Metal single-atom catalysts (M-SACs) have emerged as an attractive concept for promoting heterogeneous reactions, but the synthesis of high-loading M-SACs remains a challenge. Here, we report a multilayer stabilization strategy for constructing M-SACs in nitrogen-, sulfur- and fluorine-co-doped graphitized carbons (M=Fe, Co, Ru, Ir and Pt). Metal precursors are embedded into perfluorotetradecanoic acid multilayers and are further coated with polypyrrole prior to pyrolysis. Aggregation of the metals is thus efficiently inhibited to achieve M-SACs with a high metal loading (similar to 16wt%). Fe-SAC serves as an efficient oxygen reduction catalyst with half-wave potentials of 0.91 and 0.82V (versus reversible hydrogen electrode) in alkaline and acid solutions, respectively. Moreover, as an air electrode in zinc-air batteries, Fe-SAC demonstrates a large peak power density of 247.7mWcm(-2) and superior long-term stability(.) Our versatile method paves an effective way to develop high-loading M-SACs for various applications.
Lipid membranes are found in most intracellular organelles, and their heterogeneities play an essential role in regulating the organelles' biochemical functionalities. Here we report a Spectrum and Polarization Optical Tomography (SPOT) technique to study the subcellular lipidomics in live cells. Simply using one dye that universally stains the lipid membranes, SPOT can simultaneously resolve the membrane morphology, polarity, and phase from the three optical-dimensions of intensity, spectrum, and polarization, respectively. These high-throughput optical properties reveal lipid heterogeneities of ten subcellular compartments, at different developmental stages, and even within the same organelle. Furthermore, we obtain real-time monitoring of the multi-organelle interactive activities of cell division and successfully reveal their sophisticated lipid dynamics during the plasma membrane separation, tunneling nanotubules formation, and mitochondrial cristae dissociation. This work suggests research frontiers in correlating single-cell super-resolution lipidomics with multiplexed imaging of organelle interactome. Lipid membranes are heterogeneous and dynamically regulated in cells. Here the authors report a Spectrum and Polarisation Optical Tomography (SPOT) method where they use Nile Red dye to resolve membrane morphology, polarity and phase in cells.
Moire lattices formed in twisted van der Waals bilayers provide a unique, tunable platform to realize coupled electron or exciton lattices unavailable before. While twist angle between the bilayer has been shown to be a critical parameter in engineering the moire potential and enabling novel phenomena in electronic moire systems, a systematic experimental study as a function of twist angle is still missing. Here we show that not only are moire excitons robust in bilayers of even large twist angles, but also properties of the moire excitons are dependant on, and controllable by, the moire reciprocal lattice period via twist-angle tuning. From the twist-angle dependence, we furthermore obtain the effective mass of the interlayer excitons and the electron inter-layer tunneling strength, which are difficult to measure experimentally otherwise. These findings pave the way for understanding and engineering rich moire-lattice induced phenomena in angle-twisted semiconductor van der Waals heterostructures. Here, the authors show that the properties of the moire excitons in twisted van der Waals bilayers of transition metal dichalcogenides are determined by the moire reciprocal lattice period, and can be controlled via twist-angle tuning.
Non-structural proteins (nsp) constitute the SARS-CoV-2 replication and transcription complex (RTC) to play a pivotal role in the virus life cycle. Here we determine the atomic structure of a SARS-CoV-2 mini RTC, assembled by viral RNA-dependent RNA polymerase (RdRp, nsp12) with a template-primer RNA, nsp7 and nsp8, and two helicase molecules (nsp13-1 and nsp13-2), by cryo-electron microscopy. Two groups of mini RTCs with different conformations of nsp13-1 are identified. In both of them, nsp13-1 stabilizes overall architecture of the mini RTC by contacting with nsp13-2, which anchors the 5-extension of RNA template, as well as interacting with nsp7-nsp8-nsp12-RNA. Orientation shifts of nsp13-1 results in its variable interactions with other components in two forms of mini RTC. The mutations on nsp13-1:nsp12 and nsp13-1:nsp13-2 interfaces prohibit the enhancement of helicase activity achieved by mini RTCs. These results provide an insight into how helicase couples with polymerase to facilitate its function in virus replication and transcription. SARS-CoV-2 virus replication and transcription is mediated by the replication and transcription complex (RTC) that is composed of 16 non-structural proteins (nsp). Here, the authors present the cryo-EM structure of a SARS-CoV-2 mini RTC consisting of the viral RNA-dependent RNA polymerase with a template-primer RNA, the RdRp cofactors nsp7 and nsp8 and two nsp13 helicase molecules, and they propose a model for helicase-polymerase coupling during SARS-CoV-2 RTC assembly.
Almost all plants in the genus Populus are dioecious (i.e. trees are either male or female), but it is unknown whether dioecy evolved in a common ancestor or independently in different subgenera. Here, we sequence the small peritelomeric X- and Y-linked regions of P. deltoides chromosome XIX. Two genes are present only in the Y-linked region. One is a duplication of a non-Y-linked, female-specifically expressed response regulator, which produces siRNAs that block this gene's expression, repressing femaleness. The other is an LTR/Gypsy transposable element family member, which generates long non-coding RNAs. Overexpression of this gene in A. thaliana promotes androecium development. We also find both genes in the sex-determining region of P. simonii, a different poplar subgenus, which suggests that they are both stable components of poplar sex-determining systems. By contrast, only the duplicated response regulator gene is present in the sex-linked regions of P. davidiana and P. tremula. Therefore, findings in our study suggest dioecy may have evolved independently in different poplar subgenera.
The space charge layer (SCL) is generally considered one of the origins of the sluggish interfacial lithium-ion transport in all-solid-state lithium-ion batteries (ASSLIBs). However, in-situ visualization of the SCL effect on the interfacial lithium-ion transport in sulfide-based ASSLIBs is still a great challenge. Here, we directly observe the electrode/electrolyte interface lithium-ion accumulation resulting from the SCL by investigating the net-charge-density distribution across the high-voltage LiCoO2/argyrodite Li6PS5Cl interface using the in-situ differential phase contrast scanning transmission electron microscopy (DPC-STEM) technique. Moreover, we further demonstrate a built-in electric field and chemical potential coupling strategy to reduce the SCL formation and boost lithium-ion transport across the electrode/electrolyte interface by the in-situ DPC-STEM technique and finite element method simulations. Our findings will strikingly advance the fundamental scientific understanding of the SCL mechanism in ASSLIBs and shed light on rational electrode/electrolyte interface design for high-rate performance ASSLIBs. Understanding the effect of the space charge layer (SCL) in all-solid-state lithium-ion batteries is challenging due to lack of direct experimental observations. Here the authors visualize the SCL using an in-situ DPC-STEM imaging technique, based on which they further introduce a built-in electric field to suppress its formation.
Optical transient surveys have led to the discovery of dozens of stellar tidal disruption events (TDEs) by massive black hole in the centers of galaxies. Despite extensive searches, X-ray follow-up observations have produced no or only weak X-ray detections in most of them. Here we report the discovery of delayed X-ray brightening around 140 days after the optical outburst in the TDE OGLE16aaa, followed by several flux dips during the decay phase. These properties are unusual for standard TDEs and could be explained by the presence of supermassive black hole binary or patchy obscuration. In either scenario, the X-rays can be produced promptly after the disruption but are blocked in the early phase, possibly by a radiation-dominated ejecta which leads to the bulk of optical and ultraviolet emission. Our findings imply that the reprocessing is important in the TDE early evolution, and X-ray observations are promising in revealing supermassive black hole binaries. The discrepancy between the optical and X-ray properties of tidal disruption events (TDE) is an unresolved issue. Here, the authors show delayed X-ray brightening after the optical flare in TDE OGLE16aaa followed by several flux dips during the decay phase that could be explained by the presence of supermassive black hole binary or patchy obscuration.
Supported atomic clusters with uniform metal sites and definite low-nuclearity are intermediate states between single-atom catalysts (SACs) and nanoparticles in size. Benefiting from the presence of metal-metal bonds, supported atomic clusters can trigger synergistic effects among every metal atom, which contributes to achieving unique catalytic properties different from SACs and nanoparticles. However, the scalable and precise synthesis and atomic-level insights into the structure-properties relationship of supported atomic clusters is a great challenge. This perspective presents the latest progress of the synthesis of supported atomic clusters, highlights how the structure affects catalytic properties, and discusses the limitations as well as prospects. Supported atomic clusters with precise nuclearity are intermediate states between single-atom catalysts and nanoparticles in size. Here the authors summarize and discuss synthetic strategies of supported atomic clusters with unique catalytic properties for heterogeneous reactions.
Engineering membranes for molecular separation in organic solvents is still a big challenge. When the selectivity increases, the permeability tends to drastically decrease, increasing the energy demands for the separation process. Ideally, organic solvent nanofiltration membranes should be thin to enhance the permeant transport, have a well-tailored nanoporosity and high stability in harsh solvents. Here, we introduce a trianglamine macrocycle as a molecular building block for cross-linked membranes, prepared by facile interfacial polymerization, for high-performance selective separations. The membranes were prepared via a two-in-one strategy, enabled by the amine macrocycle, by simultaneously reducing the thickness of the thin-film layers (<10nm) and introducing permanent intrinsic porosity within the membrane (6.3 angstrom). This translates into a superior separation performance for nanofiltration operation, both in polar and apolar solvents. The hyper-cross-linked network significantly improved the stability in various organic solvents, while the amine host macrocycle provided specific size and charge molecular recognition for selective guest molecules separation. By employing easily customized molecular hosts in ultrathin membranes, we can significantly tailor the selectivity on-demand without compromising the overall permeability of the system.
HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors. Resistance to anti-HER2 therapies in breast cancer remains a significant clinical challenge. Here, the authors demonstrate that EZH2 regulates response to HER2-targeting therapies in breast cancer, in part, by modulating the expression of PPP2R2B.
O-GlcNAc modification plays critical roles in regulating the stress response program and cellular homeostasis. However, systematic and multi-omics studies on the O-GlcNAc regulated mechanism have been limited. Here, comprehensive data are obtained by a chemical reporter-based method to survey O-GlcNAc function in human breast cancer cells stimulated with the genotoxic agent adriamycin. We identify 875 genotoxic stress-induced O-GlcNAc chromatin-associated proteins (OCPs), including 88 O-GlcNAc chromatin-associated transcription factors and cofactors (OCTFs), subsequently map their genomic loci, and construct a comprehensive transcriptional reprogramming network. Notably, genotoxicity-induced O-GlcNAc enhances the genome-wide interactions of OCPs with chromatin. The dynamic binding switch of hundreds of OCPs from enhancers to promoters is identified as a crucial feature in the specific transcriptional activation of genes involved in the adaptation of cancer cells to genotoxic stress. The OCTF nuclear factor erythroid 2-related factor-1 (NRF1) is found to be a key response regulator in O-GlcNAc-modulated cellular homeostasis. These results provide a valuable clue suggesting that OCPs act as stress sensors by regulating the expression of various genes to protect cancer cells from genotoxic stress. Protein O-GlcNAcylation is involved in regulating gene expression and maintaining cellular homeostasis. Here, the authors develop a chemical reporter-based strategy for the proteomic profiling and genome-wide mapping of genotoxic stress-induced O-GlcNAcylated chromatin-associated proteins.
A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19873-9
Proteoglycans (PGs) are composed of a core protein and one or more chains of glycosaminoglycans (GAGs). The highly heterogeneous GAG chains play an irreplaceable role in the functions of PGs. However, the lack of an approach to control the exact structure of GAG chains conjugated to PGs tremendously hinders functional studies of PGs. Herein, by using glypican-3 as a model, we establish an aldehyde tag-based approach to assemble PGs with specific GAG chains on the surface of living cells. We show that the engineered glypican-3 can regulate Wnt and Hedgehog signaling like the wild type. Furthermore, we also present a method for studying the interaction of PGs with their target glycoproteins by combining the assembly of PGs carrying specific GAG chains with metabolic glycan labeling, and most importantly, we obtain evidence of GPC3 directly interacting with Frizzled. In conclusion, this study provides a very useful platform for structural and functional studies of PGs with specific GAG chains. Currently, it is not possible to generate proteoglycans displaying glycosaminoglycan chains with specific structures. Here the authors show that by using an aldehyde tag-based methodology it is possible to insert these specific chains onto proteoglycans expressed on the cell surface.
Rapid, inexpensive, robust diagnostics are essential to control the spread of infectious diseases. Current state of the art diagnostics are highly sensitive and specific, but slow, and require expensive equipment. Here we report the development of a molecular diagnostic test for SARS-CoV-2 based on an enhanced recombinase polymerase amplification (eRPA) reaction. eRPA has a detection limit on patient samples down to 5 viral copies, requires minimal instrumentation, and is highly scalable and inexpensive. eRPA does not cross-react with other common coronaviruses, does not require RNA purification, and takes similar to 45min from sample collection to results. eRPA represents a first step toward at-home SARS-CoV-2 detection and can be adapted to future viruses within days of genomic sequence availability.
Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants. Identifying variants capable of causing genetic disease is challenging. The authors use semisupervised learning to predict pathogenic missense variants and their impacts on protein structure and function, enabling a molecular mechanism-driven approach to studying different types of human disease.