There is an urgent need to create novel models using human disease-relevant cells to study SARS-CoV-2 biology and to facilitate drug screening. As SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs, particularly alveolar type II-like cells, are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes 1. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high throughput screen of FDA-approved drugs and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid (MPA), and quinacrine dihydrochloride (QNHC). Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics. The development of anti-SARS-CoV-2 drugs could change the scope of the ongoing COVID-19 pandemic. While this strategy is being pursued, high throughput screens are typically performed in transformed cell lines which fail to capture the physiologically relevant dynamics of human SARS-CoV-2 infection. To overcome limitations of these cell lines, several adult organoid models have been developed to study SARS-CoV-2 2-4. Here, we developed human pluripotent stem cell-derived lung and colonic organoids (hPSC-LOs and hPSC-COs) optimized as in vitro platforms for high throughput drug screening. hPSC-LOs are permissive to SARS-CoV-2 We differentiated hPSCs to lung organoids (hPSC-LOs) based on previously reported stepwise strategies 5-13 (Extended Data Fig. 1a-1c). qRT-PCR and RNA-seq profiling validates the expression of alveolar type II (AT2) cell markers in the hPSC-LOs (Extended Data Fig. 1d, 1e). Intra-cellular flow cytometry further confirmed the presence of Pro-SP-C + cells in hPSC-LOs (Extended Data Fig. 1f). Single cell transcriptomic profiles of hPSC-LOs identified AT2-like cells, which were enriched for adult human lung AT2 cell markers (Fig. 1a-1c and Extended Data Fig. 2a-2c).

Ferroptosis, a recently identified and iron-dependent cell death, differs from other cell death such as apoptosis, necroptosis, pyroptosis, and autophagy-dependent cell death. This form of cell death does not exhibit typical morphological and biochemical characteristics, including cell shrinkage, mitochondrial fragmentation, nuclear condensation. The dysfunction of lipid peroxide clearance, the presence of redox-active iron as well as oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are three essential features of ferroptosis. Iron metabolism and lipid peroxidation signaling are increasingly recognized as central mediators of ferroptosis. Ferroptosis plays an important role in the regulation of oxidative stress and inflammatory responses. Accumulating evidence suggests that ferroptosis is implicated in a variety of cardiovascular diseases such as atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure, indicating that targeting ferroptosis will present a novel therapeutic approach against cardiovascular diseases. Here, we provide an overview of the features, process, function, and mechanisms of ferroptosis, and its increasingly connected relevance to oxidative stress, inflammation, and cardiovascular diseases.

It is demonstrated that the n-type thermoelectric performance of donor-acceptor (D-A) copolymers can be enhanced by a factor of >1000 by tailoring the density of states (DOS). The DOS distribution is tailored by embedding sp -nitrogen atoms into the donor moiety of the D-A backbone. Consequently, an electrical conductivity of 1.8 S cm and a power factor of 4.5 µW m K are achieved. Interestingly, an unusual sign switching (from negative to positive) of the Seebeck coefficient of the unmodified D-A copolymer at moderately high dopant loading is observed. A direct measurement of the DOS shows that the DOS distributions become less broad upon modifying the backbone in both pristine and doped states. Additionally, doping-induced charge transfer complexes (CTC) states, which are energetically located below the neutral band, are observed in DOS of the doped unmodified D-A copolymer. It is proposed that charge transport through these CTC states is responsible for the positive Seebeck coefficients in this n-doped system. This is supported by numerical simulation and temperature dependence of Seebeck coefficient. The work provides a unique insight into the fundamental understanding of molecular doping and sheds light on designing efficient n-type OTE materials from a perspective of tailoring the DOS.

The development of many organs, including the lung, depends upon a process known as branching morphogenesis, in which a simple epithelial bud gives rise to a complex tree-like system of tubes specialized for the transport of gas or fluids. Previous studies on lung development have highlighted a role for fibroblast growth factors (FGFs), made by the mesodermal cells, in promoting the proliferation, budding, and chemotaxis of the epithelial endoderm. Here, by using a three-dimensional culture system, we provide evidence for a novel role for Netrins, best known as axonal guidance molecules, in modulating the morphogenetic response of lung endoderm to exogenous FGFs. This effect involves inhibition of localized changes in cell shape and phosphorylation of the intracellular mitogen-activated protein kinase(s) (ERK1/2, for extracellular signal-regulated kinase-1 and -2), elicited by exogenous FGFs. The temporal and spatial expression of netrin 1, netrin 4, and Unc5b genes and the localization of Netrin-4 protein in vivo suggest a model in which Netrins in the basal lamina locally modulate and fine-tune the outgrowth and shape of emergent epithelial buds.