PYR1/PYL/RCAR proteins (PYLs) are confirmed abscisic acid (ABA) receptors, which inhibit protein phosphatase 2C (PP2C) upon binding to ABA. Arabidopsis thaliana has 14 PYLs, yet their functional ...distinction remains unclear. Here, we report systematic biochemical characterization of PYLs. A subclass of PYLs, represented by PYL10, inhibited PP2C in the absence of any ligand. Crystal structures of PYL10, both in the free form and in the HAB1 (PP2C)-bound state, revealed the structural basis for its constitutive activity. Structural-guided biochemical analyses revealed that ABA-independent inhibition of PP2C requires the PYLs to exist in a monomeric state. In addition, the residues guarding the entrance to the ligand-binding pocket of these PYLs should be bulky and hydrophobic. Based on these principles, we were able to generate monomeric PYL2 variants that gained constitutive inhibitory effect on PP2Cs. These findings provide an important framework for understanding the complex regulation of ABA signaling by PYL proteins.
► A subclass of PYLs was identified to inhibit PP2C in the absence of ABA ► Structures of PYL10 in apo- and PP2C-bound forms were obtained ► The molecular basis underlying the constitutive activity of PYLs was revealed ► The results shed light on the engineering of plants for enhanced stress-tolerance
Hydrogen is an ideal energy carrier because of its high chemical energy, environmental friendliness and renewability. In order to realize the safe, efficient and compact hydrogen storage, various ...solid-state hydrogen storage materials based on the physisorption or chemisorption of hydrogen have been developed over the past decades. Among them, magnesium hydride, MgH2, is identified as one of the most promising candidates due to its high hydrogen storage density, low cost and abundance of Mg element. However, the sluggish kinetics and high thermodynamic stability of MgH2 result in its high operation temperature and low hydrogen sorption rate, impeding its practical application. In this article, the recent progress in catalysis and nanoconfinement effects on the hydrogen storage properties of MgH2 is comprehensively reviewed. In particular, the synergetic roles of catalysis and nanoconfinement in MgH2 are highlighted. Furthermore, the future challenges and prospects of emerging research for MgH2 are discussed. It is suggested that the nonmetal-doped porous carbon materials could be a class of ideal additives to enhance the hydrogen storage properties of MgH2 by the synergetic effects of catalysis and nanoconfinement.
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•Recent progress in MgH2 modified through catalysis and nanoconfinement is reviewed.•Synergetic roles of catalysis and nanoconfinement in MgH2 are highlighted.•Future challenges and prospects of emerging research for MgH2 are discussed.•Nonmetal-doped porous carbon materials are suggested to be ideal additives for MgH2.
Voltage-gated sodium （Nav） channels are essential for the rapid upstroke of action potentials and the propa- gation of electrical signals in nerves and muscles. Defects of Nav channels are associated ...with a variety of channelopathies. More than 1000 disease-related muta- tions have been identified in Nay channels, with Nay1.1 and Nay1.5 each harboring more than 400 mutations. Nay channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav chan- nels are required to understand their function and dis- ease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium （Car） channel Carl.1 provides a template for homology-based structural modeling of the evolutionarily related Nay channels. In this Resource article, we summarized all the reported disease-related mutations in human Nav channels, generated a homologous model of human Nay1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Nay channels, the analysis presented here serves as the base framework for mechanistic investi- gation of Nav channelopathies and for potential struc- ture-based drug discovery.
As one of the most important engineering materials, aluminum alloys have been widely applied in many fields. However, the requirement of enhancing their mechanical properties without sacrificing the ...ductility is always a challenge in the development of aluminum alloys. Thanks to the excellent physical and mechanical properties, graphene nanoflakes (GNFs) have been applied as promising reinforcing elements in various engineering materials, including polymers and ceramics. However, the investigation of GNFs as reinforcement phase in metals or alloys, especially in aluminum alloys, is still very limited. In this study, the aluminum alloy reinforced by GNFs was successfully prepared via powder metallurgy approach. The GNFs were mixed with aluminum alloy powders through ball milling and followed by hot isostatic pressing. The green body was then hot extruded to obtain the final GNFs reinforced aluminum alloy nanocomposite. The scanning electron microscopy and transmission electron microscope analysis show that GNFs were well dispersed in the aluminum alloy matrix and no chemical reactions were observed at the interfaces between the GNFs and aluminum alloy matrix. The mechanical properties׳ testing results show that with increasing filling content of GNFs, both tensile and yield strengths were remarkably increased without losing the ductility performance. These results not only provided a pathway to achieve the goal of preparing high strength aluminum alloys with excellent ductilitybut they also shed light on the development of other metal alloys reinforced by GNFs.
The discovery of RNA-mediated gene-silencing pathways, including RNA interference, highlights a fundamental role of short RNAs in eukaryotic gene regulation and antiviral defence. Members of the ...Dicer and Argonaute protein families are essential components of these RNA-silencing pathways. Notably, these two families possess an evolutionarily conserved PAZ (Piwi/Argonaute/Zwille) domain whose biochemical function is unknown. Here we report the nuclear magnetic resonance solution structure of the PAZ domain from Drosophila melanogaster Argonaute 1 (Ago1). The structure consists of a left-handed, six-stranded β-barrel capped at one end by two α-helices and wrapped on one side by a distinctive appendage, which comprises a long β-hairpin and a short α-helix. Using structural and biochemical analyses, we demonstrate that the PAZ domain binds a 5-nucleotide RNA with 1:1 stoichiometry. We map the RNA-binding surface to the open face of the β-barrel, which contains amino acids conserved within the PAZ domain family, and we define the 5′-to-3′ orientation of single-stranded RNA bound within that site. Furthermore, we show that PAZ domains from different human Argonaute proteins also bind RNA, establishing a conserved function for this domain.
For decades, treatment of hepatitis B virus (HBV) infection has been relying on interferon (IFN)-based therapies and nucleoside/nucleotide analogues (NAs) that selectively target the viral polymerase ...reverse transcriptase (RT) domain and thereby disrupt HBV viral DNA synthesis. We have summarized here the key steps in the HBV viral life cycle, which could potentially be targeted by novel anti-HBV therapeutics. A wide range of next-generation direct antiviral agents (DAAs) with distinct mechanisms of actions are discussed, including entry inhibitors, transcription inhibitors, nucleoside/nucleotide analogues, inhibitors of viral ribonuclease H (RNase H), modulators of viral capsid assembly, inhibitors of HBV surface antigen (HBsAg) secretion, RNA interference (RNAi) gene silencers, antisense oligonucleotides (ASOs), and natural products. Compounds that exert their antiviral activities mainly through host factors and immunomodulation, such as host targeting agents (HTAs), programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, and Toll-like receptor (TLR) agonists, are also discussed. In this Perspective, we hope to provide an overview, albeit by no means being comprehensive, for the recent development of novel therapeutic agents for the treatment of chronic HBV infection, which not only are able to sustainably suppress viral DNA but also aim to achieve functional cure warranted by HBsAg loss and ultimately lead to virus eradication and cure of hepatitis B.
Mitochondria are well-known cellular organelles that play a vital role in cellular bioenergetics, heme biosynthesis, thermogenesis, calcium homeostasis, lipid catabolism, and other metabolic ...activities. Given the extensive role of mitochondria in cell function, mitochondrial dysfunction plays a part in many diseases, including diabetes and Alzheimer's disease (AD). In most cases, there is overwhelming evidence that impaired mitochondrial function is a causative factor in these diseases. Studying mitochondrial function in diseased cells vs healthy cells may reveal the modified mechanisms and molecular components involved in specific disease states. In this chapter, we provide a concise overview of the major recent findings on mitochondrial abnormalities and their link to synaptic dysfunction relevant to neurodegeneration and cognitive decline in AD and diabetes. Our increased understanding of the role of mitochondrial perturbation indicates that the development of specific small molecules targeting aberrant mitochondrial function could provide therapeutic benefits for the brain in combating aging-related dementia and neurodegenerative diseases by powering up brain energy and improving synaptic function and transmission.
Wnt signalling is involved in multiple aspects of embryonic development and adult tissue homeostasis, notably via controlling cellular proliferation and differentiation. Wnt signalling is subject to ...stringent positive and negative regulation to promote proper development and homeostasis yet avoid aberrant growth. Such multi‐layer regulation includes post‐translational modification and processing of Wnt proteins themselves, R‐spondin (Rspo) amplification of Wnt signalling, diverse receptor families, and intracellular and extracellular antagonists and destruction and transcription complexes. In the gastrointestinal tract, Wnt signalling is crucial for development and renewal of the intestinal epithelium. Intestinal stem cells (ISCs) undergo symmetric division and neutral drift dynamics to renew the intestinal epithelium. Sources of Wnts and Wnt amplifers such as R‐spondins are beginning to be elucidated as well as their functional contribution to intestinal homeostasis. In this review we focus on regulation of ISCs and intestinal homeostasis by the Wnt/Rspo pathway, the potential cellular sources of Wnt signalling regulators and highlight potential future areas of study.
Wnt signalling in intestinal homeostasis. The tightly regulated Wnt signalling pathway is active at the crypt base where Wnt and Rspo signals (blue) are coming from intestinal mesenchymal and epithelial compartments. It is crucial in intestinal homeostasis by acting on crypt base columnar intestinal stem cells (green) to promote self‐renewal, yet has little effect on quiescent intestinal stem cells (red).
Arthropod-borne viruses (arboviruses) are ecologically distinct from many other pathogens because of the involvement of arthropod vectors and animal reservoirs. Several mosquito-borne arboviruses ...have emerged in various geographic regions during the past few decades. Since the beginning of the 21st century, the emergence of two mosquito-borne arboviruses, chikungunya and Zika, has taken place globally. Millions of infections have not only changed the epidemiology of previously obscure viruses, but also put the world’s public health capability to the test. Newly recognized pathogenic mechanisms and modes of transmission demand the development of new strategies for disease control and treatment. The advancement of vaccine candidates in various phases of clinical trials and the evaluation of vector control strategies in the field provide the promise of new solutions for endemic or emerging diseases. In this review, the emergence of six medically important mosquito-borne arboviruses and new tools for disease control will be discussed.
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