资源环境科技发展态势分析平台

Our understanding of how human embryos develop before gastrulation, including spatial self-organization and cell type ontogeny, remains limited by available two-dimensional technological platforms(1,2) that do not recapitulate the in vivo conditions(3-5). Here we report a three-dimensional (3D) blastocyst-culture system that enables human blastocyst development up to the primitive streak anlage stage. These 3D embryos mimic developmental landmarks and 3D architectures in vivo, including the embryonic disc, amnion, basement membrane, primary and primate unique secondary yolk sac, formation of anterior-posterior polarity and primitive streak anlage. Using single-cell transcriptome profiling, we delineate ontology and regulatory networks that underlie the segregation of epiblast, primitive endoderm and trophoblast. Compared with epiblasts, the amniotic epithelium shows unique and characteristic phenotypes. After implantation, specific pathways and transcription factors trigger the differentiation of cytotrophoblasts, extravillous cytotrophoblasts and syncytiotrophoblasts. Epiblasts undergo a transition to pluripotency upon implantation, and the transcriptome of these cells is maintained until the generation of the primitive streak anlage. These developmental processes are driven by different pluripotency factors. Together, findings from our 3D-culture approach help to determine the molecular and morphogenetic developmental landscape that occurs during human embryogenesis.

A 3D culture system to model human embryonic development, together with single-cell transcriptome profiling, provides insights into the molecular developmental landscape during human post-implantation embryogenesis.

Single-cell analyses have revealed extensive heterogeneity between and within human tumours(1-4), but complex single-cell phenotypes and their spatial context are not at present reflected in the histological stratification that is the foundation of many clinical decisions. Here we use imaging mass cytometry(5) to simultaneously quantify 35 biomarkers, resulting in 720 high-dimensional pathology images of tumour tissue from 352 patients with breast cancer, with long-term survival data available for 281 patients. Spatially resolved, single-cell analysis identified the phenotypes of tumour and stromal single cells, their organization and their heterogeneity, and enabled the cellular architecture of breast cancer tissue to be characterized on the basis of cellular composition and tissue organization. Our analysis reveals multicellular features of the tumour microenvironment and novel subgroups of breast cancer that are associated with distinct clinical outcomes. Thus, spatially resolved, single-cell analysis can characterize intratumour phenotypic heterogeneity in a disease-relevant manner, with the potential to inform patient-specific diagnosis.

A single-cell, spatially resolved analysis of breast cancer demonstrates the heterogeneity of tumour and stroma tissue and provides a more-detailed method of patient classification than the current histology-based system.

The recently discovered flat electronic bands and strongly correlated and superconducting phases in magic-angle twisted bilayer graphene (MATBG)(1,2) crucially depend on the interlayer twist angle, theta. Although control of the global theta with a precision of about 0.1 degrees has been demonstrated(1-7), little information is available on the distribution of the local twist angles. Here we use a nanoscale on-tip scanning superconducting quantum interference device (SQUID-on-tip)(8) to obtain tomographic images of the Landau levels in the quantum Hall state(9) and to map the local theta variations in hexagonal boron nitride (hBN)-encapsulated MATBG devices with relative precision better than 0.002 degrees and a spatial resolution of a few moire periods. We find a correlation between the degree of theta disorder and the quality of the MATBG transport characteristics and show that even state-of-the-art devices-which exhibit correlated states, Landau fans and superconductivity-display considerable local variation in theta of up to 0.1 degrees, exhibiting substantial gradients and networks of jumps, and may contain areas with no local MATBG behaviour. We observe that the correlated states in MATBG are particularly fragile with respect to the twist-angle disorder. We also show that the gradients of theta generate large gate-tunable in-plane electric fields, unscreened even in the metallic regions, which profoundly alter the quantum Hall state by forming edge channels in the bulk of the sample and may affect the phase diagram of the correlated and superconducting states. We thus establish the importance of theta disorder as an unconventional type of disorder enabling the use of twist-angle gradients for bandstructure engineering, for realization of correlated phenomena and for gate-tunable built-in planar electric fields for device applications.

SQUID-on-tip tomographic imaging of Landau levels in magic-angle graphene provides nanoscale maps of local twist-angle disorder and shows that its properties are fundamentally different from common types of disorder.

A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential.

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)(1-4). Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (M-pro) of SARS-CoV-2: M-pro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2(5,6). We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M-pro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of M-pro. Six of these compounds inhibited M-pro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 mu M. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.

The synthesis of tertiary amines is achieved through a carbonyl alkylative amination reaction facilitated by visible light, in which an aldehyde and an amine condense to form an iminium ion that subsequently reacts with alkyl radical.