Generation of functional and vascularized organs from human induced pluripotent stem cells (iPSCs) will facilitate our understanding of human developmental biology and disease modeling, hopefully ...offering a drug-screening platform and providing novel therapies against end-stage organ failure. Here we describe a protocol for the in vitro generation of a 3D liver bud from human iPSC cultures and the monitoring of further hepatic maturation after transplantation at various ectopic sites. iPSC-derived specified hepatic cells are dissociated and suspended with endothelial cells and mesenchymal stem cells. These mixed cells are then plated onto a presolidified matrix, and they form a 3D spherical tissue mass termed a liver bud (iPSC-LB) in 1-2 d. To facilitate additional maturation, 4-d-old iPSC-LBs are transplanted in the immunodeficient mouse. Live imaging has identified functional blood perfusion into the preformed human vascular networks. Functional analyses show the appearance of multiple hepatic functions in a chronological manner in vivo.
As of June 8, 2020, the global reported number of COVID-19 cases had reached more than 7 million with over 400 000 deaths. The household transmissibility of the causative pathogen, severe acute ...respiratory syndrome coronavirus 2 (SARS-CoV-2), remains unclear. We aimed to estimate the secondary attack rate of SARS-CoV-2 among household and non-household close contacts in Guangzhou, China, using a statistical transmission model.
In this retrospective cohort study, we used a comprehensive contact tracing dataset from the Guangzhou Center for Disease Control and Prevention to estimate the secondary attack rate of COVID-19 (defined as the probability that an infected individual will transmit the disease to a susceptible individual) among household and non-household contacts, using a statistical transmission model. We considered two alternative definitions of household contacts in the analysis: individuals who were either family members or close relatives, such as parents and parents-in-law, regardless of residential address, and individuals living at the same address regardless of relationship. We assessed the demographic determinants of transmissibility and the infectivity of COVID-19 cases during their incubation period.
Between Jan 7, 2020, and Feb 18, 2020, we traced 195 unrelated close contact groups (215 primary cases, 134 secondary or tertiary cases, and 1964 uninfected close contacts). By identifying households from these groups, assuming a mean incubation period of 5 days, a maximum infectious period of 13 days, and no case isolation, the estimated secondary attack rate among household contacts was 12·4% (95% CI 9·8–15·4) when household contacts were defined on the basis of close relatives and 17·1% (13·3–21·8) when household contacts were defined on the basis of residential address. Compared with the oldest age group (≥60 years), the risk of household infection was lower in the youngest age group (<20 years; odds ratio OR 0·23 95% CI 0·11–0·46) and among adults aged 20–59 years (OR 0·64 95% CI 0·43–0·97). Our results suggest greater infectivity during the incubation period than during the symptomatic period, although differences were not statistically significant (OR 0·61 95% CI 0·27–1·38). The estimated local reproductive number (R) based on observed contact frequencies of primary cases was 0·5 (95% CI 0·41–0·62) in Guangzhou. The projected local R, had there been no isolation of cases or quarantine of their contacts, was 0·6 (95% CI 0·49–0·74) when household was defined on the basis of close relatives.
SARS-CoV-2 is more transmissible in households than SARS-CoV and Middle East respiratory syndrome coronavirus. Older individuals (aged ≥60 years) are the most susceptible to household transmission of SARS-CoV-2. In addition to case finding and isolation, timely tracing and quarantine of close contacts should be implemented to prevent onward transmission during the viral incubation period.
US National Institutes of Health, Science and Technology Plan Project of Guangzhou, Project for Key Medicine Discipline Construction of Guangzhou Municipality, Key Research and Development Program of China.
Multipartite entangled states are crucial for numerous applications in quantum information science. However, the generation and verification of multipartite entanglement on fully controllable and ...scalable quantum platforms remains an outstanding challenge. We report the deterministic generation of an 18-qubit Greenberger-Horne-Zeilinger (GHZ) state and multicomponent atomic Schrödinger cat states of up to 20 qubits on a quantum processor, which features 20 superconducting qubits, also referred to as artificial atoms, interconnected by a bus resonator. By engineering a one-axis twisting Hamiltonian, the system of qubits, once initialized, coherently evolves to multicomponent atomic Schrödinger cat states-that is, superpositions of atomic coherent states including the GHZ state-at specific time intervals as expected. Our approach on a solid-state platform should not only stimulate interest in exploring the fundamental physics of quantum many-body systems, but also enable the development of applications in practical quantum metrology and quantum information processing.
Cytochrome P450 (CYP450)‐catalyzed oxidative coupling is an efficient strategy for using simple building blocks to construct complex structural scaffolds of natural products. Among them, ...heterodimeric coupling between two different monomers is relatively scarce, and the corresponding CYP450s are largely undiscovered. In this study, we discovered a fungal CYP450 (CpsD) and its associated cps cluster from 37208 CYP450s of Pfam PF00067 family member database and subsequently identified a group of new skeleton indole piperazine alkaloids (campesines A−G) by combination of genome mining and heterologous synthesis. Importantly, CYP450 CpsD mainly catalyzes intermolecular oxidative heterocoupling of two different indole piperazine monomers to generate an unexpected 6/5/6/6/6/6/5/6 eight‐ring scaffold through the formation of one C−C bond and two C−N bonds, illuminating its first dimerase role in this family of natural products. The proposed catalytic mechanism of CpsD was deeply investigated by diversified substrate derivatization. Moreover, dimeric campesine G shows good insecticidal activity against the global honeybee pest Galleria mellonella. Our study shows a representative example of discovering new skeleton monomeric and dimeric indole piperazine alkaloids from microbial resources, expands our knowledge of bond formation by CYP450s and supports further development of the newly discovered and engineered campesine family compounds as potential biopesticides.
A fungal cytochrome P450 (CpsD) and its associated cps cluster were discovered from 37208 CYP450s by genome mining. CpsD catalyzes intermolecular oxidative heterocoupling of two different indole piperazine monomers to give a group of unexpected 6/5/6/6/6/6/5/6 eight‐ring‐scaffold heterodimeric compounds through the formation of one C−C and two C−N bonds. Dimeric campesine G shows good insecticidal activity against the pest Galleria mellonella.
The numerical approach is a vital means for evaluating the stability of flawed rocks. In this paper, the extended non‐ordinary state‐based peridynamics (NOSB‐PD) theory is employed to simulate the ...fracture process of rocks containing two pre‐existing flaws. Two stress criteria, including the maximum tensile stress criterion and the Mohr–Coulomb criterion, are implemented into the NOSB‐PD numerical method to respectively judge the tensile and shear failure of rock materials. The effects of inclination angles and ligament angles on the crack initiation and coalescence modes for flawed rocks are investigated based on the numerical results. The numerical results are in good agreement with the previous experimental results. The fracture mechanism of flawed rocks is revealed based on the evolutionary distribution characteristics of the maximum principal stress field and shear stress field obtained by the extended NOSB‐PD theory.
Highlights
The extended non‐ordinary state‐based peridynamics (NOSB‐PD) theory is employed.
The fracture characteristics of flawed rocks are investigated by the extended NOSB‐PD.
The fracture failure mechanism of flawed rocks is revealed by the extended NOSB‐PD.
COVID-19 has impacted populations around the world, with the fatality rate varying dramatically across countries. Selenium, as one of the important micronutrients implicated in viral infections, was ...suggested to play roles.
An ecological study was performed to assess the association between the COVID-19 related fatality and the selenium content both from crops and topsoil, in China.
Totally, 14,045 COVID-19 cases were reported from 147 cities during 8 December 2019-13 December 2020 were included. Based on selenium content in crops, the case fatality rates (CFRs) gradually increased from 1.17% in non-selenium-deficient areas, to 1.28% in moderate-selenium-deficient areas, and further to 3.16% in severe-selenium-deficient areas (P = 0.002). Based on selenium content in topsoil, the CFRs gradually increased from 0.76% in non-selenium-deficient areas, to 1.70% in moderate-selenium-deficient areas, and further to 1.85% in severe-selenium-deficient areas (P < 0.001). The zero-inflated negative binomial regression model showed a significantly higher fatality risk in cities with severe-selenium-deficient selenium content in crops than non-selenium-deficient cities, with incidence rate ratio (IRR) of 3.88 (95% CIs: 1.21-12.52), which was further confirmed by regression fitting the association between CFR of COVID-19 and selenium content in topsoil, with the IRR of 2.38 (95% CIs: 1.14-4.98) for moderate-selenium-deficient cities and 3.06 (1.49-6.27) for severe-selenium-deficient cities.
Regional selenium deficiency might be related to an increased CFR of COVID-19. Future studies are needed to explore the associations between selenium status and disease outcome at individual-level.
A combinatorial nickel‐catalyzed monofluoroalkylation of aryl halides with unactivated fluoroalkyl halides by reductive cross‐coupling has been developed. This method demonstrated high efficiency, ...mild conditions, and excellent functional‐group tolerance, thus enabling the late‐stage monofluoroalkylation of diverse drugs. The key to success was the combination of diverse readily available bidentate and monodentate pyridine‐type nitrogen ligands with nickel, which in situ generated a variety of readily tunable catalysts to promote fluoroalkylation with broad scope with respect to both coupling partners. This combinatorial catalysis strategy offers a solution for nickel‐catalyzed reductive cross‐coupling reactions and provides an efficient way to synthesize fluoroalkylated druglike molecules for drug discovery.
Combining forces: Aryl halides undergo efficient monofluoroalkylation with unactivated fluoroalkyl halides by reductive cross‐coupling with excellent functional‐group tolerance (see scheme). The mild and efficient transformation was developed by the combination of diverse readily available bidentate and monodentate pyridine‐type nitrogen ligands with nickel to generate a variety of readily tunable catalysts in situ.
Motivated by recent work on rotating black hole shadow (Chang and Zhu in Phys Rev D 101:084029, 2020), we investigate the shadow behaviours of rotating Hayward–de Sitter black hole for static ...observers at a finite distance in terms of astronomical observables. This paper uses the newly introduced distortion parameter (Chang and Zhu in Phys Rev D 102:044012, 2020) to describe the shadow’s shape quantitatively. We show that the spin parameter would distort shadows and the magnetic monopole charge would increase the degree of deformation. The distortion will increase as the distance between the observer and the black hole increases, and distortion reduces as the cosmological constant increases. Besides, the increase of the spin parameter, magnetic monopole charge and cosmological constant will cause the shadows shrunken.
Paleobotanical and sedimentological records indicate that marked climatic and environmental transitions had taken place in East China by the early Miocene. These transitions were driven by ...paleogeographic and global climatic shifts, but the respective roles of these shifts in the Asian climate remain unclear. Here, we use the low‐resolution Norwegian Earth System Model and Community Atmosphere Model version 4 to compare the effects of Tibetan Plateau (TP) growth, Paratethys Sea retreat and global cooling on the East Asian climate change that occurred by the early Miocene. The modeling results indicate that these three factors had clearly different climatic effects in East China. In particular, TP growth increased annual precipitation in East China, while Paratethys Sea retreat and global cooling generally decreased annual precipitation in East China. In addition, the three factors studied all drove aridification in inland Asia. Considering the increased precipitation, arid/semiarid‐to‐humid shift in vegetation and high plant diversity present in East China by the early Miocene, as shown in geological records, TP growth thus played a major role in these respects.
Key Points
Tibetan Plateau (TP) growth increased annual precipitation in East China
Paratethys Sea retreat and global cooling decreased annual precipitation in East China
TP growth, Paratethys Sea retreat and global cooling all drove aridification in inland Asia
Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to ...study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)–based screening model for analyzing DILI pathology at organoid resolution.
We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform.
HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9–based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis.
Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.
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