Manipulating metal atoms in a controllable way for the synthesis of materials with the desired structure and properties is the holy grail of chemical synthesis. The recent emergence of single atomic site catalysts (SASC) demonstrates that we are moving toward this goal. Owing to the maximum efficiency of atom-utilization and unique structures and properties, SASC have attracted extensive research attention and interest. The prerequisite for the scientific research and practical applications of SASC is to fabricate highly reactive and stable metal single atoms on appropriate supports. In this review, various synthetic strategies for the synthesis of SASC are summarized with concrete examples highlighting the key issues of the synthesis methods to stabilize single metal atoms on supports and to suppress their migration and agglomeration. Next, we discuss how synthesis conditions affect the structure and catalytic properties of SASC before ending this review by highlighting the prospects and challenges for the synthesis as well as further scientific researches and practical applications of SASC.

Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs1. Recognition of modified histones by “reader” proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of BET bromodomain inhibitors2, 3. We recently identified the YEATS domain as a novel acetyllysine-binding module4, yet its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralog AF9, is required for disease maintenance in acute myeloid leukaemia (AML). CRISPR-Cas9 mediated depletion of ENL led to anti-leukemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and ChIP-seq analyses revealed that ENL binds to acetylated histone H3, and colocalizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemias. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced RNA polymerase II recruitment to ENL target genes, leading to suppression of oncogenic gene expression programs. Importantly, disruption of ENL’s functionality further sensitized leukaemia cells to BET inhibitors. Together, our study identifies ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in AML and suggests that displacement of ENL from chromatin may be a promising epigenetic therapy alone or in combination with BET inhibitors for AML.

We describe the identification and initial characterization of neurobeachin, a neuron-specific multidomain protein of 327 kDa with a high-affinity binding site (K d , 10 nM) for the type II regulatory subunit of protein kinase A (PKA RII). Neurobeachin is peripherally associated with pleomorphic tubulovesicular endomembranes near the trans sides of Golgi stacks and throughout the cell body and cell processes. It is also found in a subpopulation of synapses, where it is concentrated at the postsynaptic plasma membrane. In live cells, perinuclear neurobeachin is dispersed by brefeldin A (BFA) within 1 min, and in permeabilized cells a recruitment of neurobeachin from cytosol to Golgi-near membranes is stimulated by GTP␥S and prevented by brefeldin A. Spots of neurobeachin recruitment are close to but distinct from recruitment sites of COP-I, AP-1, and AP-3 coat proteins involved in vesicle budding. These observations indicate that neurobeachin binding to membranes close to the trans-Golgi requires an ADP-ribosylation factor-like GTPase, possibly in association with a novel type of protein coat. A neurobeachin isoform that does not bind RII, beige-like protein (BGL), is expressed in many tissues. Neurobeachin, BGL, and ϳ10 other mammalian gene products share a characteristic C-terminal BEACH-WD40 sequence module, which is also present in gene products of invertebrates, plants, protozoans, and yeasts, thus defining a new protein family. The prototype member of this family of BEACH domain proteins, lysosomal trafficking regulator (LYST), is deficient in genetic defects of protein sorting in lysosome biogenesis (the beige mouse and Chediak-Higashi syndrome). Neurobeachin's subcellular localization, its coat proteinlike membrane recruitment, and its sequence similarity to LYST suggest an involvement in neuronal post-Golgi membrane traffic, one of its functions being to recruit protein kinase A to the membranes with which it associates. Key words: AKAP; ARF; BEACH domain; BGL; coat protein; Golgi complex; LYST; membrane traffic; neurobeachin; protein kinase A; scaffolding protein; synapse; TGNThe progression of membranes and proteins through the stages and compartments of the secretory and endocytic pathways is a highly organized and regulated process. The maintenance of the overall architecture of endomembranes and of the plasma membrane requires a balance of lipid flows into and out of the various compartments, and proteins destined for diverse organelles or plasma membrane domains must be appropriately sorted and targeted, whereas resident proteins of specific pathway stages must be retained or retrieved. These events require the interplay of lipids, membrane proteins, soluble cytosolic and lumenal proteins, and cytoskeletal and motor proteins. Their internal coordination and external regulation is known to involve protein phosphorylation and small and heterotrimeric G-proteins.In neurons, the mechanisms for the trafficking of membranes and membrane proteins must be particularly active and complex. Because of their m...

Metal−organic frameworks (MOF) have recently emerged as versatile precursors to fabricate functional MOF derivatives for oxygen evolution reactions (OER). Herein, we developed a controlled partial pyrolysis strategy to construct robust NiCo/Fe 3 O 4 heteroparticles within MOF-74 for efficient OER using trimetallic NiCoFe-MOF-74 as precursor. The partial pyrolysis method preserves the framework structure of MOF for effective substrates diffusion while producing highly active nanoparticles. The as-prepared NiCo/Fe 3 O 4 /MOF-74 delivered remarkably stable OER current with an overpotential as low as 238 mV at 10.0 mA cm −2 and an Tafel slop of 29 mV/dec, outperforming those of pristine NiCoFe-MOF-74, totally decomposed MOF derivatives, and most reported non-noble metal based electrocatalysts. The key for the formation of NiCo/Fe 3 O 4 /MOF-74 nanostructures is that the metals can be decomposed from NiCoFe-MOF-74 in the order of Ni, Co, and Fe under controlled heat treatment. Density functional theory calculations reveals that the underlying NiCo promotes the OER activity of Fe 3 O 4 through exchange stabilization of active oxygen species.

p53, circRNAs and miRNAs are important components of the regulatory network that activates the EMT program in cancer metastasis. In prostate cancer (PCa), however, it has not been investigated whether and how p53 regulates EMT by circRNAs and miRNAs. Here we show that a Amotl1-derived circRNA, termed circAMOTL1L, is downregulated in human PCa, and that decreased circAMOTL1L facilitates PCa cell migration and invasion through downregulating E-cadherin and upregulating vimentin, thus leading to EMT and PCa progression. Mechanistically, we demonstrate that circAMOTL1L serves as a sponge for binding miR-193a-5p in PCa cells, relieving miR-193a-5p repression of Pcdha gene cluster (a subset of the cadherin superfamily members). Accordingly, dysregulation of the circAMOTL1L-miR-193a-5p-Pcdha8 regulatory pathway mediated by circAMOTL1L downregulation contributes to PCa growth in vivo. Further, we show that RBM25 binds directly to circAMOTL1L and induces its biogenesis, whereas p53 regulates EMT via direct activation of RBM25 gene. These findings have linked p53/RBM25-mediated circAMOTL1L-miR-193a-5p-Pcdha regulatory axis to EMT in metastatic progression of PCa. Targeting this newly identified regulatory axis provides a potential therapeutic strategy for aggressive PCa.