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Abstract: Understanding lineage specification during human pre-implantation development is a key requirement to improve assisted reproductive technologies and stem cell research. Single-cell RNAseq has allowed insights into the processes orchestrating human pre-implantation development. However, the exact sequence of molecular events leading to cell fate specification remains to be defined. Here, we employ pseudotime analysis of scRNAseq data to reconstruct the developmental progress of early mouse and human embryo development. Using time-lapse annotated embryos, we provide an integrated analysis allowing precise ordering of continuous transcriptomic changes throughout human development. Our analysis revealed that human trophectoderm/inner cell mass transcriptomes diverge at the transition from the B2 to B3 blastocyst stage, just before blastocyst expansion. Moreover, we explore the dynamics of fate markers IFI16 and GATA4 and show that they gradually become mutually exclusive upon establishment of epiblast and primitive endoderm fates, respectively. We also provide evidence that NR2F2 marks trophectoderm maturation initiating from the polar side, and subsequently spreads to all cells after implantation. Altogether, our study pinpoints the precise timing of lineage specification events in the human embryo and identifies transcriptomic hallmarks and cell fate markers.

I will highlight how we used this knowledge of human embryos to benchmark existing stem cell models, including integrated models such as blastoids.

Speaker:        Dr. Laurent David, Group Leader of Centre for Translational Immunology, Associate Professor in Cell Biology, Nantes Université

Topic:             Studying Human Peri-Implantation Development with Embryos and Stem Cell Models

Time:              4 PM (HKG)

Link:                Here

CTSCB Stem Cell Seminar Series

Date: October 5, 2022

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Abstract: Harnessing the power of the immune system to treat cancer has proven to be a promising therapeutic option for patients. The overall goal of Dr. Rafiq's research is to use mechanistic insight of immune effector cell function and interaction with cancer cells in the tumor microenvironment to inform the development and translation of novel engineered cellular immunotherapies. In particular, her work focuses on the genetic engineering of synthetic receptors known as Chimeric Antigen Receptors (CAR). Despite the transformative effect CAR T cells have had on the treatment of some types of leukemias and lymphoma in recent years, obstacles remain in expanding this technology for more widespread use in cancer.  As a translational cancer researcher, Dr. Rafiq's studies aim to engineer novel CARs to target both solid and hematological malignancies as well as deliver immune-modulating or toxic agents locally to the tumor microenvironment.

Speaker:        Dr. Sawrish Rafiq, Assistant Professor of Department of Hematology and Medical Oncology, Emory University School of Medicine

Topic:             Engineering Functionally Improved CAR T Cells for Hematological and Solid Tumors

Time:              9 AM (HKG)


CTSCB Stem Cell Seminar Series

Date: September 27, 2022

Abstract: The Regenerative Medicine of the future will rely on being able to produce a wide variety of “designer” tissues of choice (neurons, heart cells, liver cells, etc) that can be used for Personalised tissue replacement in the clinic. This dream has become achievable thanks to the Nobel Prize winning discovery 16 years ago of human induced Pluripotent Stem (iPS) cells, a revolutionary technology allowing any cells in our body to be converted into pluripotent stem cells from which almost any desired target tissue of choice could be derived by differentiation in vitro.

However, key challenges have to be overcome before the promise of stem cell therapeutics becomes a reality. First, we do not yet know how to control with precision the differentiation of iPS cells into the target tissues of choice. Most procedures to induce differentiation of iPS cells remain quite inefficient, unspecific, and unsafe (i.e. some of the cells obtained after differentiation retain the capacity to keep proliferating and make tumours, for reasons that are not understood). Secondly, even when generated in exactly the same way in the laboratory, iPS cells derived from some people can be programmed better into target tissues than those from other people, for reasons that remain unknown.

In this talk Professor Carazo Salas will describe multicolour, multiday high-content microscopy phenomics pipelines that his group has recently established that enable to visualise and predict the dynamical cell fate changes of human Pluripotent Stem Cells (hPSCs) ‘live’, collectively and at single-cell level. He will describe the integrated experimental and computational approaches they have developed to make this possible, including novel ‘live’ reporters of cell fate and multi-reporter hPSC lines generated by CRISPR/Cas9 allowing multiplexed monitoring of proliferation and fate dynamics as well as deep learning-enhanced morphological phenotyping methods, and briefly exemplify the biological discoveries they are enabling. Mapping the complex spatiotemporal dynamics of human stem cells as they proliferate and make cell fate decisions will be key in the future to improve our understanding of how to robustly engineer differentiated tissues for therapeutic applications.

Speaker:        Professor Rafael E. Carazo Salas, Professor and Chair of Biomedical Sciences, University of Bristol

Topic:             Predicting 'Live' Cell Fate Dynamics in hPSCs by Deep Learning-Enhanced Morphological Profiling

Time:              5 PM (HKG)


CTSCB Stem Cell Seminar Series

Date: September 14, 2022

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Abstract: The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has demonstrated clinical efficacy in the treatment of advanced cancers, with anti-CD19 CAR-T cells achieving up to 90% complete remission among patients with relapsed B-cell malignancies. However, challenges such as antigen escape and immunosuppression limit the long-term efficacy of adoptive T-cell therapy. Here, I will discuss the development of and clinical data on next-generation T cells that can target multiple cancer antigens and resist antigen escape. I will also present recent work on tuning CAR signaling activities via rational protein design to achieve greater in vivo anti-tumor efficacy. This presentation will highlight the potential of synthetic biology in generating novel mammalian cell systems with multifunctional outputs for therapeutic applications.

Speaker:        Dr. Yvonne Chen, Associate Professor, Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles

Topic:             Engineering Nex-Generation T Cells for Cancer Immunotherapy

Time:              10 AM (HKG)

CTSCB Stem Cell Seminar Series

Date: August 24, 2022

Abstract: Recent years have seen the rapid growth of big data in immunology and immune-oncology research. However, leveraging the vast amount of public data resources to make new findings is still challenging for most immunologists due to the complexity and heterogeneity of published datasets. I will introduce two data-integrative frameworks developed to help immunologists to understand intercellular signaling mechanisms, with applications in studying cancer immunotherapy resistance. The first framework CytoSig (https://cytosig.ccr.cancer.gov) contains a vast amount of cytokine treatment response data curated from public repositories. CytoSig can reliably predict cytokine signaling cascades in human inflammatory diseases and cancers. The second framework Tres (https://resilience.ccr.cancer.gov) provides many T-cell genomics datasets and interactive functions for immune oncologists to study molecular markers of T-cell anti-tumor efficacies. The Tres model also identified FIBP knockout as a new approach to potentiate cellular immunotherapies in solid tumors.

Speaker:        Dr. Peng Jiang, Earl Stadtman Investigator - National Cancer Institute at National Institutes of Health

Topic:             Big Data Approaches to Study Intercellular Signaling in Cancer Immunotherapy Resistance

Time:              10 AM (HKG)

CTSCB Stem Cell Seminar Series

Date: June 28, 2022

Abstract: The process of implantation and the cellular interactions at the embryo-maternal interface are intrinsically difficult to analyse, as the implanting embryo is concealed by the uterine tissues. To examine the mechanisms mediating the interconnection of the embryo and the mother, we established a 3D biomimetic culture environment that harbours the key features of the implantation niche. This allowed direct analysis of trophoblast invasion and revealed the first embryonic interactions with the maternal vasculature. We found that implantation is mediated by the collective migration of penetrating strands of trophoblast giant cells, which acquire the expression of vascular receptors, ligands, and adhesion molecules, assembling a network for communication with the maternal blood vessels.

Speaker:        Dr. Ivan Bedshov, Principal Investigator - Max Planck Institute for Molecular Biomoedicine Muenster

Topic:             Cellular Mechanisms of Embryonic Development and Embryo-Maternal Interactions during Implantation

Time:              4 PM (HKG)

CTSCB Stem Cell Seminar Series

Date: June 14, 2022

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Abstract: Old age is a major risk factor for many human diseases. Sporadic Alzheimer’s Disease (AD) represents a prime example, as it exclusively affects people at old age. Sporadic AD represents the overwhelming majority of all cases, and familial genetically defined early-onset cases are rare. Still, most research on AD has been performed on genetic causes and their directly related pathways, also because we were in lack of models that can reflect complex human genetics, physiology, and age in an appropriate human neuronal context. While patient-specific iPSC-based models represent an attractive solution, iPSC reprogramming results in cellular rejuvenation and thus yields phenotypically young neurons. By contrast, direct conversion of old patient fibroblasts into induced neurons (iNs) preserves endogenous signatures of aging. To control for the involvement of aging in human neuronal models for AD, we combined both technologies and generated age-equivalent fibroblast-derived iNs, as well as rejuvenated iPSC-derived neurons from a large cohort of AD patients and controls. In addition to their rejuvenated state, we found that iPSC neurons transcriptionally resemble prenatal developmental stages, while iNs reflect old epigenetic ages, adult-like transcriptome stages, and show little correlation with the prenatal brain. Thus, not surprisingly, only age-equivalent adult-like iNs, but not rejuvenated prenatal-like iPSC neurons, revealed strong AD patient-specific signatures that revealed high concordance with bulk and single cell transcriptome data from earlier post-mortem studies. Longitudinal identity and cellular ontogenesis mapping revealed that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, glycolytic reprogramming, and de-differentiation, and which share similarities with malignant cancer cell transformation and age-dependent epigenetic erosion. Pathological isoform switching of the glycolytic enzyme pyruvate kinase (PKM) towards the cancer-associated PKM2 isoform conferred a large proportion of the transcriptional and metabolic alterations in AD iNs, both via metabolic malfunctions and via nuclear translocation. Our patient-based iN model thus identifies AD-related neuronal changes as part of an active cellular program that impairs neuronal cell identity and neuronal resilience by utilizing cancer-related patho-mechanisms.

Speaker:        Dr. Jerome Mertens, Assistant Professor and Head of Neural Aging Laboratory - University of Innsbruck

Topic:             Neuronal Fate Loss and Metabolic Transformation in Age-Equivalent Alzheimer Patient Neurons

Time:              4 PM (HKG)

CTSCB-HKUST Joint Seminar

Date: May 27, 2022

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Abstract: Reconstructing the circuits that control how cells adopt specific fates and engineering these circuits to reprogram cellular functions are major challenges in biology. I will introduce a series of experimental and computational frameworks such as “Waddington-OT”, “Raman2RNA” for reconstructing molecular dynamics over time and in live cells through single-cell genomics and imaging. I will introduce how we can use these approaches to  decode the cellular and molecular mechanisms governing reprogramming and development.

Speaker:        Dr. Jian Shu, Assistant Professor - Harvard Medical School & Massachusetts General Hospital, Associate Member at Broad Institute of MIT and Harvard

Topic:             Decoding and Engineering Cell Fates and Circuits

Time:              9 AM (HKG)

CTSCB-HKUST Joint Seminar

Date: May 20, 2022

Abstract: Despite the unprecedented clinical success of chimeric antigen receptor (CAR) T cell therapy against B cell malignancies, its widespread application is limited by lengthy and labor-intensive ex vivo manufacturing procedures that result in: (i) high cost; (ii) delays to infuse CAR-T cells to patients with rapidly progressing disease; and (iii) CAR-T cells with heterogeneous composition and terminal differentiation, which limit their engraftment and persistence. In this presentation, I will present two biomaterial technologies to streamline CAR-T cell manufacturing and reduce processing time to just a few hours. Our scaffolds facilitate in situ T cell activation and proliferation and provide the appropriate interface for viral vector-mediated gene transfer and subsequent T cell release. Scaffolds seeded with human peripheral blood mononuclear cells and CD19-encoding retroviral particles and implanted subcutaneously on the same day efficiently generate CAR-T cells in vivo. These in vivo-generated CAR-T cells enter the blood stream, control tumor growth and show enhanced persistence compared to conventionally produced CAR-T cells. Taken together, MASTER promises to transform CAR-T cell therapy, through fast-tracking manufacturing and potentially reducing the costs of this therapy.

Speaker:        Dr. Yevgeny Brudno, Joint Assistant Professor at Department  of Biomedical Engineering - University of North Carolina and North Carolina State University

Topic:             Bioinstructive Implantable Scaffolds to Streamline Production of CAR-T Cell Therapy

Time:              9 AM (HKG)

CTSCB Stem Cell Seminar Series

Date: April 22, 2022

Abstract: Recent advances in single-cell technologies have elucidated the transcriptional heterogeneity in cancer cells and has enabled identification of sub-populations in tumors. However, the functional consequences of this transcriptional heterogeneity remain unknown. Do distinct transcriptional units correspond to functional differences in tumor cells? And can we identify and predict immature tumor initiating cells that have been shown to drive tumor growth and metastasis? We performed single cell RNA sequencing in breast cancer patient samples and developed a novel computational tool, CytoTRACE that can agnostically determine immature cell populations across different tissues, organisms, and diseased states. By using a combination of single-cell data, CytoTRACE, bulk tumor deconvolution, patient derived xenografts and lineage tracing we have identified distinct populations of cells in breast cancer responsible for tumor growth and metastasis. We have found that the hematopoietic transcriptional adaptor and T-cell leukemia oncogene, LMO2, is critical for early metastatic dissemination. Our work is now focused on the molecular signaling that maintains/drives transitions of distinct cell populations and the factors in the microenvironment that influence these transitions.

Speaker:        Dr. Shaheen Sikandar, Assistant Professor of MCD Biology - The University of California, Santa Cruz

Topic:             Elucidating Functional Heterogeneity in Breast Cancer Cells

Time:              9 AM (HKG)

CTSCB Stem Cell Seminar Series

Date: March 25, 2022

Abstract: The Morrison laboratory studies the cellular and molecular mechanisms that regulate stem cell function and the role these mechanisms play in cancer. They identified a series of mechanisms that distinguish the self-renewal of stem cells from the proliferation of restricted progenitors in the same tissues and identified niches that maintain stem cells in adult hematopoietic tissues. The Morrison lab has also studied the mechanisms that regulate metastasis, discovering that melanoma metastasis is limited by oxidative stress. Rare metastasizing cells survive this stress by undergoing metabolic changes that reduce the generation of reactive oxygen species and confer oxidative stress resistance. This suggests the possibility of limiting cancer progression with pro-oxidant therapies that exacerbate the oxidative stress experienced by cancer cells.  Dr. Morrison completed a B.Sc. in biology and chemistry at Dalhousie University (1991), a Ph.D. in immunology at Stanford University (1996), and a postdoctoral fellowship in neurobiology at Caltech (1999). Dr. Morrison is a Howard Hughes Medical Institute Investigator (since 2000) and the founding Director of Children’s Research Institute at the University of Texas Southwestern Medical Center (since 2011). He was elected to the National Academy of Medicine in 2018 and the National Academy of Sciences in 2020. Dr. Morrison served as the President of the International Society for Stem Cell Research (2015-16), testified before the U.S. Congress, and served as a leader in the successful “Proposal 2” campaign to protect stem cell research in Michigan’s state constitution (2008).

Speaker:        Professor Sean Morrison, Director - Children's Research Institute at University of Texas Southewestern Medical Center

Topic:             Stem Cell Niche Bioology: Beyond Growth Factors

Time:             10 AM (HKG)

CTSCB-HKUST Joint Seminar

Date: March 15, 2022

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Abstract: The process of implantation and the cellular interactions at the embryo-maternal interface are intrinsically difficult to analyse, as the implanting embryo is concealed by the uterine tissues. To examine the mechanisms mediating the interconnection of the embryo and the mother, we established a 3D biomimetic culture environment that harbours the key features of the implantation niche. This allowed direct analysis of trophoblast invasion and revealed the first embryonic interactions with the maternal vasculature. We found that implantation is mediated by the collective migration of penetrating strands of trophoblast giant cells, which acquire the expression of vascular receptors, ligands, and adhesion molecules, assembling a network for communication with the maternal blood vessels.

Speaker:        Professor Emmanuelle Passegue, Director - Columbia Stem Cell Initiative; Alumni Professor of Genetics and Development

Topic:             Hematopoietic Stem Cells in Stress, Disease

Time:              9 AM (HKG)

CTSCB-HKUST Joint Seminar

Date: March 1, 2022

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Abstract: The process of implantation and the cellular interactions at the embryo-maternal interface are intrinsically difficult to analyse, as the implanting embryo is concealed by the uterine tissues. To examine the mechanisms mediating the interconnection of the embryo and the mother, we established a 3D biomimetic culture environment that harbours the key features of the implantation niche. This allowed direct analysis of trophoblast invasion and revealed the first embryonic interactions with the maternal vasculature. We found that implantation is mediated by the collective migration of penetrating strands of trophoblast giant cells, which acquire the expression of vascular receptors, ligands, and adhesion molecules, assembling a network for communication with the maternal blood vessels.

Speaker:        Dr. Daniel Lucas, Assistant Professor - UC Department of Pediatrics Clincinnati Children's Hospital

Topic:             Anatomy of Hematopoiesis in the Bone Marrow

Time:              11 AM (HKG)

CTSCB Stem Cell Seminar Series

Date: Feb 15, 2022

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Abstract: The process of implantation and the cellular interactions at the embryo-maternal interface are intrinsically difficult to analyse, as the implanting embryo is concealed by the uterine tissues. To examine the mechanisms mediating the interconnection of the embryo and the mother, we established a 3D biomimetic culture environment that harbours the key features of the implantation niche. This allowed direct analysis of trophoblast invasion and revealed the first embryonic interactions with the maternal vasculature. We found that implantation is mediated by the collective migration of penetrating strands of trophoblast giant cells, which acquire the expression of vascular receptors, ligands, and adhesion molecules, assembling a network for communication with the maternal blood vessels.

Speaker:        Dr. Ankur Sharma, Head of Onco-Fetal Ecosystem Laboratory - Harry Perkins Institute of Medical Research & Curtin University

Topic:             Oncofetal ecosystem in HCC: Spatial localisation and clinical implications

Time:              11 AM (HKG)

CTSCB Stem Cell Seminar Series

Date: Jan 18, 2022

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Job Fair


Time: 12 NN

Venue: Unit 1105, 11/F, 17W Science Park West Avenue,

HKSTP, Shatin, N.T.


Brief Intro: Centre for Translational Stem Cell Biology is going to hold a soft-opening on….

Link: http://www.linkedin.com/in/ctscbhk


Full detail: Centre for Translational Stem Cell Biology is going to hold a soft opening on January 14, 2022 to celebrate the establishment. Our Managing Director, Prof. Pengtao Liu, cordially invites everyone of you to join us on the big day. Refreshment will be provided. Click the link to register!

Date: January 14, 2022

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Abstract: The process of implantation and the cellular interactions at the embryo-maternal interface are intrinsically difficult to analyse, as the implanting embryo is concealed by the uterine tissues. To examine the mechanisms mediating the interconnection of the embryo and the mother, we established a 3D biomimetic culture environment that harbours the key features of the implantation niche. This allowed direct analysis of trophoblast invasion and revealed the first embryonic interactions with the maternal vasculature. We found that implantation is mediated by the collective migration of penetrating strands of trophoblast giant cells, which acquire the expression of vascular receptors, ligands, and adhesion molecules, assembling a network for communication with the maternal blood vessels.

Speaker:        Dr. Andy Tay, Presidential Yong Professor - National University of Singapore

Topic:             Overcoming Hurdles in Immune-cell Engineering with Nanotechnology

Time:              9 AM (HKG)

CTSCB Stem Cell Seminar Series

Date: Dec 7, 2021

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Publication

  • Yang J, Ryan DJ, Wang W… Lu L, Liu P. (2017). Establishment in Culture of Mouse Expanded Potential Stem Cells. Nature, 550 (7676): 393-397. http://dx.doi.org/0.1038/nature24052
  • Sugimura R, Jha DK, Han A… Doulatov S, Daley GQ. (2017) Haematopoietic Stem and Progenitor Cells from Human Pluripotent Stem Cells. Nature 545 (7655): 432–438. https://doi.org/10.1038/nature22370
  • Veerapandian V, Ackermann JO, Srivastava Y… Yang X, Jauch R. (2018) Directed Evolution of Reprogramming Factors by Cell Selection and Sequencing. Stem Cell Reports 11: 593-606. https://doi.org/10.1016/j.stemcr.2018.07.002
  • Ibarra-Soria X, Jawaid W, Pijuan-Sala B… Göttgens B*, Marioni JC*. (2018) Defining murine organogenesis at single-cell resolution reveals a role for the leukotriene pathway in regulating blood progenitor formation. Nat Cell Biol. 20(2): 127-134. (*Corresponding author) https://doi.org/10.1038/s41556-017-0013-z
  • Gao X, Nowak-Imialek M, Chen X… Niemann H, Liu P. (2019) Establishment of human and pig expanded potential stem cells uncovers conserved signaling requirements. Nature Cell Biology, 21(6): 687-699. http://dx.doi.org/10.1038/s41556-019-0333-2
  • Pijuan-Sala B, Gtiffiths JA, Guibentif C… Marioni JC, Göttgens B. (2019) A single-cell molecular map of mouse gastrulation and early organogenesis. Nature 566(7745) 490-495. https://doi.org/10.1038/s41586-019-0933-9
  • Huang R, Huang Y, Guo Y… Lu M, Li T. (2019) Systematic characterization and prediction of post-translational modification cross-talk between proteins. Bioinformatics 35 (15): 2626-2633. http://dx.doi.org/10.1093/bioinformatics/bty1033
  • Chen ACH, Peng Q, Fong SW, Yeung WSB, Lee YL. (2020) Sirt1 is regulated by miR-135a and involved in DNA damage repair during mouse cellular reprogramming. Aging (Albany NY) 12(8): 7431-7447. https://doi.org/10.18632/aging.103090

Publication

  • Yu Y, Tsang JC, Wang C… Dougan G, Liu P. (2016) Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its development pathway. Nature 29 (539): 102-106. https://doi.org/10.1038/nature20105
  • CY Tam, WMM Li, YP Gao… CS Lau and VSF Chan. (2017) Human CLEC16A regulates autophagy through modulating mTOR activity. Experimental Cell Research 352: 304-312.  https://doi.org/10.1016/j.yexcr.2017.02.017 
  • Lee JC, Biasci D, Roberts R… Mansfield  Parkes M and Smith KGC. (2017) Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nat Genet 49(2), 262-268.  https://doi.org/10.1038/ng.3755 
  • Yang W, Garrett L, Feng D… Yang Y, Gao B. (2017) Wnt-induced Vangl2 phosphorylation is dose-dependently required for planar cell polarity in mammalian development. Cell Res 27 (12): 1466-1484.  https://doi.org/10.1038/cr.2017.127 
  • IKY Lam, JX Chow, CS Lau, VSF Chan. (2018) MicroRNA-mediated immune regulation in rheumatic diseases. Cancer Lett 9 (431): 201-212.  http://dx.doi.org/10.1016/j.canlet.2018.05.044  
  • Forbester JL, Lees EA, Goulding D… Powrie F, Dougan G. (2018) Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells. Proc Natl Acad Sci USA 115: 10118-10123. https://doi.org/10.1073/pnas.1811866115
  • Gao B, Ajima R, Yang W… Yamaguchi TP, Yang Y. (2018) Coordinated directional outgrowth and pattern formation by integration of Wnt5a and Fgfsignaling in planar cell polarity. Development 145 (8). https://doi.org/10.1242/dev.163824
  • Li PH, Wong WWY, Leung ENY, Lau CS, Au E. (2020) Novel mutations identified in the first Chinese pedigree of complete C6 deficiency. Clin Transl Immunology 9(7): e1148. https://doi.org/10.1002/cti2.1148 
  • Stewart BJ, Ferdinand JR, Clatworthy MR. (2020) Using single-cell technologies to map the human immune system – implications for nephrology. Nat Rev Nephrol. 16(2): 112-128. https://doi.org/10.1038/s41581-019-0227-3
  • Duque-Correa MA, Maizels RM, Grencis RK, Berriman M. (2020) Organoids - New Models for Host-Helminth Interactions. Trends Parasitol 36(2): 170-181. https://doi.org/10.1016/j.pt.2019.10.013