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Non-volatile resistive switching, also known as memristor1 effect, where an electric field switches the resistance states of a two-terminal device, has emerged as an important concept in the development of high-density information storage, computing and reconfigurable systems2–9. The past decade has witnessed substantial advances in non-volatile resistive switching materials such as metal oxides and solid electrolytes. It was long believed that leakage currents would prevent the observation of this phenomenon for nanometre-thin insulating layers. However, the recent discovery of non-volatile resistive switching in two-dimensional monolayers of transition metal dichalcogenide10,11 and hexagonal boron nitride12 sandwich structures (also known as atomristors) has refuted this belief and added a new materials dimension owing to the benefits of size scaling10,13. Here we elucidate the origin of the switching mechanism in atomic sheets using monolayer MoS2 as a model system. Atomistic imaging and spectroscopy reveal that metal substitution into a sulfur vacancy results in a non-volatile change in the resistance, which is corroborated by computational studies of defect structures and electronic states. These findings provide an atomistic understanding of non-volatile switching and open a new direction in precision defect engineering, down to a single defect, towards achieving the smallest memristor for applications in ultra-dense memory, neuromorphic computing and radio-frequency communication systems2,3,11.A combination of atomistic imaging and spectroscopy reveals that metal substitution into a sulfur vacancy is the underlying mechanism for resistive switching in transition metal dichalcogenide monolayers.

Organic emitters with persistent phosphorescence have shown potential application in optoelectronic devices. However, rational design and phosphorescence tuning are still challenging. Here, a series of metal-free luminophores without heavy atoms and carbonyl groups from commercial/lab-synthesized carbazole and benzene were synthesized to realize tunable molecular emission from fluorescence to phosphorescence by simply substituent variation. All the molecules emit blue fluorescence in both solution and solid state. Upon removal of excitation source, the fluorinated luminophores show obvious phosphorescence. The lab-synthesized carbazole based molecules exhibit a huge lifetime difference to the commercially purchased ones due to the existence of isomer in the latter samples. The small energy gap between singlet and triplet state and low reorganization energy help enhance intersystem crossing to contribute to a more competitive radiative process from triplet to ground state. Blue and white organic light-emitting devices are fabricated by using fluorinated luminophore as emitting layer. Though organic emitters with room temperature phosphorescence (RTP) are attractive for various applications, realizing highly efficient and long lifetime emission remains a challenge. Here, the authors report the role of push-pull electronic effects on emission for organic RTP emitters.

BES1 and BZR1 were originally identified as two key transcription factors specifically regulating brassinosteroid (BR)-mediated gene expression. They belong to a family consisting of six members, BES1, BZR1, BEH1, BEH2, BEH3, and BEH4. bes1 and bzr1 single mutants do not exhibit any characteristic BR phenotypes, suggesting functional redundancy of these proteins. Here, by generating higher order mutants, we show that a quintuple mutant is male sterile due to defects in tapetum and microsporocyte development in anthers. Our genetic and biochemical analyses demonstrate that BES1 family members also act as downstream transcription factors in the EMS1-TPD1-SERK1/2 pathway. Ectopic expression of both TPD1 and EMS1 in bri1-116 , a BR receptor null mutant, leads to the accumulation of non-phosphorylated, active BES1, similar to activation of BES1 by BRI1-BR-BAK1 signaling. These data suggest that two distinctive receptor-like kinase-mediated signaling pathways share BES1 family members as downstream transcription factors to regulate different aspects of plant development. BES1 and BZR1 transcription factors are activated by the BRI1-BAK1 receptor complex during brassinosteroid signaling. Here the authors show that BES1-family members also act in anthers, downstream of another receptor-like kinase-mediated signaling pathway, EMS1-TPD1-SERK1/2, to promote tapetum development.

The genetic manipulation of basidiomycete mushrooms is notoriously difficult and immature, and there is a lack of research reports on clustered regularly interspaced short palindromic repeat (CRISPR) based gene editing of functional genes in mushrooms. In this work, Ganoderma lucidum, a famous traditional medicinal basidiomycete mushroom, which produces a type of unique triterpenoid-anti-tumor ganoderic acids (GAs), was used, and a CRISPR/CRISPR-associated protein-9 nuclease (Cas9) editing system for functional genes of GA biosynthesis was constructed in the mushroom. As proof of concept, the effect of different gRNA constructs with endogenous u6 promoter and self-cleaving ribozyme HDV on ura3 disruption efficiency was investigated at first. The established system was applied to edit a cytochrome P450 monooxygenase (CYP450) gene cyp5150l8, which is responsible for a three-step biotransformation of lanosterol at C-26 to ganoderic acid 3-hydroxy-lanosta-8, 24-dien-26 oic acid. As a result, precisely edited cyp5150l8 disruptants were obtained after sequencing confirmation. The fermentation products of the wild type (WT) and cyp5150l8 disruptant were analyzed, and a significant decrease in the titer of four identified GAs was found in the mutant compared to WT. Another CYP gene involved in the biosynthesis of squalene-type triterpenoid 2, 3; 22, 23-squalene dioxide, cyp505d13, was also disrupted using the established CRISPR-Cas9 based gene editing platform of G. lucidum. The work will be helpful to strain molecular breeding and biotechnological applications of G. lucidum and other basidiomycete mushrooms.

Diols encompass important bulk and fine chemicals for the chemical, pharmaceutical and cosmetic industries. During the past decades, biological production of C3-C5 diols from renewable feedstocks has received great interest. Here, we elaborate a general principle for effectively synthesizing structurally diverse diols by expanding amino acid metabolism. Specifically, we propose to combine oxidative and reductive formations of hydroxyl groups from amino acids in a thermodynamically favorable order of four reactions catalyzed by amino acid hydroxylase, L-amino acid deaminase, α-keto acid decarboxylase and aldehyde reductase consecutively. The oxidative formation of hydroxyl group from an alkyl group is energetically more attractive than the reductive pathway, which is exclusively used in the synthetic pathways of diols reported so far. We demonstrate this general route for microbial production of branched-chain diols in E. coli . Ten C3-C5 diols are synthesized. Six of them, namely isopentyldiol (IPDO), 2-methyl-1,3-butanediol (2-M-1,3-BDO), 2-methyl-1,4-butanediol (2-M-1,4-BDO), 2-methyl-1,3-propanediol (MPO), 2-ethyl-1,3-propanediol (2-E-1,3-PDO), 1,4-pentanediol (1,4-PTD), have not been biologically synthesized before. This work opens up opportunities for synthesizing structurally diverse diols and triols, especially by genome mining, rational design or directed evolution of proper enzymes. Diols are important bulk and fine chemicals, but bioproduciton of branch-chain diols is hampered by the unknown biological route. Here, the authors report the expanding of amino acid metabolism for biosynthesis of branch-chain diols via a general route of combined oxidative and reductive formations of hydroxyl groups.

Background More and more evidence showed that long non-coding RNAs (lncRNAs) play important roles in the development and progression of human sophisticated diseases. Therefore, predicting human lncRNA-disease associations is a challenging and urgently task in bioinformatics to research of human sophisticated diseases. Results In the work, a global network-based computational framework called as LRWRHLDA were proposed which is a universal network-based method. Firstly, four isomorphic networks include lncRNA similarity network, disease similarity network, gene similarity network and miRNA similarity network were constructed. And then, six heterogeneous networks include known lncRNA-disease, lncRNA-gene, lncRNA-miRNA, disease-gene, disease-miRNA, and gene-miRNA associations network were applied to design a multi-layer network. Finally, the Laplace normalized random walk with restart algorithm in this global network is suggested to predict the relationship between lncRNAs and diseases. Conclusions The ten-fold cross validation is used to evaluate the performance of LRWRHLDA. As a result, LRWRHLDA achieves an AUC of 0.98402, which is higher than other compared methods. Furthermore, LRWRHLDA can predict isolated disease-related lnRNA (isolated lnRNA related disease). The results for colorectal cancer, lung adenocarcinoma, stomach cancer and breast cancer have been verified by other researches. The case studies indicated that our method is effective.

L-tryptophan (L-trp) is a biosynthetic precursor of various bioactive components with pharmaceutical interest. The development of an efficient L-trp production strain using targeted molecular engineering approaches is challenging due to the requirement of several precursors and the complex regulations of the pathways involved. In this study, we present a rationally engineered and genetically stable L-trp overproducing Escherichia coli strain. The streamlined strain E. coli S028 is able to efficiently produce 34–40 g/L of L-trp with a yield of 0.15 g L-trp/g glucose and a productivity of 0.60 g/L/h in fed-batch fermentations. The titer and productivity of L-trp achieved are over twice as much as those reported so far for rationally developed L-trp producers. In addition, for the first time, both intracellular and extracellular concentrations of L-trp and the key metabolites in a L-trp hyperproducer strain were measured with an automated fast-sampling unit which is connected to a well-controlled bioreactor. The time series metabolic analysis gives valuable information about the regulation of L-trp synthesis in a highly productive strain and reveals targets for further improvement. Among others, it was found that L-trp and the byproduct glutamate (L-glu) accumulated to an extremely high level in the cell initially whereas the intracellular concentrations of glutamine (L-gln) stayed at a relatively low level throughout the fermentation. The metabolic analysis suggests that (a) the engineered serine biosynthesis pathway was able to effectively synthesize the substrate serine (intracellular concentration > 8 mM) for L-trp production, while (b) the substrate L-gln with an intracellular concentration of 0.8–1.2 mM seems to limit the biosynthesis of L-trp, even though L-glu was overproduced intra- and extracellularly. Thus, an increased availability of glutamine synthetase which catalyzes L-glu conversion to L-gln and an overexpression of the L-trp exporter gene could be important targets for further strain improvement.

• The plant hormone jasmonic acid (JA) is involved in the cold stress response, and the inducer of CBF expression 1 (ICE1)- C-repeat binding factor (CBF) regulatory cascade plays a key role in the regulation of cold stress tolerance. In this study, we showed that a novel B-box (BBX) protein MdBBX37 positively regulates JA-mediated cold-stress resistance in apple. • We found that MdBBX37 bound to the MdCBF1 and MdCBF4 promoters to activate their transcription, and also interacted with MdICE1 to enhance the transcriptional activity of MdICE1 on MdCBF1, thus promoting its cold tolerance. • Two JA signaling repressors, MdJAZ1 and MdJAZ2 (JAZ, JAZMONATE ZIM-DOMAIN), interacted with MdBBX37 to repress the transcriptional activity of MdBBX37 on MdCBF1 and MdCBF4, and also interfered with the interaction between MdBBX37 and MdICE1, thus negatively regulating JA-mediated cold tolerance. E3 ligase MdMIEL1 (MIEL1, MYB30-Interacting E3 Ligase1) reduced MdBBX37-improved cold resistance by mediating ubiquitination and degradation of the MdBBX37 protein. • The data reveal that MIEL1 and JAZ proteins co-regulate JA-mediated cold stress tolerance through the BBX37-ICE1-CBF module in apple. These results will aid further examination of the post-translational modification of BBX proteins and the regulatory mechanism of JA-mediated cold stress tolerance.

Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48 ± 0.02] × 10vs. 1.00 ± 0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46 ± 0.12, vs.1.00 ± 0.37, t = 2.42, P < 0.05) and viral replication ([6.18 ± 0.95] × 10vs. 1.00 ± 0.43, t = 3.98, P < 0.05). Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.

The use of gaseous and air-captured CO 2 for technical biosynthesis is highly desired, but elusive so far due to several obstacles including high energy (ATP, NADPH) demand, low thermodynamic driving force and limited biosynthesis rate. Here, we present an ATP and NAD(P)H-free chemoenzymatic system for amino acid and pyruvate biosynthesis by coupling methanol with CO 2 . It relies on a re-engineered glycine cleavage system with the NAD(P)H-dependent L protein replaced by biocompatible chemical reduction of protein H with dithiothreitol. The latter provides a higher thermodynamic driving force, determines the reaction direction, and avoids protein polymerization of the rate-limiting enzyme carboxylase. Engineering of H protein to effectively release the lipoamide arm from a protected state further enhanced the system performance, achieving the synthesis of glycine, serine and pyruvate at g/L level from methanol and air-captured CO 2 . This work opens up the door for biosynthesis of amino acids and derived products from air. The use of gaseous and air-captured CO 2 for technical biosynthesis is highly desired but challenging due to high energy demands. Here, the authors present an ATP and NAD(P)H-free chemoenzymatic system for glycine, serine, and pyruvate biosynthesis by coupling methanol with gaseous and air-captured CO 2 .