SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M
, is ...a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (
and
) targeting M
Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 M
in complex with
or
, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of
and
are covalently bound to cysteine 145 of M
Both compounds showed good pharmacokinetic properties in vivo, and
also exhibited low toxicity, which suggests that these compounds are promising drug candidates.
Exosomes are cell-derived nanovesicles that are involved in the intercellular transportation of materials. Therapeutics, such as small molecules or nucleic acid drugs, can be incorporated into ...exosomes and then delivered to specific types of cells or tissues to realize targeted drug delivery. Targeted delivery increases the local concentration of therapeutics and minimizes side effects. Here, we present a detailed review of exosomes engineering through genetic and chemical methods for targeted drug delivery. Although still in its infancy, exosome-mediated drug delivery boasts low toxicity, low immunogenicity, and high engineerability, and holds promise for cell-free therapies for a wide range of diseases.
Metal‐containing nanoparticles (M‐NPs) in metal/nitrogen‐doped carbon (M‐N‐C) catalysts have been considered hostile to the acidic oxygen reduction reaction (ORR). The relation between M‐NPs and the ...active sites of metal coordinated with nitrogen (MNx) is hard to establish in acid medium owing to the poor stability of M‐NPs. Herein, we develop a strategy to successfully construct a new FeCo‐N‐C catalyst containing highly active M‐NPs and MN4 composite sites (M/FeCo‐SAs‐N‐C). Enhanced catalytic activity and stability of M/FeCo‐SAs‐N‐C is shown experimentally. Calculations reveal that there is a strong interaction between M‐NPs and FeN4 sites, which can favor ORR by activating the O−O bond, thus facilitating a direct 4 e− process. Those findings firstly shed light on the highly active M‐NPs and FeN4 composite sites for catalyzing acid oxygen reduction reaction, and the relevant reaction mechanism is suggested.
Highly active metal‐containing nanoparticles and FeN4 composite sites have been constructed. Experiment and calculation results reveal the enormous potential for activating the O−O bond and promoting the direct 4 e− dissociation pathway in the acidic oxygen reduction reaction (ORR), which could fundamentally improve ORR activity and inhibit the formation of reactive oxygen species.
Investigations and applications of renewable and sustainable energy have become central for addressing the issue of emissions of greenhouse gases from the use of fossil transportation fuels. ...Triglyceride-based liquid fuels have great potential as substitutes for petroleum and its derivatives. To date, the proven technologies for converting triglycerides into biofuels include transesterification, thermal cracking conversion, and hydrogenation. This paper presents an overview of recent research on these conversion technologies, employing homogeneous, heterogeneous, enzymatic, and photocatalytic catalysts. We focus on technical aspects critical to triglyceride conversion, including feedstock analysis, mechanism research, analysis of technological advantages and disadvantages, and catalyst development and selection. Biodiesel produced by the transesterification process must be blended with diesel before use due to its higher oxide content. The resultant “green diesel” has a broader range of applications, especially when its structure has been upgraded. Life cycle assessment (LCA) and greenhouse gas (GHG) emissions are reviewed to assess the renewability and sustainability of biofuels. We discuss the typical biodiesel production technologies with their development status, as well as the relevant policies and prospects for biofuels, mainly concerning biodiesel and aviation biofuel. It is hoped that our work will be of guiding significance for future biofuel research.
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•Overview of triglycerides biomass resources and their composition characteristics.•Overview of various possibilities conversion technologies for biofuel production are provided.•Overview of the composition characteristics of biodiesel and aviation biofuel and further upgraded for improving quality.•LCA and GHG emissions are reviewed to assess the renewability and sustainability of biofuels.
This paper summarizes recent studies on the effects of urbanization on climate in China. The effects of urbanization on local climate trends have been re-estimated based on homogenized observations ...and using improved methods. In this respect, the effect of urbanization on the observed warming trend of local surface air temperatures during the last few decades is determined as being about 20% at urban stations such as the Beijing Observatory. The large-scale weakening trend of wind speed is also about 20% more prominent at the city center than its surroundings. The effect of urbanization on precipitation is not profound, but results of high-resolution regional climate modeling suggest that this effect may depend on the urban extent. Although the urban heat island (UHI) should favor local atmospheric convection and hence precipitation, the increasingly extending urban land-use may reduce precipitation over the urban cluster in North China. It is found that urbanization can play a more notable role in extreme events than usual weather. High-resolution simulations show a positive feedback between the UHI and the super-heat wave in Shanghai during JulyeAugust 2013. Relevant studies dealing with urban climate adaptation are discussed in relation to recent findings.
Gene vectors are nucleic acids that carry genetic materials or gene editing devices into cells to exert the sustained production of therapeutic proteins or to correct erroneous genes of the cells. ...However, the cell membrane sets a barrier for the entry of nucleic acid molecules, and nucleic acids are easily degraded or neutralized when they are externally administered into the body. Carriers to encapsulate, protect and deliver nucleic acid molecules therefore are essential for clinical applications of gene therapy. The secreted organelles, exosomes, which naturally mediate the communications between cells, have been engineered to encapsulate and deliver nucleic acids to the desired tissues and cells. The fusion of exosomes with liposomes can increase the loading capacity and also retain the targeting capability of exosomes. Altogether, this review summarizes the most recent designs of exosome-based applications for gene delivery and their future perspectives in gene therapy.
Exosome encapsulation protects and delivers AAV vectors for gene therapy.
Driven by the persisting poor understanding of the sluggish kinetics of the hydrogen evolution reaction (HER) on Pt in alkaline media, a direct correlation of the interfacial water structure and ...activity is still yet to be established. Herein, using Pt and Pt–Ni nanoparticles we first demonstrate a strong dependence of the proton donor structure on the HER activity and pH. The structure of the first layer changes from the proton acceptors to the donors with increasing pH. In the base, the reactivity of the interfacial water varied its structure, and the activation energies of water dissociation increased in the sequence: the dangling O−H bonds < the trihedrally coordinated water < the tetrahedrally coordinated water. Moreover, optimizing the adsorption of H and OH intermediates can re‐orientate the interfacial water molecules with their H atoms pointing towards the electrode surface, thereby enhancing the kinetics of HER. Our results clarified the dynamic role of the water structure at the electrode–electrolyte interface during HER and the design of highly efficient HER catalysts.
On nickel–platinum alloy nanoparticles under alkaline conditions, the reactivity of interfacial water varies with its structure and the order of water dissociation. The inclusion of nickel re‐orientates interfacial water molecules with their hydrogen atoms pointing towards the electrode surface, thereby enhancing the kinetics of the hydrogen evolution reaction (HER).
Aims: To determine floristic units and centres of plant species endemism using quantitative methods and different taxonomic groups. Location: The Qinghai-Tibetan Plateau in south-western China – the ...world's highest and geologically youngest plateau. Methods: The plateau was divided into 260 grid cells, each 1° × 1°, and the numbers of different seed-plant taxa, including genera, total species, endemic species and alpine species, were recorded in each cell. Hierarchical clustering and non-metric multidimensional scaling (NMDS) ordination were used to divide the flora quantitatively, and ANOSIM (analysis of similarities) was used to evaluate differences between the derived groups in the composition of taxa. The stress value was used to assess the fitness of the NMDS ordination. Species endemism was measured using corrected weighted endemism, and centres of species endemism were delimited on the basis of floristic units. Results: The plateau harbours a total of 12,058 seed-plant species and infraspecific taxa in 1619 genera; 38.2% of the species are endemic to the plateau and 27.7% are alpine plants. When two or four groups were considered, cluster analysis based on genera gave the best definition, whereas when 12 groups were considered, analysis of endemic species gave the best definition. The flora of the Qinghai-Tibetan Plateau represents two floristic subkingdoms, four floristic regions and 12 floristic subregions. Three centres of species endemism were identified, associated with five floristic subregions. Main conclusions: Quantitative analysis can reveal associations within a flora, and partly confirm intuitive classifications. Genera provide clear divisions of higher floristic ranks, and endemic species give the clearest classifications of lower floristic ranks. Alpine species are important taxa for classifying the flora of mountainous regions. A centre of species endemism based on a floristic unit can be conveniently identified and delimited, and the spatial scale of this centre is determined by the taxonomic rank used.
Astrocytes are crucial regulators in the central nervous system. Abnormal activation of astrocytes contributes to some behavior deficits. However, mechanisms underlying the effects remain unclear. ...Here, we studied the activation of A1 astrocytes and their contribution to murine behavior deficits.
A1 astrocytes were induced by treatment with lipopolysaccharide (LPS) in vitro. The functional phenotype of astrocytes was determined by quantitative RT-PCR, ELISA, and immunohistochemistry. To assess the role of A1 astrocytes in vivo, mice were injected intraperitoneally with LPS. Then, murine behaviors were tested, and the hippocampus and cortex were analyzed by quantitative RT-PCR, ELISA, and immunohistochemistry. The function of IL-10 and fluorocitrate on A1 astrocyte activation was also examined.
Our results show that astrocytes isolated from B6.129S6-Il10
/J homozygotes (IL-10
) were prone to characteristics of A1 reactive astrocytes. Compared with their wild-type counterparts, IL-10
astrocytes exhibited higher expression of glial fibrillary acidic protein (GFAP). Whether or not they were stimulated with LPS, IL-10
astrocytes exhibited enhanced expression of A1-specific transcripts and proinflammatory factors IL-1β, IL-6, and TNFα. In addition, IL-10
astrocytes demonstrated hyperphosphorylation of STAT3. Moreover, astrocytes from IL-10
mice showed attenuated phagocytic ability and were neurotoxic. IL-10
mice demonstrated increased immobility time in the forced swim test and defective learning and memory behavior in the Morris water maze test. Moreover, enhanced neuroinflammation was found in the hippocampus and cortex of IL-10
mice, accompanying with more GFAP-positive astrocytes and severe neuron loss in the hippocampus. Pretreatment IL-10
mice with IL-10 or fluorocitrate decreased the expression of proinflammatory factors and A1-specific transcripts in the hippocampus and cortex, and then alleviated LPS-induced depressive-like behavior.
These results demonstrate that astrocytes isolated from B6.129S6-Il10
/J homozygotes are prone to A1 phenotype and contribute to the depression-like behavior and memory deficits. Inhibiting A1 astrocyte activation may be an attractive therapeutic strategy in some neurodegenerative diseases.
Enzymatic reactions in living cells are highly dynamic but simultaneously tightly regulated. Enzyme engineers seek to construct multienzyme complexes to prevent intermediate diffusion, to improve ...product yield, and to control the flux of metabolites. Here we choose a pair of short peptide tags (RIAD and RIDD) to create scaffold-free enzyme assemblies to achieve these goals. In vitro, assembling enzymes in the menaquinone biosynthetic pathway through RIAD-RIDD interaction yields protein nanoparticles with varying stoichiometries, sizes, geometries, and catalytic efficiency. In Escherichia coli, assembling the last enzyme of the upstream mevalonate pathway with the first enzyme of the downstream carotenoid pathway leads to the formation of a pathway node, which increases carotenoid production by 5.7 folds. The same strategy results in a 58% increase in lycopene production in engineered Saccharomyces cerevisiae. This work presents a simple strategy to impose metabolic control in biosynthetic microbe factories.
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