETi chemotype that potently engages endogenous BRD4 and enhances PGRN expression in neuronal cells. Our results reveal a new epigenetic target for treating PGRN-deficient forms of FTD and provide mechanistic insight to aid in translating this discovery into therapeutics.
- Published
- 2024
- Full Text
- View/download PDF
10. Spatial restrictions hinder avoidance of choke species in an Indigenous rights‐based fishery
- Author
-
Philina A. English, Candace M. Picco, Jessica C. Edwards, Dana R. Haggarty, Robyn E. Forrest, and Sean C. Anderson
- Subjects
bycatch ,commercial longline data ,community fishery ,Indigenous rights ,spatial management ,spatiotemporal random fields ,Human ecology. Anthropogeography ,GF1-900 ,Ecology ,QH540-549.5 - Abstract
Abstract Nutrient‐rich waters along the Pacific coast of North America support diverse fish communities that have helped sustain coastal peoples for millennia. Five Nuu‐chah‐nulth First Nations on the west coast of what is now known as Vancouver Island, Canada, hold constitutional Indigenous rights to conduct a multispecies community fishery, which includes Pacific Halibut (Hippoglossus stenolepis). A 2009 court decision defined the extent of these Indigenous rights to be within 9 nm of the coast, thereby not fully recognizing the knowledge and authority of the traditional leadership and raising concerns about the potential for an increase in rockfish bycatch. Yelloweye Rockfish (Sebastes ruberrimus) are a potential ‘choke’ species for this fishery because the two species occupy similar depth ranges. A choke species is one that is caught incidentally while targeting other species and, if caught in excess of its quota limits, can trigger a halt to fishing on the target species. Guided by the insights of local Indigenous peoples and using both fishery‐independent survey and commercial longline catch data, we investigated the effects of fishing depth and spatial restriction on the relative catch weights of these two species using spatiotemporal models. We find evidence that a confined fishing area can limit opportunities for avoiding choke species. Specifically, fishing at depths deeper than 175 m, which occur outside the court defined area (CDA), would provide more opportunities for catching halibut while avoiding Yelloweye Rockfish than are currently available within the CDA. This Indigenous‐informed, analytical approach to a management problem is just one example of how Western scientists can engage in coproduction of knowledge with Indigenous peoples to transition from the ‘status quo’ towards a practice of ‘Two‐Eyed Seeing’ that more effectively balances Indigenous rights and species conservation. Policy implications: Our study highlights (1) the importance of considering choke species distributions and opportunities for their avoidance when implementing spatial harvest restrictions and (2) how related analytical and management decisions can benefit from being guided by the advice of Indigenous knowledge holders. Read the free Plain Language Summary for this article on the Journal blog.
- Published
- 2024
- Full Text
- View/download PDF
11. Developing a data repository to support interdisciplinary research into childhood stunting: a UKRI GCRF Action Against Stunting Hub protocol paper
- Author
-
Peter Wood, Bharati Kulkarni, Babacar Faye, Little Flower Augustine, Paul Haggarty, Claire Heffernan, Modou Lamin Jobarteh, D M Dinesh Yadav, Assana Diop, Manne Munikumar, Kaitlin Conway-Moore, Darius Tetsa Tata, Val Katerinchuk, and Fassiatou Tairou
- Subjects
Pediatrics ,RJ1-570 - Published
- 2024
- Full Text
- View/download PDF
12. Epigenetic studies in children at risk of stunting and their parents in India, Indonesia and Senegal: a UKRI GCRF Action Against Stunting Hub protocol paper
- Author
-
Graham W Horgan, Bharati Kulkarni, Babacar Faye, Little Flower Augustine, Anouschka S Ramsteijn, Paul Haggarty, Umi Fahmida, Min Kyaw Htet, Rajender Rao Kalashikam, Tiffany C Angelin, Mifa Nurfadilah, Nur L Zahra, Dwi Yanti, Aicha Djigal, Magatte Ndiaye, Dinesh Yadav DM, Manjula Gorre, Dantham Subrahamanyam, Sai Santhosh Vadakattu, and Manne Munikumar
- Subjects
Pediatrics ,RJ1-570 - Published
- 2024
- Full Text
- View/download PDF
13. Improving gut health and growth in early life: a protocol for an individually randomised, two-arm, open-label, controlled trial of a synbiotic in infants in Kaffrine District, Senegal
- Author
-
Benjamin Momo Kadia, Stephen J Allen, Babacar Faye, Doudou Sow, Marietou Khouma, Anouschka S Ramsteijn, Beatriz Calvo-Urbano, Modou L Jobarteh, Elaine Ferguson, Paul Haggarty, Joanne P Webster, Alan W Walker, and Claire Heffernan
- Subjects
Pediatrics ,RJ1-570 - Published
- 2024
- Full Text
- View/download PDF
14. Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing
- Author
-
Lien D. Nguyen, Zhiyun Wei, M. Catarina Silva, Sergio Barberán-Soler, Jiarui Zhang, Rosalia Rabinovsky, Christina R. Muratore, Jonathan M. S. Stricker, Colin Hortman, Tracy L. Young-Pearse, Stephen J. Haggarty, and Anna M. Krichevsky
- Subjects
Science - Abstract
Abstract MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. Therefore, miRNA replacement or inhibition can be harnessed as potential therapeutics. However, existing strategies for miRNA modulation using oligonucleotides and gene therapies are challenging, especially for neurological diseases, and none have yet gained clinical approval. We explore a different approach by screening a biodiverse library of small molecule compounds for their ability to modulate hundreds of miRNAs in human induced pluripotent stem cell-derived neurons. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key neuroprotective miRNA downregulated in Alzheimer’s disease and other tauopathies. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. More generally, our dataset of 1370 drug-like compounds and their effects on the miRNome provides a valuable resource for further miRNA-based drug discovery.
- Published
- 2023
- Full Text
- View/download PDF
15. Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing
- Author
-
Nguyen, Lien D., Wei, Zhiyun, Silva, M. Catarina, Barberán-Soler, Sergio, Zhang, Jiarui, Rabinovsky, Rosalia, Muratore, Christina R., Stricker, Jonathan M. S., Hortman, Colin, Young-Pearse, Tracy L., Haggarty, Stephen J., and Krichevsky, Anna M.
- Published
- 2023
- Full Text
- View/download PDF
16. Anthropometric, biochemical, dietary, morbidity and well-being assessments in women and children in Indonesia, India and Senegal: a UKRI GCRF Action Against Stunting Hub protocol paper
- Author
-
Benjamin Momo Kadia, Stephen Allen, Rebecca Pradeilles, Bharati Kulkarni, Babacar Faye, Alan Walker, Raghu Pullakhandam, Teena Dasi, Ravindranadh Palika, Santosh Kumar Banjara, Ibrahima Diallo, Elaine Ferguson, Paul Haggarty, Joanne P Webster, Claire Heffernan, Umi Fahmida, Min Kyaw Htet, Tiffany C Angelin, Modou Lamin Jobarteh, Hilary Davies-Kershaw, Kiruthika Selvaraj, Nur L Zahra, Dwi Yanti, Dewi Shinta, Radhika Madhari, Sylvia Fernandez Rao, Dharani Pratyusha Palepu, Dinesh Yadev, Saliou Diouf, Philomene Lopez-Sall, Babacar Diallo, Princillia Mouissi, Sally Fall, Aicha Djigal, Tabitha D Van Immerzeel, Fassia Tairou, Assana Diop, Sara Strout, and Darius Tetsa Tata
- Subjects
Pediatrics ,RJ1-570 - Published
- 2024
- Full Text
- View/download PDF
17. Eggs for Improving Nutrition, cognitive development and reducing linear growth retardation among Infants and young Children (ENRICH): protocol of an egg supplementation trial among children aged 9–18 months in Hyderabad, India
- Author
-
Bharati Kulkarni, Little Flower Augustine, Raghu Pullakhandam, Teena Dasi, Ravindranadh Palika, Santosh Kumar Banjara, Elaine Ferguson, Paul Haggarty, Claire Heffernan, Rajender Rao Kalashikam, Modou Lamin Jobarteh, Hilary Davies-Kershaw, Kiruthika Selvaraj, Radhika Madhari, Sylvia Fernandez Rao, Dharani Pratyusha Palepu, Ramachandrappa Naveen Kumar, Sai Ram Challa, Monica Chilumula, and Preethi Gopinath
- Subjects
Pediatrics ,RJ1-570 - Published
- 2024
- Full Text
- View/download PDF
18. Assessment of the role of gut health in childhood stunting in a multisite, longitudinal study in India, Indonesia and Senegal: a UKRI GCRF Action Against Stunting Hub protocol
- Author
-
Benjamin Momo Kadia, Stephen Allen, Bharati Kulkarni, Babacar Faye, Teena Dasi, Doudou Sow, Anouschka S Ramsteijn, Beatriz Calvo-Urbano, Elaine Ferguson, Paul Haggarty, Joanne P Webster, Alan W Walker, Claire Heffernan, Umi Fahmida, Min Kyaw Htet, Rajender Rao Kalashikam, Ritu Sharma, Arienta R P Sudibya, Sari Kusuma, Tiffany C Angelin, Mifa Nurfadilah, Modou Lamin Jobarteh, Ndeye Sokhna Diop, and Isobel Gabain
- Subjects
Pediatrics ,RJ1-570 - Published
- 2024
- Full Text
- View/download PDF
19. Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy.
- Author
-
Silva, M, Nandi, Ghata, Donovan, Katherine, Cai, Quan, Berry, Bethany, Nowak, Radoslaw, Fischer, Eric, Gray, Nathanael, Ferguson, Fleur, and Haggarty, Stephen
- Subjects
PROTAC ,frontotemporal dementia ,human neuronal models ,human stem cells ,structure-activity relationships ,targeted protein degradation ,tau - Abstract
Accumulation of misfolded, aggregating proteins concurrent with disease onset and progression is a hallmark of neurodegenerative proteinopathies. An important class of these are tauopathies, such as frontotemporal dementia (FTD) and Alzheimers disease (AD), associated with accumulation of aberrant forms of tau protein in the brain. Pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization and changes in solubility, cellular redistribution, and spreading. Development and testing of experimental therapeutics that target these pathological tau conformers requires use of cellular models that recapitulate neuronal endogenous, non-heterologous tau expression under genomic and physiological contexts relevant to disease. In this study, we employed FTD-patient induced pluripotent stem cells (iPSC)-derived neurons, expressing a tau variant or mutation, as primary models for driving a medicinal chemistry campaign around tau targeting degrader series. Our screening goal was to establish structure-activity relationships (SAR) for the different chemical series to identify the molecular composition that most efficiently led to tau degradation in human FTD ex vivo neurons. We describe the identification of the lead compound QC-01-175 and follow-up optimization strategies for this molecule. We present three final lead molecules with tau degradation activity in mutant neurons, which establishes potential disease relevance and will drive future studies on specificity and pharmacological properties.
- Published
- 2022
20. Global COVID-19 lockdown highlights humans as both threats and custodians of the environment
- Author
-
Bates, Amanda E, Primack, Richard B, Biggar, Brandy S, Bird, Tomas J, Clinton, Mary E, Command, Rylan J, Richards, Cerren, Shellard, Marc, Geraldi, Nathan R, Vergara, Valeria, Acevedo-Charry, Orlando, Colón-Piñeiro, Zuania, Ocampo, David, Ocampo-Peñuela, Natalia, Sánchez-Clavijo, Lina M, Adamescu, Cristian M, Cheval, Sorin, Racoviceanu, Tudor, Adams, Matthew D, Kalisa, Egide, Kuuire, Vincent Z, Aditya, Vikram, Anderwald, Pia, Wiesmann, Samuel, Wipf, Sonja, Badihi, Gal, Henderson, Matthew G, Loetscher, Hanspeter, Baerenfaller, Katja, Benedetti-Cecchi, Lisandro, Bulleri, Fabio, Bertocci, Iacopo, Maggi, Elena, Rindi, Luca, Ravaglioli, Chiara, Boerder, Kristina, Bonnel, Julien, Mathias, Delphine, Archambault, Philippe, Chauvaud, Laurent, Braun, Camrin D, Thorrold, Simon R, Brownscombe, Jacob W, Midwood, Jonathan D, Boston, Christine M, Brooks, Jill L, Cooke, Steven J, China, Victor, Roll, Uri, Belmaker, Jonathan, Zvuloni, Assaf, Coll, Marta, Ortega, Miquel, Connors, Brendan, Lacko, Lisa, Jayathilake, Dinusha RM, Costello, Mark J, Crimmins, Theresa M, Barnett, LoriAnne, Denny, Ellen G, Gerst, Katharine L, Marsh, RL, Posthumus, Erin E, Rodriguez, Reilly, Rosemartin, Alyssa, Schaffer, Sara N, Switzer, Jeff R, Wong, Kevin, Cunningham, Susan J, Sumasgutner, Petra, Amar, Arjun, Thomson, Robert L, Stofberg, Miqkayla, Hofmeyr, Sally, Suri, Jessleena, Stuart-Smith, Rick D, Day, Paul B, Edgar, Graham J, Cooper, Antonia T, De Leo, Fabio Cabrera, Garner, Grant, Brisay, Paulson G Des, Schrimpf, Michael B, Koper, Nicola, Diamond, Michael S, Dwyer, Ross G, Baker, Cameron J, Franklin, Craig E, Efrat, Ron, Berger-Tal, Oded, Hatzofe, Ohad, Eguíluz, Víctor M, Rodríguez, Jorge P, Fernández-Gracia, Juan, Elustondo, David, Calatayud, Vicent, English, Philina A, Archer, Stephanie K, Dudas, Sarah E, and Haggarty, Dana R
- Subjects
Life on Land ,Pandemic ,Biodiversity ,Restoration ,Global monitoring ,Environmental Sciences ,Biological Sciences ,Agricultural and Veterinary Sciences ,Ecology - Abstract
The global lockdown to mitigate COVID-19 pandemic health risks has altered human interactions with nature. Here, we report immediate impacts of changes in human activities on wildlife and environmental threats during the early lockdown months of 2020, based on 877 qualitative reports and 332 quantitative assessments from 89 different studies. Hundreds of reports of unusual species observations from around the world suggest that animals quickly responded to the reductions in human presence. However, negative effects of lockdown on conservation also emerged, as confinement resulted in some park officials being unable to perform conservation, restoration and enforcement tasks, resulting in local increases in illegal activities such as hunting. Overall, there is a complex mixture of positive and negative effects of the pandemic lockdown on nature, all of which have the potential to lead to cascading responses which in turn impact wildlife and nature conservation. While the net effect of the lockdown will need to be assessed over years as data becomes available and persistent effects emerge, immediate responses were detected across the world. Thus, initial qualitative and quantitative data arising from this serendipitous global quasi-experimental perturbation highlights the dual role that humans play in threatening and protecting species and ecosystems. Pathways to favorably tilt this delicate balance include reducing impacts and increasing conservation effectiveness.
- Published
- 2021
21. High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
- Author
-
Cheng, Chialin, Reis, Surya A, Adams, Emily T, Fass, Daniel M, Angus, Steven P, Stuhlmiller, Timothy J, Richardson, Jared, Olafson, Hailey, Wang, Eric T, Patnaik, Debasis, Beauchamp, Roberta L, Feldman, Danielle A, Silva, M Catarina, Sur, Mriganka, Johnson, Gary L, Ramesh, Vijaya, Miller, Bruce L, Temple, Sally, Kosik, Kenneth S, Dickerson, Bradford C, and Haggarty, Stephen J
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Brain Disorders ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease ,Neurosciences ,Acquired Cognitive Impairment ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research - Induced Pluripotent Stem Cell ,Stem Cell Research ,Alzheimer's Disease Related Dementias (ADRD) ,Dementia ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Aetiology ,Neurological ,Basic Helix-Loop-Helix Transcription Factors ,Biomarkers ,Cell Line ,Glutamates ,Humans ,Image Processing ,Computer-Assisted ,Induced Pluripotent Stem Cells ,Models ,Biological ,Nerve Tissue Proteins ,Neurons ,Phosphorylation ,Protein Kinases ,Proteomics ,Pyridines ,Pyrimidines ,Small Molecule Libraries ,Tauopathies ,tau Proteins - Abstract
Mutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded tau protein that can propagate between neurons ultimately leading to cell death (tauopathy). Recently, a p.A152T tau variant was identified as a risk factor for FTD, Alzheimer's disease, and synucleinopathies. Here we used induced pluripotent stem cells (iPSC) from a patient carrying this p.A152T variant to create a robust, functional cellular assay system for probing pathophysiological tau accumulation and phosphorylation. Using stably transduced iPSC-derived neural progenitor cells engineered to enable inducible expression of the pro-neural transcription factor Neurogenin 2 (Ngn2), we generated disease-relevant, cortical-like glutamatergic neurons in a scalable, high-throughput screening compatible format. Utilizing automated confocal microscopy, and an advanced image-processing pipeline optimized for analysis of morphologically complex human neuronal cultures, we report quantitative, subcellular localization-specific effects of multiple kinase inhibitors on tau, including ones under clinical investigation not previously reported to affect tau phosphorylation. These results demonstrate the potential for using patient iPSC-derived ex vivo models of tauopathy as genetically accurate, disease-relevant systems to probe tau biochemistry and support the discovery of novel therapeutics for tauopathies.
- Published
- 2021
22. A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies
- Author
-
Karch, Celeste M, Kao, Aimee W, Karydas, Anna, Onanuga, Khadijah, Martinez, Rita, Argouarch, Andrea, Wang, Chao, Huang, Cindy, Sohn, Peter Dongmin, Bowles, Kathryn R, Spina, Salvatore, Silva, M Catarina, Marsh, Jacob A, Hsu, Simon, Pugh, Derian A, Ghoshal, Nupur, Norton, Joanne, Huang, Yadong, Lee, Suzee E, Seeley, William W, Theofilas, Panagiotis, Grinberg, Lea T, Moreno, Fermin, McIlroy, Kathryn, Boeve, Bradley F, Cairns, Nigel J, Crary, John F, Haggarty, Stephen J, Ichida, Justin K, Kosik, Kenneth S, Miller, Bruce L, Gan, Li, Goate, Alison M, Temple, Sally, Alquezar, Carolina, Bowles, Kathryn, Butler, David, Hernandez, Israel, Hennes, Valerie, and Kampmann, Martin
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Regenerative Medicine ,Stem Cell Research - Induced Pluripotent Stem Cell ,Alzheimer's Disease Related Dementias (ADRD) ,Dementia ,Aging ,Acquired Cognitive Impairment ,Neurodegenerative ,Stem Cell Research ,Neurosciences ,Brain Disorders ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Alzheimer's Disease ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Pick's Disease ,Genetics ,Orphan Drug ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Cell Line ,Fibroblasts ,Gene Editing ,Humans ,Induced Pluripotent Stem Cells ,Mutation ,Neural Stem Cells ,Neurogenesis ,Neurons ,Tauopathies ,tau Proteins ,Tau Consortium Stem Cell Group ,CRISPR/Cas9 ,MAPT ,corticobasal degeneration ,fibroblasts ,frontotemporal dementia ,induced pluripotent stem cells ,neural progenitor cells ,progressive supranuclear palsy ,tau ,tauopathy ,Clinical Sciences ,Biochemistry and cell biology - Abstract
Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.
- Published
- 2019
23. Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility
- Author
-
Fass, Daniel M., Lewis, Michael C., Ahmad, Rushdy, Szucs, Matthew J., Zhang, Qiangge, Fleishman, Morgan, Wang, Dongqing, Kim, Myung Jong, Biag, Jonathan, Carr, Steven A., Scolnick, Edward M., Premont, Richard T., and Haggarty, Stephen J.
- Published
- 2022
- Full Text
- View/download PDF
24. A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy
- Author
-
Hernandez, Israel, Luna, Gabriel, Rauch, Jennifer N, Reis, Surya A, Giroux, Michel, Karch, Celeste M, Boctor, Daniel, Sibih, Youssef E, Storm, Nadia J, Diaz, Antonio, Kaushik, Susmita, Zekanowski, Cezary, Kang, Alexander A, Hinman, Cassidy R, Cerovac, Vesna, Guzman, Elmer, Zhou, Honjun, Haggarty, Stephen J, Goate, Alison M, Fisher, Steven K, Cuervo, Ana M, and Kosik, Kenneth S
- Subjects
Neurosciences ,Neurodegenerative ,Rare Diseases ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,Alzheimer's Disease Related Dementias (ADRD) ,Acquired Cognitive Impairment ,Dementia ,Development of treatments and therapeutic interventions ,Aetiology ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Brain ,Disease Models ,Animal ,Enzyme Inhibitors ,Farnesyltranstransferase ,Female ,GTP-Binding Proteins ,Humans ,Induced Pluripotent Stem Cells ,Lysosomes ,Male ,Mice ,Mice ,Transgenic ,Mutation ,Neurons ,Piperidines ,Proteolysis ,Pyridines ,RNA ,Small Interfering ,Tauopathies ,Translational Research ,Biomedical ,tau Proteins ,Biological Sciences ,Medical and Health Sciences - Abstract
Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifications of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in human induced pluripotent stem cell-derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.
- Published
- 2019
25. A microRNA cluster in the Fragile-X region expressed during spermatogenesis targets FMR1.
- Author
-
Ramaiah, Madhuvanthi, Tan, Kun, Plank, Terra-Dawn M, Song, Hye-Won, Dumdie, Jennifer N, Jones, Samantha, Shum, Eleen Y, Sheridan, Steven D, Peterson, Kevin J, Gromoll, Jörg, Haggarty, Stephen J, Cook-Andersen, Heidi, and Wilkinson, Miles F
- Subjects
Testis ,Animals ,Humans ,Mice ,MicroRNAs ,RNA ,Messenger ,3' Untranslated Regions ,Spermatogenesis ,Gene Expression Regulation ,RNA Interference ,Multigene Family ,Male ,Fragile X Mental Retardation Protein ,FMR1 ,evolution ,microRNA ,testis ,translation ,FMR1 ,Brain Disorders ,Intellectual and Developmental Disabilities (IDD) ,Genetics ,Rare Diseases ,Pediatric ,Biotechnology ,Fragile X Syndrome ,Developmental Biology ,Biochemistry and Cell Biology - Abstract
Testis-expressed X-linked genes typically evolve rapidly. Here, we report on a testis-expressed X-linked microRNA (miRNA) cluster that despite rapid alterations in sequence has retained its position in the Fragile-X region of the X chromosome in placental mammals. Surprisingly, the miRNAs encoded by this cluster (Fx-mir) have a predilection for targeting the immediately adjacent gene, Fmr1, an unexpected finding given that miRNAs usually act in trans, not in cis Robust repression of Fmr1 is conferred by combinations of Fx-mir miRNAs induced in Sertoli cells (SCs) during postnatal development when they terminate proliferation. Physiological significance is suggested by the finding that FMRP, the protein product of Fmr1, is downregulated when Fx-mir miRNAs are induced, and that FMRP loss causes SC hyperproliferation and spermatogenic defects. Fx-mir miRNAs not only regulate the expression of FMRP, but also regulate the expression of eIF4E and CYFIP1, which together with FMRP form a translational regulatory complex. Our results support a model in which Fx-mir family members act cooperatively to regulate the translation of batteries of mRNAs in a developmentally regulated manner in SCs.
- Published
- 2019
26. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
- Author
-
Swarup, Vivek, Hinz, Flora I, Rexach, Jessica E, Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T, Cheng, Chialin, Haggarty, Stephen J, Grossman, Murray, Van Deerlin, Vivianna M, Trojanowski, John Q, Lah, James J, Levey, Allan I, Kondou, Shinichi, and Geschwind, Daniel H
- Subjects
Biomedical and Clinical Sciences ,Health Sciences ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Genetics ,Dementia ,Alzheimer's Disease ,Rare Diseases ,Aging ,Brain Disorders ,Neurosciences ,Orphan Drug ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Human Genome ,Acquired Cognitive Impairment ,Biotechnology ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Animals ,Cell Death ,Disease Models ,Animal ,Evolution ,Molecular ,Frontotemporal Dementia ,Gene Expression Regulation ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,Genetic Vectors ,Humans ,Mice ,Inbred C57BL ,Mice ,Transgenic ,MicroRNAs ,Neurodegenerative Diseases ,Proteomics ,RNA ,Messenger ,Reproducibility of Results ,Transcriptome ,tau Proteins ,International Frontotemporal Dementia Genomics Consortium ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - Abstract
Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.
- Published
- 2019
27. Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis
- Author
-
Petrozziello, Tiziana, Bordt, Evan A., Mills, Alexandra N., Kim, Spencer E., Sapp, Ellen, Devlin, Benjamin A., Obeng-Marnu, Abigail A., Farhan, Sali M. K., Amaral, Ana C., Dujardin, Simon, Dooley, Patrick M., Henstridge, Christopher, Oakley, Derek H., Neueder, Andreas, Hyman, Bradley T., Spires-Jones, Tara L., Bilbo, Staci D., Vakili, Khashayar, Cudkowicz, Merit E., Berry, James D., DiFiglia, Marian, Silva, M. Catarina, Haggarty, Stephen J., and Sadri-Vakili, Ghazaleh
- Published
- 2022
- Full Text
- View/download PDF
28. Do children privilege phonological cues in noun class learning?
- Author
-
Culbertson, Jennifer, Jarvinen, Hanna, Haggarty, Frances, and Smith, Kenny
- Subjects
Noun class ,Language Acquisition ,Artificial language learning ,category learning - Abstract
Previous research on acquisition of noun class systems, such asgrammatical gender, has shown that child learners rely dispro-portionately on phonological cues to class, even when compet-ing semantic cues are more reliable. Culbertson, Gagliardi, andSmith (2017) use artificial language learning experiments withadults to argue that over-reliance on phonology may be dueto the fact that phonological cues are available first; learnersbase early representations on surface phonological dependen-cies, only later integrating semantic cues from noun meanings.Here, we show that child learners (6-7 year-olds) show thissame sensitivity to early availability. However, we also findintriguing evidence of developmental changes in sensitivity tosemantics; when both cues are simultaneously available chil-dren are more likely to rely on a phonology cue than adults.Our results suggest that early availability and a bias in favorof phonological cues may both contribute to children’s over-reliance on phonology in natural language acquisition.
- Published
- 2018
29. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles
- Author
-
Subramanian, Aravind, Narayan, Rajiv, Corsello, Steven M, Peck, David D, Natoli, Ted E, Lu, Xiaodong, Gould, Joshua, Davis, John F, Tubelli, Andrew A, Asiedu, Jacob K, Lahr, David L, Hirschman, Jodi E, Liu, Zihan, Donahue, Melanie, Julian, Bina, Khan, Mariya, Wadden, David, Smith, Ian C, Lam, Daniel, Liberzon, Arthur, Toder, Courtney, Bagul, Mukta, Orzechowski, Marek, Enache, Oana M, Piccioni, Federica, Johnson, Sarah A, Lyons, Nicholas J, Berger, Alice H, Shamji, Alykhan F, Brooks, Angela N, Vrcic, Anita, Flynn, Corey, Rosains, Jacqueline, Takeda, David Y, Hu, Roger, Davison, Desiree, Lamb, Justin, Ardlie, Kristin, Hogstrom, Larson, Greenside, Peyton, Gray, Nathanael S, Clemons, Paul A, Silver, Serena, Wu, Xiaoyun, Zhao, Wen-Ning, Read-Button, Willis, Wu, Xiaohua, Haggarty, Stephen J, Ronco, Lucienne V, Boehm, Jesse S, Schreiber, Stuart L, Doench, John G, Bittker, Joshua A, Root, David E, Wong, Bang, and Golub, Todd R
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Cell Line ,Tumor ,Drug Resistance ,Neoplasm ,Gene Expression Profiling ,Humans ,Neoplasms ,Organ Specificity ,Pharmaceutical Preparations ,Sequence Analysis ,RNA ,Small Molecule Libraries ,Functional genomics ,chemical biology ,gene expression profiling ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.
- Published
- 2017
30. An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons
- Author
-
Boselli, Monica, Lee, Byung-Hoon, Robert, Jessica, Prado, Miguel A, Min, Sang-Won, Cheng, Chialin, Silva, M Catarina, Seong, Changhyun, Elsasser, Suzanne, Hatle, Ketki M, Gahman, Timothy C, Gygi, Steven P, Haggarty, Stephen J, Gan, Li, King, Randall W, and Finley, Daniel
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Alzheimer's Disease ,Dementia ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Neurosciences ,Aging ,Acquired Cognitive Impairment ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Generic health relevance ,Animals ,Cells ,Cultured ,Cytoplasm ,Embryo ,Mammalian ,Enzyme Inhibitors ,Fibroblasts ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Neurons ,Proteasome Endopeptidase Complex ,Proteolysis ,Pyrroles ,Rats ,Sprague-Dawley ,Ubiquitin ,Ubiquitin Thiolesterase ,Ubiquitination ,tau Proteins ,neurodegenerative disease ,proteasome ,small molecule ,tauopathy ,ubiquitin ,IU1 ,IU1-47 ,Chemical Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
The ubiquitin-proteasome system (UPS) is responsible for most selective protein degradation in eukaryotes and regulates numerous cellular processes, including cell cycle control and protein quality control. A component of this system, the deubiquitinating enzyme USP14, associates with the proteasome where it can rescue substrates from degradation by removal of the ubiquitin tag. We previously found that a small-molecule inhibitor of USP14, known as IU1, can increase the rate of degradation of a subset of proteasome substrates. We report here the synthesis and characterization of 87 variants of IU1, which resulted in the identification of a 10-fold more potent USP14 inhibitor that retains specificity for USP14. The capacity of this compound, IU1-47, to enhance protein degradation in cells was tested using as a reporter the microtubule-associated protein tau, which has been implicated in many neurodegenerative diseases. Using primary neuronal cultures, IU1-47 was found to accelerate the rate of degradation of wild-type tau, the pathological tau mutants P301L and P301S, and the A152T tau variant. We also report that a specific residue in tau, lysine 174, is critical for the IU1-47-mediated tau degradation by the proteasome. Finally, we show that IU1-47 stimulates autophagic flux in primary neurons. In summary, these findings provide a powerful research tool for investigating the complex biology of USP14.
- Published
- 2017
31. Vicarious ratings of social touch the effect of age and autistic traits
- Author
-
Connor J. Haggarty, David J. Moore, Paula D. Trotter, Rachel Hagan, Francis P. McGlone, and Susannah C. Walker
- Subjects
Medicine ,Science - Abstract
Abstract Tactile sensitivities are common in Autism Spectrum Conditions (autism). Psychophysically, slow, gentle stroking touch is typically rated as more pleasant than faster or slower touch. Vicarious ratings of social touch results in a similar pattern of velocity dependent hedonic ratings as directly felt touch. Here we investigated whether adults and children’s vicarious ratings vary according to autism diagnosis and self-reported autistic traits. Adults’ scoring high on the AQ rated stroking touch on the palm as less pleasant than a Low AQ group. However, in contrast to our hypothesis, we did not find any effect of autism diagnosis on children’s touch ratings despite parental reports highlighting significant somatosensory sensitivities. These results are discussed in terms of underpinning sensory and cognitive factors.
- Published
- 2021
- Full Text
- View/download PDF
32. High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
- Author
-
Chialin Cheng, Surya A. Reis, Emily T. Adams, Daniel M. Fass, Steven P. Angus, Timothy J. Stuhlmiller, Jared Richardson, Hailey Olafson, Eric T. Wang, Debasis Patnaik, Roberta L. Beauchamp, Danielle A. Feldman, M. Catarina Silva, Mriganka Sur, Gary L. Johnson, Vijaya Ramesh, Bruce L. Miller, Sally Temple, Kenneth S. Kosik, Bradford C. Dickerson, and Stephen J. Haggarty
- Subjects
Medicine ,Science - Abstract
Abstract Mutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded tau protein that can propagate between neurons ultimately leading to cell death (tauopathy). Recently, a p.A152T tau variant was identified as a risk factor for FTD, Alzheimer's disease, and synucleinopathies. Here we used induced pluripotent stem cells (iPSC) from a patient carrying this p.A152T variant to create a robust, functional cellular assay system for probing pathophysiological tau accumulation and phosphorylation. Using stably transduced iPSC-derived neural progenitor cells engineered to enable inducible expression of the pro-neural transcription factor Neurogenin 2 (Ngn2), we generated disease-relevant, cortical-like glutamatergic neurons in a scalable, high-throughput screening compatible format. Utilizing automated confocal microscopy, and an advanced image-processing pipeline optimized for analysis of morphologically complex human neuronal cultures, we report quantitative, subcellular localization-specific effects of multiple kinase inhibitors on tau, including ones under clinical investigation not previously reported to affect tau phosphorylation. These results demonstrate the potential for using patient iPSC-derived ex vivo models of tauopathy as genetically accurate, disease-relevant systems to probe tau biochemistry and support the discovery of novel therapeutics for tauopathies.
- Published
- 2021
- Full Text
- View/download PDF
33. Lacticaseibacillus rhamnosus HN001 alters the microbiota composition in the cecum but not the feces in a piglet model
- Author
-
Wayne Young, Paul Maclean, Kelly Dunstan, Leigh Ryan, Jason Peters, Kelly Armstrong, Rachel Anderson, Hilary Dewhurst, Melanie van Gendt, Ryan N. Dilger, James Dekker, Neill Haggarty, and Nicole Roy
- Subjects
probiotic ,Lacticaseibacillus rhamnosus ,HN001 ,piglet ,microbiome ,gut ,Nutrition. Foods and food supply ,TX341-641 - Abstract
The probiotic Lacticaseibacillus rhamnosus strain HN001 has been shown to have several beneficial health effects for both pediatric and maternal groups, including reduced risk of eczema in infants and gestational diabetes and postnatal depression in mothers. While L. rhamnosus HN001 appears to modify immune and gut barrier biomarkers, its mode of action remains to be fully elucidated. To gain insights into the role of HN001 on the infant microbiome, the impacts of L. rhamnosus HN001 supplementation was studied in 10-day old male piglets that were fed either infant formula, or infant formula with L. rhamnosus HN001 at a low (1.3 × 105 CFU/ml) or high dose (7.9 × 106 CFU/ml) daily for 24 days. The cecal and fecal microbial communities were assessed by shotgun metagenome sequencing and host gene expression in the cecum and colon tissue was assessed by RNA-seq. Piglet fecal samples showed only modest differences between controls and those receiving dietary L. rhamnosus HN001. However, striking differences between the three groups were observed for cecal samples. While total lactobacilli were significantly increased only in the high dose L. rhamnosus HN001 group, both high and low dose groups showed an up to twofold reduction across the Firmicutes phylum and up to fourfold increase in Prevotella compared to controls. Methanobrevibacter was also decreased in HN001 fed piglets. Microbial genes involved in carbohydrate and vitamin metabolism were among those that differed in relative abundance between those with and without L. rhamnosus HN001. Changes in the cecal microbiome were accompanied by increased expression of tight junction pathway genes and decreased autophagy pathway genes in the cecal tissue of piglets fed the higher dose of L. rhamnosus HN001. Our findings showed supplementation with L. rhamnosus HN001 caused substantial changes in the cecal microbiome with likely consequences for key microbial metabolic pathways. Host gene expression changes in the cecum support previous research showing L. rhamnosus HN001 beneficially impacts intestinal barrier function. We show that fecal samples may not adequately reflect microbiome composition higher in the gastrointestinal tract, with the implication that effects of probiotic consumption may be missed by examining only the fecal microbiome.
- Published
- 2022
- Full Text
- View/download PDF
34. Integrated Role of Bifidobacterium animalis subsp. lactis Supplementation in Gut Microbiota, Immunity, and Metabolism of Infant Rhesus Monkeys
- Author
-
He, Xuan, Slupsky, Carolyn M, Dekker, James W, Haggarty, Neill W, and Lönnerdal, Bo
- Subjects
Microbiology ,Biological Sciences ,Biomedical and Clinical Sciences ,Medical Biochemistry and Metabolomics ,Digestive Diseases ,Nutrition ,Prevention ,Complementary and Integrative Health ,Pediatric ,Biotechnology ,3.3 Nutrition and chemoprevention ,Prevention of disease and conditions ,and promotion of well-being ,infant ,metabolome ,microbiome ,nutrition ,probiotics - Abstract
To investigate the impact of probiotic supplementation of infant formula on immune parameters, intestinal microbiota, and metabolism, five individually housed infant rhesus monkeys exclusively fed standard infant formula supplemented with probiotics (Bifidobacterium animalis subsp. lactis HN019) from birth until 3 months of age were compared with five standard formula-fed and five breast-fed monkeys. Anthropometric measurements, serum insulin, immune parameters, fecal microbiota, and metabolic profiles of serum, urine, and feces were evaluated. Consumption of B. lactis-supplemented formula reduced microbial diversity, restructured the fecal microbial community, and altered the fecal metabolome at the last two time points, in addition to increasing short-chain fatty acids in serum and urine. Circulating CCL22 was lower and threonine, branched-chain amino acids, urea, and allantoin, as well as dimethylglycine in serum and urine, were increased in the group supplemented with B. lactis compared with the standard formula-fed group. These results support a role of probiotics as effectors of gut microbial activity regulating amino acid utilization and nitrogen cycling. Future risk-benefit analyses are still needed to consolidate the existing knowledge on the long-term consequences of probiotic administration during infancy. IMPORTANCE Probiotics are becoming increasingly popular due to their perceived effects on health, despite a lack of mechanistic information on how they impart these benefits. Infant formula and complementary foods are common targets for supplementation with probiotics. However, different probiotic strains have different properties, and there is a lack of data on long-term health effects on the consumer. Given the increasing interest in supplementation with probiotics and the fact that the gastrointestinal tracts of infants are still immature, we sought to determine whether consumption of infant formula containing the probiotic Bifidobacterium animalis subsp. lactis HN019 for 3 months starting at birth would impact gut microbial colonization, as well as infant immunity and metabolism, when compared with consumption of formula alone.
- Published
- 2016
35. Assessing population recovery inside British Columbia’s Rockfish Conservation Areas with a remotely operated vehicle
- Author
-
Haggarty, Dana R, Shurin, Jonathan B, and Yamanaka, K Lynne
- Subjects
Life Below Water ,Rockfish conservation ,Marine protected area ,Rockfish ,Groundfish ,Remotely operated vehicle ,Effectiveness ,Fish habitat ,Environmental Science and Management ,Ecology ,Fisheries Sciences ,Fisheries - Published
- 2016
36. A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection.
- Author
-
Scott P Lawrence, Samra E Elser, Workineh Torben, Robert V Blair, Bapi Pahar, Pyone P Aye, Faith Schiro, Dawn Szeltner, Lara A Doyle-Meyers, Beth S Haggarty, Andrea P O Jordan, Josephine Romano, George J Leslie, Xavier Alvarez, David H O'Connor, Roger W Wiseman, Christine M Fennessey, Yuan Li, Michael Piatak, Jeffrey D Lifson, Celia C LaBranche, Andrew A Lackner, Brandon F Keele, Nicholas J Maness, Mark Marsh, and James A Hoxie
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which this signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY), replicates acutely to high levels in pigtail macaques (PTM) but is rapidly controlled. However, we previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion encoding amino acids 734-736 (ΔQTH) that overlaps the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected that generated a new signal for polarized sorting but not endocytosis. This genotype, together with the ΔGY mutation, was conserved in association with high viral loads for several months when introduced into naïve PTMs. For the first time, our findings reveal strong selection pressure for Env endocytosis and particularly for polarized sorting during pathogenic SIV infection in vivo.
- Published
- 2022
- Full Text
- View/download PDF
37. Expression profile of the matricellular protein periostin in paediatric inflammatory bowel disease
- Author
-
Tracy Coelho, Eva Sonnenberg-Riethmacher, Yifang Gao, Enrico Mossotto, Alisher Khojanazarov, Annie Griffin, Saida Mukanova, Aiymkul Ashimkhanova, Rachel Haggarty, Anton Borissenko, James J. Ashton, Imogen S. Stafford, Akshay Batra, Nadeem A. Afzal, Michael P. Stanton, Bhumita Vadgama, Kapura Adrisova, Robert M. Beattie, Anthony P. Williams, Sarah Ennis, and Dieter Riethmacher
- Subjects
Medicine ,Science - Abstract
Abstract The precise role of periostin, an extra-cellular matrix protein, in inflammatory bowel disease (IBD) is unclear. Here, we investigated periostin in paediatric IBD including its relationship with disease activity, clinical outcomes, genomic variation and expression in the colonic tissue. Plasma periostin was analysed using ELISA in 144 paediatric patients and 38 controls. Plasma levels were assessed against validated disease activity indices in IBD and clinical outcomes. An immuno-fluorescence for periostin and detailed isoform-expression analysis in the colonic tissue was performed in 23 individuals. We integrated a whole-gene based burden metric ‘GenePy’ to assess the impact of variation in POSTN and 23 other genes functionally connected to periostin. We found that plasma periostin levels were significantly increased during remission compared to active Crohn’s disease. The immuno-fluorescence analysis demonstrated enhanced peri-cryptal ring patterns in patients compared to controls, present throughout inflamed, as well as macroscopically non-inflamed colonic tissue. Interestingly, the pattern of isoforms remained unchanged during bowel inflammation compared to healthy controls. In addition to its role during the inflammatory processes in IBD, periostin may have an additional prominent role in mucosal repair. Additional studies will be necessary to understand its role in the pathogenesis, repair and fibrosis in IBD.
- Published
- 2021
- Full Text
- View/download PDF
38. Unsettling Faculty Minds: A Faculty Learning Community on Indigenization
- Author
-
Yeo, Michelle, Haggarty, Liam, Wida, Wathu, Ayoungman, Kent, Pearl, Catherine M. L., Stogre, Tanya, and Waldie, Angela
- Abstract
This chapter describes a faculty learning community formed at our university, in partnership with local Indigenous communities, as part of our response to Canada's Truth and Reconciliation Commission Calls to Action. We interviewed participants about their experiences in this group, including their challenges and transformations.
- Published
- 2019
- Full Text
- View/download PDF
39. Imprinting methylation predicts hippocampal volumes and hyperintensities and the change with age in later life
- Author
-
Marlene Lorgen-Ritchie, Alison D. Murray, Roger Staff, Anne C. Ferguson-Smith, Marcus Richards, Graham W. Horgan, Louise H. Phillips, Gwen Hoad, Chris McNeil, Antonio Ribeiro, and Paul Haggarty
- Subjects
Medicine ,Science - Abstract
Abstract Epigenetic imprinting is important for neurogenesis and brain function. Hippocampal volumes and brain hyperintensities in late life have been associated with early life circumstances. Epigenetic imprinting may underpin these associations. Methylation was measured at 982 sites in 13 imprinted locations in blood samples from a longitudinal cohort by bisulphite amplicon sequencing. Hippocampal volumes and hyperintensities were determined at age 64y and 72y using MRI. Hyperintensities were determined in white matter, grey matter and infratentorial regions. Permutation methods were used to adjust for multiple testing. At 64y, H19/IGF2 and NESPAS methylation predicted hippocampal volumes. PEG3 predicted hyperintensities in hippocampal grey matter, and white matter. GNASXL predicted grey matter hyperintensities. Changes with age were predicted for hippocampal volume (MEST1, KvDMR, L3MBTL, GNASXL), white matter (MEST1, PEG3) and hippocampal grey matter hyperintensities (MCTS2, GNASXL, NESPAS, L3MBTL, MCTS2, SNRPN, MEST1). Including childhood cognitive ability, years in education, or socioeconomic status as additional explanatory variables in regression analyses did not change the overall findings. Imprinting methylation in multiple genes predicts brain structures, and their change over time. These findings are potentially relevant to the development of novel tests of brain structure and function across the life-course, strategies to improve cognitive outcomes, and our understanding of early influences on brain development and function.
- Published
- 2021
- Full Text
- View/download PDF
40. Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
- Author
-
M. Catarina Silva, Ghata Nandi, Katherine A. Donovan, Quan Cai, Bethany C. Berry, Radoslaw P. Nowak, Eric S. Fischer, Nathanael S. Gray, Fleur M. Ferguson, and Stephen J. Haggarty
- Subjects
tau ,structure-activity relationships ,targeted protein degradation ,PROTAC ,human stem cells ,human neuronal models ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Accumulation of misfolded, aggregating proteins concurrent with disease onset and progression is a hallmark of neurodegenerative proteinopathies. An important class of these are tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD), associated with accumulation of aberrant forms of tau protein in the brain. Pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization and changes in solubility, cellular redistribution, and spreading. Development and testing of experimental therapeutics that target these pathological tau conformers requires use of cellular models that recapitulate neuronal endogenous, non-heterologous tau expression under genomic and physiological contexts relevant to disease. In this study, we employed FTD-patient induced pluripotent stem cells (iPSC)-derived neurons, expressing a tau variant or mutation, as primary models for driving a medicinal chemistry campaign around tau targeting degrader series. Our screening goal was to establish structure-activity relationships (SAR) for the different chemical series to identify the molecular composition that most efficiently led to tau degradation in human FTD ex vivo neurons. We describe the identification of the lead compound QC-01-175 and follow-up optimization strategies for this molecule. We present three final lead molecules with tau degradation activity in mutant neurons, which establishes potential disease relevance and will drive future studies on specificity and pharmacological properties.
- Published
- 2022
- Full Text
- View/download PDF
41. Advances toward precision medicine for bipolar disorder: mechanisms & molecules
- Author
-
Haggarty, Stephen J., Karmacharya, Rakesh, and Perlis, Roy H.
- Published
- 2021
- Full Text
- View/download PDF
42. Lack of recreational fishing compliance may compromise effectiveness of Rockfish Conservation Areas in British Columbia
- Author
-
Haggarty, Dana R, Martell, Steve JD, and Shurin, Jonathan B
- Subjects
Life on Land ,Life Below Water ,Ecology ,Zoology ,Fisheries Sciences ,Fisheries - Abstract
Compliance with spatial fishing regulations (e.g., marine protected areas, fishing closures) is one of the most important, yet rarely measured, determinants of ecological recovery. We used aerial observations of recreational fishing events from creel surveys before, during, and after 77 Rockfish Conservation Areas (RCAs) were established in British Columbia, Canada. There was no evidence of a change in fishing effort in 83% of the RCAs, and effort in five RCAs increased after establishment. Fishing effort in open areas adjacent to the RCAs declined with time and was higher than effort in the RCAs in all 3 years. Next, we used compliance data for 105 RCAs around Vancouver Island to model the drivers of compliance. Compliance was related to the level of fishing effort around the RCA, the size and perimeter-to-area ratio of RCAs, proximity to fishing lodges, and the level of enforcement. Noncompliance in RCAs may be hampering their effectiveness and impeding rockfish recovery. Education and enforcement efforts to reduce fishing effort inside protected areas are critical to the recovery of depleted fish stocks.
- Published
- 2016
43. Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability
- Author
-
Silva, M Catarina, Cheng, Chialin, Mair, Waltraud, Almeida, Sandra, Fong, Helen, Biswas, M Helal U, Zhang, Zhijun, Huang, Yadong, Temple, Sally, Coppola, Giovanni, Geschwind, Daniel H, Karydas, Anna, Miller, Bruce L, Kosik, Kenneth S, Gao, Fen-Biao, Steen, Judith A, and Haggarty, Stephen J
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Alzheimer's Disease Related Dementias (ADRD) ,Acquired Cognitive Impairment ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Frontotemporal Dementia (FTD) ,Dementia ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Stem Cell Research - Induced Pluripotent Stem Cell ,Aging ,Neurodegenerative ,Neurosciences ,Stem Cell Research ,Brain Disorders ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Amino Acid Substitution ,Autophagy ,Biomarkers ,Cell Differentiation ,Cell Line ,Codon ,Frontotemporal Dementia ,Gene Expression Regulation ,Humans ,Induced Pluripotent Stem Cells ,Mutation ,Neural Stem Cells ,Neurons ,Protein Isoforms ,Protein Processing ,Post-Translational ,Stress ,Physiological ,tau Proteins ,Clinical Sciences ,Biochemistry and cell biology - Abstract
Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.
- Published
- 2016
44. A psychiatric disease-related circular RNA controls synaptic gene expression and cognition
- Author
-
Zimmerman, Amber J., Hafez, Alexander K., Amoah, Stephen K., Rodriguez, Brian A., Dell’Orco, Michela, Lozano, Evelyn, Hartley, Brigham J., Alural, Begüm, Lalonde, Jasmin, Chander, Praveen, Webster, Maree J., Perlis, Roy H., Brennand, Kristen J., Haggarty, Stephen J., Weick, Jason, Perrone-Bizzozero, Nora, Brigman, Jonathan L., and Mellios, Nikolaos
- Published
- 2020
- Full Text
- View/download PDF
45. Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons
- Author
-
M. Catarina Silva, Ghata A. Nandi, Sharon Tentarelli, Ian K. Gurrell, Tanguy Jamier, Diane Lucente, Bradford C. Dickerson, Dean G. Brown, Nicholas J. Brandon, and Stephen J. Haggarty
- Subjects
Science - Abstract
Disruption of autophagy function in cellular and animal models of tauopathy increases tau aggregation. Here, the authors describe a small-molecule screen to identify compounds that promote autophagy clearance of tau and rescue disease-relevant phenotypes in tauopathy patient-derived neurons.
- Published
- 2020
- Full Text
- View/download PDF
46. HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease
- Author
-
Ping-Chieh Pao, Debasis Patnaik, L. Ashley Watson, Fan Gao, Ling Pan, Jun Wang, Chinnakkaruppan Adaikkan, Jay Penney, Hugh P. Cam, Wen-Chin Huang, Lorena Pantano, Audrey Lee, Alexi Nott, Trongha X. Phan, Elizabeta Gjoneska, Sara Elmsaouri, Stephen J. Haggarty, and Li-Huei Tsai
- Subjects
Science - Abstract
Defects in DNA repair have been linked to brain aging and neurodegenerative disorders. Here the authors reveal a role for HDAC1 in stimulating OGG1 activity to alleviate 8-oxoG lesions with implications in the aging brain and neurodegenerative diseases.
- Published
- 2020
- Full Text
- View/download PDF
47. Discovery of suppressors of CRMP2 phosphorylation reveals compounds that mimic the behavioral effects of lithium on amphetamine-induced hyperlocomotion
- Author
-
Wen-Ning Zhao, Brian T. D. Tobe, Namrata D. Udeshi, Lucius L. Xuan, Cameron D. Pernia, Daniel P. Zolg, Amanda J. Roberts, Deepak Mani, Sarah R. Blumenthal, Iren Kurtser, Debasis Patnaik, Irina Gaisina, Joshua Bishop, Steven D. Sheridan, Jasmin Lalonde, Steven A. Carr, Evan Y. Snyder, and Stephen J. Haggarty
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract The effective treatment of bipolar disorder (BD) represents a significant unmet medical need. Although lithium remains a mainstay of treatment for BD, limited knowledge regarding how it modulates affective behavior has proven an obstacle to discovering more effective mood stabilizers with fewer adverse side effects. One potential mechanism of action of lithium is through inhibition of the serine/threonine protein kinase GSK3β, however, relevant substrates whose change in phosphorylation may mediate downstream changes in neuroplasticity remain poorly understood. Here, we used human induced pluripotent stem cell (hiPSC)-derived neuronal cells and stable isotope labeling by amino acids in cell culture (SILAC) along with quantitative mass spectrometry to identify global changes in the phosphoproteome upon inhibition of GSK3α/β with the highly selective, ATP-competitive inhibitor CHIR-99021. Comparison of phosphorylation changes to those induced by therapeutically relevant doses of lithium treatment led to the identification of collapsin response mediator protein 2 (CRMP2) as being highly sensitive to both treatments as well as an extended panel of structurally distinct GSK3α/β inhibitors. On this basis, a high-content image-based assay in hiPSC-derived neurons was developed to screen diverse compounds, including FDA-approved drugs, for their ability to mimic lithium’s suppression of CRMP2 phosphorylation without directly inhibiting GSK3β kinase activity. Systemic administration of a subset of these CRMP2-phosphorylation suppressors were found to mimic lithium’s attenuation of amphetamine-induced hyperlocomotion in mice. Taken together, these studies not only provide insights into the neural substrates regulated by lithium, but also provide novel human neuronal assays for supporting the development of mechanism-based therapeutics for BD and related neuropsychiatric disorders.
- Published
- 2020
- Full Text
- View/download PDF
48. TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling
- Author
-
Pauline Martin, Vilas Wagh, Surya A. Reis, Serkan Erdin, Roberta L. Beauchamp, Ghalib Shaikh, Michael Talkowski, Elizabeth Thiele, Steven D. Sheridan, Stephen J. Haggarty, and Vijaya Ramesh
- Subjects
Tuberous sclerosis complex ,TSC1 ,mTORC1 ,Induced pluripotent stem cells ,Neural progenitor cells ,Early neurodevelopment ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. Methods Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. Results Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. Conclusion MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD.
- Published
- 2020
- Full Text
- View/download PDF
49. Expression profile of the matricellular protein periostin in paediatric inflammatory bowel disease
- Author
-
Coelho, Tracy, Sonnenberg-Riethmacher, Eva, Gao, Yifang, Mossotto, Enrico, Khojanazarov, Alisher, Griffin, Annie, Mukanova, Saida, Ashimkhanova, Aiymkul, Haggarty, Rachel, Borissenko, Anton, Ashton, James J., Stafford, Imogen S., Batra, Akshay, Afzal, Nadeem A., Stanton, Michael P., Vadgama, Bhumita, Adrisova, Kapura, Beattie, Robert M., Williams, Anthony P., Ennis, Sarah, and Riethmacher, Dieter
- Published
- 2021
- Full Text
- View/download PDF
50. Imprinting methylation predicts hippocampal volumes and hyperintensities and the change with age in later life
- Author
-
Lorgen-Ritchie, Marlene, Murray, Alison D., Staff, Roger, Ferguson-Smith, Anne C., Richards, Marcus, Horgan, Graham W., Phillips, Louise H., Hoad, Gwen, McNeil, Chris, Ribeiro, Antonio, and Haggarty, Paul
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.