11 results on '"Louis-François Handfield"'
Search Results
2. Unsupervised clustering of subcellular protein expression patterns in high-throughput microscopy images reveals protein complexes and functional relationships between proteins.
- Author
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Louis-François Handfield, Yolanda T Chong, Jibril Simmons, Brenda J Andrews, and Alan M Moses
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Biology (General) ,QH301-705.5 - Abstract
Protein subcellular localization has been systematically characterized in budding yeast using fluorescently tagged proteins. Based on the fluorescence microscopy images, subcellular localization of many proteins can be classified automatically using supervised machine learning approaches that have been trained to recognize predefined image classes based on statistical features. Here, we present an unsupervised analysis of protein expression patterns in a set of high-resolution, high-throughput microscope images. Our analysis is based on 7 biologically interpretable features which are evaluated on automatically identified cells, and whose cell-stage dependency is captured by a continuous model for cell growth. We show that it is possible to identify most previously identified localization patterns in a cluster analysis based on these features and that similarities between the inferred expression patterns contain more information about protein function than can be explained by a previous manual categorization of subcellular localization. Furthermore, the inferred cell-stage associated to each fluorescence measurement allows us to visualize large groups of proteins entering the bud at specific stages of bud growth. These correspond to proteins localized to organelles, revealing that the organelles must be entering the bud in a stereotypical order. We also identify and organize a smaller group of proteins that show subtle differences in the way they move around the bud during growth. Our results suggest that biologically interpretable features based on explicit models of cell morphology will yield unprecedented power for pattern discovery in high-resolution, high-throughput microscopy images.
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- 2013
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3. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro
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Elena Prigmore, Louis-François Handfield, Michael R. Stratton, Tong Li, Mercedes Jimenez-Linan, Lucy Gardner, Luz Garcia-Alonso, Tarryn Porter, Krishnaa T. Mahbubani, Vitalii Kleshchevnikov, Anna Arutyunyan, Hassan Massalha, Monika Dabrowska, Paul Ayuk, Kwasi Kwakwa, Ashley Moffett, Benjamin Woodhams, Kourosh Saeb-Parsy, Ridma C. Fernando, Regina Hoo, Elizabeth Tuck, Konstantina Nikolakopoulou, Stijn van Dongen, Valentina Lorenzi, Jong-Eun Park, Kenny Roberts, Cecilia Icoresi Mazzeo, Margherita Y. Turco, Vasyl Vaskivskyi, Martin Prete, Aleksandra Tarkowska, Roser Vento-Tormo, Krzysztof Polanski, Carmen Sancho-Serra, Cecilia Lindskog, Omer Ali Bayraktar, Vladimir Yu. Kiselev, Sarah A. Teichmann, Lia S. Campos, Luiza Moore, Roberts, Kenny [0000-0001-6155-0821], Nikolakopoulou, Konstantina [0000-0003-2306-590X], Woodhams, Benjamin [0000-0003-2801-5733], Arutyunyan, Anna [0000-0003-0453-5443], Polanski, Krzysztof [0000-0002-2586-9576], Li, Tong [0000-0002-8240-4476], Vaskivskyi, Vasyl [0000-0002-4080-4965], Mahbubani, Krishnaa T. [0000-0002-1327-2334], Stratton, Michael R. [0000-0001-6035-153X], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Moffett, Ashley [0000-0002-8388-9073], Moore, Luiza [0000-0001-5315-516X], Bayraktar, Omer A. [0000-0001-6055-277X], Teichmann, Sarah A. [0000-0002-6294-6366], Vento-Tormo, Roser [0000-0002-9870-8474], Apollo - University of Cambridge Repository, Mahbubani, Krishnaa T [0000-0002-1327-2334], Stratton, Michael R [0000-0001-6035-153X], Bayraktar, Omer A [0000-0001-6055-277X], Teichmann, Sarah A [0000-0002-6294-6366], Mahbubani, Krishnaa [0000-0002-1327-2334], and Teichmann, Sarah [0000-0002-6294-6366]
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631/45 ,Cell type ,Notch signaling pathway ,Reproduktionsmedicin och gynekologi ,In Vitro Techniques ,Cell fate determination ,Biology ,Endometrium ,Tissue Culture Techniques ,Transcriptome ,Spatio-Temporal Analysis ,Downregulation and upregulation ,Obstetrics, Gynecology and Reproductive Medicine ,Genetics ,Organoid ,medicine ,Humans ,Cell Lineage ,Gonadal Steroid Hormones ,Menstrual Cycle ,Receptors, Notch ,Uterus ,article ,Wnt signaling pathway ,Cell Differentiation ,Endometrial Neoplasms ,Cell biology ,Organoids ,Wnt Proteins ,medicine.anatomical_structure ,Cellular Microenvironment ,Female ,631/80 ,Signal Transduction - Abstract
The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively. Correction in: Nature Genetics, 55, page 165 (2023)DOI: 10.1038/s41588-022-01287-6
- Published
- 2021
4. Local statistics allow quantification of cell-to-cell variability from high-throughput microscope images.
- Author
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Louis-François Handfield, Bob Strome, Yolanda T. Chong, and Alan M. Moses
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- 2015
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5. Author Correction: Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro
- Author
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Luz Garcia-Alonso, Louis-François Handfield, Kenny Roberts, Konstantina Nikolakopoulou, Ridma C. Fernando, Lucy Gardner, Benjamin Woodhams, Anna Arutyunyan, Krzysztof Polanski, Regina Hoo, Carmen Sancho-Serra, Tong Li, Kwasi Kwakwa, Elizabeth Tuck, Valentina Lorenzi, Hassan Massalha, Martin Prete, Vitalii Kleshchevnikov, Aleksandra Tarkowska, Tarryn Porter, Cecilia Icoresi Mazzeo, Stijn van Dongen, Monika Dabrowska, Vasyl Vaskivskyi, Krishnaa T. Mahbubani, Jong-eun Park, Mercedes Jimenez-Linan, Lia Campos, Vladimir Yu. Kiselev, Cecilia Lindskog, Paul Ayuk, Elena Prigmore, Michael R. Stratton, Kourosh Saeb-Parsy, Ashley Moffett, Luiza Moore, Omer A. Bayraktar, Sarah A. Teichmann, Margherita Y. Turco, and Roser Vento-Tormo
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Genetics - Published
- 2022
6. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro
- Author
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Luz Garcia-Alonso, Ridma C. Fernando, Regina Hoo, Kenny Roberts, Vasyl Vaskivskyi, Vitalii Kleshchevnikov, Aleksandra Tarkowska, Anna Arutyunyan, Jong-Eun Park, Roser Vento-Tormo, Cecilia Icoresi Mazzeo, Tong Li, Tarryn Porter, Kourosh Saeb-Parsy, Paul Ayuk, Michael R. Stratton, Monika Dabrowska, Ashley Moffett, Louis-François Handfield, Elena Prigmore, Ben Woodhams, Stijn van Dongen, Elizabeth Tuck, Krishna T. Mahbubani, Mercedes Jimenez-Linan, Lucy Gardner, Konstantina Nikolakopoulou, Kwasi Kwakwa, Margherita Y. Turco, Krzysztof Polanski, Omer Ali Bayraktar, Vladimir Yu. Kiselev, Carmen Sancho-Serra, Cecilia Lindskog, Sarah A. Teichmann, Lia S. Campos, and Luiza Moore
- Subjects
medicine.anatomical_structure ,Downregulation and upregulation ,In vivo ,Wnt signaling pathway ,medicine ,Uterus ,Organoid ,Endometriosis ,Cell fate determination ,Biology ,Endometrium ,medicine.disease ,Cell biology - Abstract
The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated single-cell and spatial reference maps of the human uterus and 3D endometrial organoid cultures. We dissect the signalling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids highlights common pathways regulating the differentiation of secretory and ciliated lineage in vivo and in vitro. We show in vitro that downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. These mechanistic insights provide a platform for future development of treatments for a range of common endometrial disorders including endometriosis and carcinoma.
- Published
- 2021
7. Molecular and cellular pathology of monogenic Alzheimer’s disease at single cell resolution
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Federica Marinaro, Alessio Strano, Nick C. Fox, Louis-François Handfield, Martin Hemberg, Lewis D. B. Evans, Natalie S. Ryan, Frederick J. Livesey, Sharad Ramanathan, Zhechun Zhang, and Moritz Haneklaus
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Cellular pathology ,Cell type ,medicine.anatomical_structure ,Cerebral cortex ,Genetic heterogeneity ,Gene expression ,Cell ,Brain atlas ,medicine ,Disease ,Biology ,Neuroscience - Abstract
Cell and molecular biology analyses of sporadic Alzheimer’s disease brain are confounded by clinical variability, ageing and genetic heterogeneity. Therefore, we used single-nucleus RNA sequencing to characterize cell composition and gene expression in the cerebral cortex in early-onset, monogenic Alzheimer’s disease. Constructing a cellular atlas of frontal cortex from 8 monogenic AD individuals and 8 matched controls, provided insights into which neurons degenerate in AD and responses of different cell types to AD at the cellular and systems level. Such responses are a combination of positively adaptive and deleterious changes, including large-scale changes in synaptic transmission and marked metabolic reprogramming in neurons. The nature and scale of the transcriptional changes in AD emphasizes the global impact of the disease across all brain cell types.One Sentence SummaryAlzheimer’s disease brain atlas provides insights into disease mechanisms
- Published
- 2020
8. Decoding the porcine developing spatial processing system and production of human entorhinal stellate cell-like cells by a direct programming approach
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Birgitte Rahbek Kornum, Ulrich Pfisterer, Menno P. Witter, Yong Liu, Vanessa Jane Hall, Louis-François Handfield, Leo Mogus, Mark Denham, Konstantin Khodosevich, Irene Lisa-Vargas, Julie Lee, Tune H. Pers, Jan Gorodkin, Stefan E. Seemann, Jimmy Tsz Hang Lee, Tobias Bergmann, Andrea Asenjo-Martinez, Nikolaos Patikas, Poul Hyttel, and Martin Hemberg
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education.field_of_study ,Interneuron ,Population ,FOXP1 ,Biology ,Entorhinal cortex ,medicine.anatomical_structure ,medicine ,Hepatic stellate cell ,Progenitor cell ,education ,Induced pluripotent stem cell ,Neuroscience ,Progenitor - Abstract
Classic studies investigating how and when the entorhinal cortex (component of the memory processing system of the brain) develops have been based on traditional thymidine autoradiography and histological techniques. In this study, we take advantage of modern technologies to trace at a high resolution, the cellular complexity of the developing porcine medial entorhinal cortex by using single-cell profiling. The postnatal medial entorhinal cortex comprises 4 interneuron, 3 pyramidal neuron and 2 stellate cell populations which emerge from intermediate progenitor and immature neuron populations. We discover four MGE-derived interneurons and one CGE-derived interneuron population as well as several IN progenitors. We also identify two oligodendrocyte progenitor populations and three populations of oligodendrocytes. We perform a proof-of-concept experiment demonstrating that porcine scRNA-seq data can be used to develop novel protocols for producing human entorhinal cells in-vitro. We identified six transcription factors (RUNX1A1, SOX5, FOXP1, MEF2C, TCF4, EYA2) important in neurodevelopment and differentiation from oneRELN+ stellate cell population. Using a lentiviral vector approach, we reprogrammed human induced pluripotent stem cells into stellate cell-like cells which expressedRELN, SATB2, LEF1and BCL11B. Our findings contribute to the understanding of the formation of the brain’s cognitive memory and spatial processing system and provides proof-of-concept for the production of entorhinal cells from human pluripotent stem cells in-vitro.
- Published
- 2019
9. Production of human entorhinal stellate cell-like cells by forward programming shows an important role of Foxp1 in reprogramming
- Author
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Tobias Bergmann, Yong Liu, Jonathan Skov, Leo Mogus, Julie Lee, Ulrich Pfisterer, Louis-Francois Handfield, Andrea Asenjo-Martinez, Irene Lisa-Vargas, Stefan E. Seemann, Jimmy Tsz Hang Lee, Nikolaos Patikas, Birgitte Rahbek Kornum, Mark Denham, Poul Hyttel, Menno P. Witter, Jan Gorodkin, Tune H. Pers, Martin Hemberg, Konstantin Khodosevich, and Vanessa Jane Hall
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medial entorhinal cortex ,forward programming ,stellate cells ,FOXP1 ,induced pluripotent stem cells ,Biology (General) ,QH301-705.5 - Abstract
Stellate cells are principal neurons in the entorhinal cortex that contribute to spatial processing. They also play a role in the context of Alzheimer’s disease as they accumulate Amyloid beta early in the disease. Producing human stellate cells from pluripotent stem cells would allow researchers to study early mechanisms of Alzheimer’s disease, however, no protocols currently exist for producing such cells. In order to develop novel stem cell protocols, we characterize at high resolution the development of the porcine medial entorhinal cortex by tracing neuronal and glial subtypes from mid-gestation to the adult brain to identify the transcriptomic profile of progenitor and adult stellate cells. Importantly, we could confirm the robustness of our data by extracting developmental factors from the identified intermediate stellate cell cluster and implemented these factors to generate putative intermediate stellate cells from human induced pluripotent stem cells. Six transcription factors identified from the stellate cell cluster including RUNX1T1, SOX5, FOXP1, MEF2C, TCF4, EYA2 were overexpressed using a forward programming approach to produce neurons expressing a unique combination of RELN, SATB2, LEF1 and BCL11B observed in stellate cells. Further analyses of the individual transcription factors led to the discovery that FOXP1 is critical in the reprogramming process and omission of RUNX1T1 and EYA2 enhances neuron conversion. Our findings contribute not only to the profiling of cell types within the developing and adult brain’s medial entorhinal cortex but also provides proof-of-concept for using scRNAseq data to produce entorhinal intermediate stellate cells from human pluripotent stem cells in-vitro.
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- 2022
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10. Extracting and Integrating Protein Localization Changes from Multiple Image Screens of Yeast Cells
- Author
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Alex Lu, Louis-Francois Handfield, and Alan Moses
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Biology (General) ,QH301-705.5 - Abstract
The evaluation of protein localization changes in cells under diverse chemical and genetic perturbations is now possible due to the increasing quantity of screens that systematically image thousands of proteins in an organism. Integrating information from different screens provides valuable contextual information about the protein function. For example, proteins that change localization in response to many different stressful environmental perturbations may have different roles than those that only change in response to a few. We developed, to our knowledge, the first protocol that permits the quantitative comparison and clustering of protein localization changes across multiple screens. Our analysis allows for the exploratory analysis of proteins according to their pattern of localization changes across many different perturbations, potentially discovering new roles by association.
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- 2018
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11. Integrating images from multiple microscopy screens reveals diverse patterns of change in the subcellular localization of proteins
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Alex X Lu, Yolanda T Chong, Ian Shen Hsu, Bob Strome, Louis-Francois Handfield, Oren Kraus, Brenda J Andrews, and Alan M Moses
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image analysis ,systems biology ,bioimage informatics ,fluorescence microscopy ,unsupervised machine leaning ,proteomics ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The evaluation of protein localization changes on a systematic level is a powerful tool for understanding how cells respond to environmental, chemical, or genetic perturbations. To date, work in understanding these proteomic responses through high-throughput imaging has catalogued localization changes independently for each perturbation. To distinguish changes that are targeted responses to the specific perturbation or more generalized programs, we developed a scalable approach to visualize the localization behavior of proteins across multiple experiments as a quantitative pattern. By applying this approach to 24 experimental screens consisting of nearly 400,000 images, we differentiated specific responses from more generalized ones, discovered nuance in the localization behavior of stress-responsive proteins, and formed hypotheses by clustering proteins that have similar patterns. Previous approaches aim to capture all localization changes for a single screen as accurately as possible, whereas our work aims to integrate large amounts of imaging data to find unexpected new cell biology.
- Published
- 2018
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