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•Hfq RNA chaperone remodels small RNAs and mRNAs for post-transcriptional regulation.•Single molecule FRET reveals the kinetics of restructuring OxyS small RNA by Hfq.•Restructuring ...requires conserved arginines on the rim of the Hfq hexamer.•Intrinsically disordered regions slow down transitions between OxyS conformations.•Basic and disordered regions of Hfq work together to restructure RNA for regulation.
The Sm protein Hfq chaperones small non-coding RNAs (sRNAs) in bacteria, facilitating sRNA regulation of target mRNAs. Hfq acts in part by remodeling the sRNA and mRNA structures, yet the basis for this remodeling activity is not understood. To understand how Hfq remodels RNA, we used single-molecule Förster resonance energy transfer (smFRET) to monitor conformational changes in OxyS sRNA upon Hfq binding. The results show that E. coli Hfq first compacts OxyS, bringing its 5′ and 3 ends together. Next, Hfq destabilizes an internal stem-loop in OxyS, allowing the RNA to adopt a more open conformation that is stabilized by a conserved arginine on the rim of Hfq. The frequency of transitions between compact and open conformations depend on interactions with Hfqs flexible C-terminal domain (CTD), being more rapid when the CTD is deleted, and slower when OxyS is bound to Caulobacter crescentus Hfq, which has a shorter and more stable CTD than E. coli Hfq. We propose that the CTDs gate transitions between OxyS conformations that are stabilized by interaction with one or more arginines. These results suggest a general model for how basic residues and intrinsically disordered regions of RNA chaperones act together to refold RNA.
Lithium‐sulfur batteries (LSBs) are considered as the development direction of the new generation energy storage system due to their high energy density and low cost. The slow redox kinetics of ...sulfur and the shuttle effect of lithium polysulfide (LiPS) are considered to be the main obstacles to the practical application of LSBs. Transition‐metal sulfide as the cathode host can improve the Li−S redox chemistry. However, there has been no investigation of the application of FeS2 host in Li−S redox chemistry. Applying the first‐principles calculations, we investigated the formation energy, band gap, Li+ diffusion, adsorption energy, catalytic performance and Li2S decomposition barrier of FeAxS2−x (A=N, P, O, Se; x=0, 0.125, 0.25, 0.375) to explore the Li−S redox chemistry and finally select excellent host material. FeA0.25S1.75 (A=P, Se) has a low Li+ diffusion barrier and superior electronic conductivity. FeO0.25S1.75 is more favorable for LiPS adsorption, followed by FeP0.25S1.75. FeP0.25S1.75(001) shows a low overpotential for the Li−S redox chemistry. In summary, FeP0.25S1.75 has more application potential in LSBs due to its physical and chemical properties, followed by FeSe0.25S1.75. This work provides theoretical guidance for the design and selection of the sulfur cathode host materials in LSBs.
Based on the first‐principles calculation, we identified criteria for screening the sulfur cathode host FeAxS2−x (A=N, P, O, Se; x=0, 0.125, 0.25, 0.375), including the formation energy, band gap, Li+ diffusion, adsorption energy, catalytic performance and Li2S decomposition. This work provides theoretical guidance for the design and selection of sulfur cathode host materials in lithium‐sulfur batteries.
Multivalent synthetic vaccines were obtained by solid‐phase synthesis of tumor‐associated MUC1 glycopeptide antigens and their coupling to a Pam3Cys lipopeptide through click reactions. These ...vaccines elicited immune responses in mice without the use of any external adjuvant. The vaccine containing four copies of a MUC1 sialyl‐TN antigen showed a significant cluster effect. It induced in mice prevailing IgG2a antibodies, which bind to MCF‐7 breast tumor cells and initiate the killing of these tumor cells by activation of the complement‐dependent cytotoxicity complex.
Multivalent vaccines containing a MUC1 glycopeptide bearing the STn antigen were chemically synthesized and immunologically evaluated. The induced immune responses in mice were dependent on the valence of the glycopeptide. The antisera exhibited strong binding to tumor cells which resulted in tumor cell death. This novel effect of clustered multivalent vaccines can be attributed to the altered pattern of the induced antibody isotypes.
Autophagy is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate whether the p62‐Keap1‐Nrf2 pathway affects the development of PAH by mediating autophagy. ...A PAH rat model was established using monocrotaline (MCT). Pulmonary artery smooth muscle cells (PASMCs) were extracted, and the changes in proliferation, migration, autophagy, and oxidative stress were analyzed following overexpression or knockdown of p62. The impact of p62 on the symptoms of PAH rats was assessed by the injection of an adenovirus overexpressing p62. We found that the knockdown of p62 increased the proliferation and migration of PASMCs, elevating the oxidative stress of PASMCs and upregulating gene expression of NADPH oxidases. Co‐IP assay results demonstrated that p62 interacted with Keap1. p62 knockdown enhanced Keap1 protein stability and Nrf2 ubiquitination. LC3II/I and ATG5 were expressed more often when p62 was knocked down. Treating with an inhibitor of autophagy reversed the impact of p62 knockdown on PASMCs. Nrf2 inhibitor treatment reduced the expression of Nrf2 and p62, while increasing the expression of Keap1, LC3II/I, and ATG5 in PASMCs. However, overexpressing p62 diminished mRVP, SPAP, and Fulton index in PAH rats and attenuated pulmonary vascular wall thickening. Overexpression of p62 also decreased the expression of Keap1, LC3II/I, and ATG5 and increased the nuclear expression of Nrf2 in PAH rats. Importantly, overexpression of p62 reduced oxidative stress and the NADPH oxidase expression in PAH rats. Overall, activation of the p62‐Keap1‐Nrf2 positive feedback signaling axis reduces the proliferation and migration of PASMCs and alleviates PAH by inhibiting autophagy and oxidative stress.
Activation of the p62‐Keap1‐Nrf2 positive feedback signaling axis reduces the proliferation and migration of PASMCs and alleviates PAH by inhibiting autophagy and oxidative stress.
Tau, an important pathological protein of Alzheimer's disease (AD), can mediate the toxicity of amyloid β (Aβ). Thus, reduction of Tau with chemical molecules may offer a novel strategy for treating ...AD. Here, we designed and synthesized a series of multifunctional molecules that contained Tau-recognition moieties and E3 ligase-binding moieties to enhance Tau degradation. Among these molecules, TH006 had the highest activity of inducing Tau degradation by increasing its poly-ubiquitination. The decrement in Tau induced by TH006 could decrease the cytotoxicity caused by Aβ. Furthermore, TH006 could regulate the Tau level in the brain of an AD mouse model. Therefore, partial reduction of Tau with such multifunctional peptides may open up a novel therapeutic strategy for AD treatment.
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•Synthesized multifunctional PROTACs peptide TH006 effectively induces Tau degradation•TH006 increases poly-ubiquitination of Tau depending on VHL E3 ligase•Decrement of Tau induced by TH006 reduces the cytotoxicity caused by Aβ•TH006 can promote Tau reduction in primary neuron cells and 3xTg-AD mice
Tau, involved in Alzheimer's disease, is an intrinsically disordered protein which is difficult to be regulated. Chu et al. design and synthesize a multifunctional PROTACs peptide, TH006, to induce intracellular Tau degraded by increasing its poly-ubiquitination. Partial reduction of Tau induced by TH006 prevents cytotoxicity caused by Aβ.
A visible‐light‐induced dioxygenation of β,γ‐unsaturated oximes for the synthesis of diverse useful isoxazolines bearing a hydroxyl moiety was developed by employing graphitic carbon nitride (g‐C3N4) ...as a heterogeneous photocatalyst under an air atmosphere. Noted that, the eminent advantages of this metal‐free protocol include step economy, easy operation, a recyclable photocatalyst, external reductant‐/oxidant‐free and mild reaction conditions. Additionally, mechanistic studies indicated hydroxyl radical was generated under the photocatalysis of g‐C3N4.
•Calculating EWRs of vegetation the Penman-Monteith formula.•Quantitative analysis of correlation between landscape index and EWRs of vegetative ecosystem on different landscape scales.•The ...influences of landscape pattern changes on EWRs of vegetative ecosystem are obvious in an arid/semiarid region of China.
With climate change and the intensification of human activities, landscape patterns have undergone important changes. These changes can have multiple impact on hydrology, nutrient transport between soil and vegetation and ecological function and health in vegetative ecosystems. Dynamic changes in landscape patterns may affect the ecological water requirements (EWRs) of vegetation. Based on meteorological data, soil data and 6 years of land use data (from 1990 to 2015), the EWRs were obtained through the Penman–Monteith formula. eight suitable landscape indices (Patch Density (PD), Connectivity Index (COHESION), Largest Patch Index (LPI), Aggregation Index (AI), Shannon Diversity Index (SHDI), Contagion Index (CONTAG), Separation Index (SPLIT), and Landscape Shape Index (LSI)) were used to explore the spatial and temporal characteristics of landscape patterns. Furthermore, the influences of landscape pattern changes on the EWRs of the middle main reaches of the Yellow River, China, were investigated. From 1990 to 2015, the total number of patches in the landscape pattern of the watershed increased, and the patch shape became more complex; the EWRs decreased from 392.7 mm to 276.5 mm, and the annual volume of the EWRs in the study area decreased from 124.8 × 108 m3 to 89.6 × 108 m3. The EWRs had a positive correlation with the LPI, indicating that the changes in the largest patch had a great impact on the EWRs. The EWRs also had a negative correlation with the SPLIT, showing that the more fragmented the landscape patches, the smaller the EWRs. With an increase in SHDI, the EWRs showed a downward trend. Furthermore, the EWRs showed a downward trend with decreasing CONTAG and COHESION. These results provide useful information for ecological restoration and provide an important reference for ecological environmental protection and the optimal allocation of water resources in arid/semiarid regions around the world. In the future, the EWRs can be regulated, and the utilization rate of water resources can be improved, by combining the current ecological environmental protection policies of the Yellow River Basin and managing future trends in landscape patterns.
In the development of vaccines for epithelial tumors, the key targets are MUC1 proteins, which have a variable number of tandem repeats (VNTR) bearing tumor-associated carbohydrate antigens (TACAs), ...such as Tn and STn. A major obstacle in vaccine development is the low immunogenicity of the short MUC1 peptide. To overcome this obstacle, we designed, synthesized, and evaluated several totally synthetic self-adjuvanting vaccine candidates with self-assembly domains. These vaccine candidates aggregated into fibrils and displayed multivalent B-cell epitopes under mild conditions. Glycosylation of Tn antigen on the Thr residue of PDTRP sequence in MUC1 VNTR led to effective immune response. These vaccines elicited a high level antibody response without any adjuvant and induced antibodies that recognized human breast tumor cells. These vaccines appeared to act through a T-cell independent pathway and were associated with the activation of cytotoxic T cells. These fully synthetic, molecularly defined vaccine candidates had several features that hold promise for anticancer therapy.
Research has shown that long noncoding RNAs (lncRNAs) play significant roles in colorectal cancer (CRC). However, the role of lnc‑UCID (lncRNA upregulating CDK6 by interacting with DHX9) in CRC ...remains largely unknown. In the present study, analyses revealed that lnc‑UCID was markedly upregulated in CRC compared with that in normal specimens. Functional experiments showed that the depletion of lnc‑UCID inhibited CRC cell invasion and migration significantly, while overexpression of lnc‑UCID had the opposite effect. A candidate target of lnc‑UCID, microRNA miR‑152‑3p, was identified using bioinformatic analysis. Moreover, in CRC tissue, we noted an inverse correlation between miR‑152‑3p and lnc‑UCID expression levels. Overexpression and knockdown experiments revealed opposing roles for miR‑152‑3p and lnc‑UCID, suggesting that lnc‑UCID negatively regulates miR‑152‑3p. Luciferase reporter assays demonstrated that miR‑152‑3p directly targets lnc‑UCID. The results suggest that lnc‑UCID acts as an endogenous miRNA sponge, competing for miR‑152‑3p binding and thereby regulating the miRNA's targets. Overall, we propose that the lnc‑UCID/miR‑152‑3p/Wnt/β‑catenin signaling axis represents a novel mechanism that explains the migration and invasion of CRC.
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