Modeling Development and Disease with Organoids

The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.

The Human Cell Atlas

Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barre syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.

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The Brazilian Zika virus strain causes birth defects in experimental models

Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. This article discusses progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, including the powerful combination of human iPSC technology with recent developments in gene editing.

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Induced pluripotent stem cell technology: a decade of progress

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the CaV1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.

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Assembly of functionally integrated human forebrain spheroids

Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure

Chronic-Phase Chronic Myeloid Leukemia Times to Death By Disease Support Tyrosine Kinase Inhibitor Dose Reductions When BCR::ABL1 Level Is <1% and Decreasing

Social media provides a platform for people to freely share their lives and feelings. However, with the increase of people's use of social media, the dark side of social media has gradually attracted people's attention. The anonymity of social media has led many people to use it to harass, abuse, and attack others, with women being a common target group. Twitter, one of the world's most well-known social media platforms, is used by hundreds of millions of people worldwide to communicate and share information every day. Although the artificial intelligence system for detecting hate comments has been applied to the maintenance of social media, it is still difficult to distinguish hate speech against women. That is because misogynistic comments are often subtle, and the currently commonly applied detection methods do not sufficiently consider the contextual information of the text. Therefore, we propose a BERT-based misogyny detection method that can fully integrate contextual information and context to classify texts. The experimental results show that our method has significant improvement compared with other methods.

Mingxi M. Song

Papers

Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure

Chronic-Phase Chronic Myeloid Leukemia Times to Death By Disease Support Tyrosine Kinase Inhibitor Dose Reductions When BCR::ABL1 Level Is <1% and Decreasing

Detecting Misogynia in Italian Tweets: A Linguistic and Contextual based Method