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Piezo proteins are evolutionarily conserved and functionally diverse mechanosensitive cation channels. However, the overall structural architecture and gating mechanisms of Piezo channels have remained unknown. Here we determine the cryo-electron microscopy structure of the full-length (2,547 amino acids) mouse Piezo1 (Piezo1) at a resolution of 4.8 Å. Piezo1 forms a trimeric propeller-like structure (about 900 kilodalton), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore. Piezo1, a mechanosensitive cation channel, senses shear stress of blood flow for proper blood vessel development, regulates red blood cell function and controls cell migration and differentiation; here a trimeric architecture of this novel class of ion channel is reported, suggesting that Piezo1 may use its peripheral propeller-like ‘blades’ as force sensors to gate the central ion-conducting pore. Piezo1 channel architecture Mechanosensitive cation channels couple mechanical stimuli to various biological activities, including touch, hearing and blood pressure regulation, through a process termed 'mechanotransduction'. Piezo proteins have recently been identified as pore-forming subunits of mechanosensitive cation channels in metazoans, and Piezo1 senses shear stress of blood flow for proper blood vessel development, regulates red blood cell function, and controls cell migration and differentiation. These authors report a high-resolution cryo-electron microscopy structure of the full-length mouse Piezo1, which reveals the trimeric three-bladed propeller-like architecture of this membrane protein. They propose that Piezo1 may use its peripheral propeller-like 'blades' as force sensors to gate the central ion-conducting pore.

Ribosome associated complex (RAC), an obligate heterodimer of HSP40 and HSP70 (Zuo1 and Ssz1 in yeast), is conserved in eukaryotes and functions as co-chaperone for another HSP70 (Ssb1/2 in yeast) to facilitate co-translational folding of nascent polypeptides. Many mechanistic details, such as the coordination of one HSP40 with two HSP70s and the dynamic interplay between RAC-Ssb and growing nascent chains, remain unclear. Here, we report three sets of structures of RAC-containing ribosomal complexes isolated from Saccharomyces cerevisiae . Structural analyses indicate that RAC on the nascent-chain-free ribosome is in an autoinhibited conformation, and in the presence of a nascent chain at the peptide tunnel exit (PTE), RAC undergoes large-scale structural remodeling to make Zuo1 J-Domain more accessible to Ssb. Our data also suggest a role of Zuo1 in orienting Ssb-SBD proximal to the PTE for easy capture of the substrate. Altogether, in accordance with previous data, our work suggests a sequence of structural remodeling events for RAC-Ssb during co-translational folding, triggered by the binding and passage of growing nascent chain from one to another. Ribosome associated complex (RAC)- HSP70 (Ssb in yeast) is a eukaryotic chaperone system involved in co-translational folding. Here, authors report structures of RAC-containing ribosomal complexes, which suggest a working model for the dynamic actions of RAC-Ssb during the process.

Regional bias of N 6 -methyladenosine (m 6 A) mRNA modification avoiding splice site region, calls for an open hypothesis whether exon-intron boundary could affect m 6 A deposition. By deep learning modeling, we find that exon-intron boundary represses a proportion (12% to 34%) of m 6 A deposition at adjacent exons (~100 nt to splice site). Experiments validate that m 6 A signal increases once the host gene does not undergo pre-mRNA splicing to produce the same mRNA. Inhibited m 6 A sites have higher m 6 A enhancers and lower m 6 A silencers locally and show high heterogeneity at different exons genome-widely, with only a small proportion (12% to 15%) of exons showing strong inhibition, enabling more stable mRNAs and flexible protein coding. m 6 A is majorly responsible for why mRNAs with more exons be more stable. Exon junction complex (EJC) only partially contributes to this exon-intron boundary m 6 A inhibition in some short internal exons, highlighting additional factors yet to be identified. m 6 A mRNA modification is not typically found near splice junctions in mRNAs. Here the authors show exon-intron boundary inhibits m6A deposition at ~100 nt region nearby splice site, enabling m 6 A distribution hallmark, more stable mRNA and flexible protein coding.

Hypericin, one of the major antidepressant constituents of St. John’s wort, was shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways. However, its exact mechanisms are unknown. Previous clinical studies reported that the mRNA modification N6-methyladenosine (m6A) interferes with the neurobiological mechanism in depressed patients, and it was also found that the antidepressant efficacy of tricyclic antidepressants (TCAs) is related to m6A modifications. Therefore, we hypothesize that the antidepressant effect of hypericin may relate to the m6A modification of epitranscriptomic regulation. We constructed a UCMS mouse depression model and found that hypericin ameliorated depressive-like behavior in UCMS mice. Molecular pharmacology experiments showed that hypericin treatment upregulated the expression of m6A-modifying enzymes METTL3 and WTAP in the hippocampi of UCMS mice. Next, we performed MeRIP-seq and RNA-seq to study m6A modifications and changes in mRNA expression on a genome-wide scale. The genome-wide m6A assay and MeRIP-qPCR results revealed that the m6A modifications of Akt3, Ntrk2, Braf, and Kidins220 mRNA were significantly altered in the hippocampi of UCMS mice after stress stimulation and were reversed by hypericin treatment. Transcriptome assays and qPCR results showed that the Camk4 and Arhgdig genes might be related to the antidepressant efficacy of hypericin. Further gene enrichment results showed that the differential genes were mainly involved in neurotrophic factor signaling pathways. In conclusion, our results show that hypericin upregulates m6A methyltransferase METTL3 and WTAP in the hippocampi of UCMS mice and stabilizes m6A modifications to exert antidepressant effects via the neurotrophin signaling pathway. This suggests that METTL3 and WTAP-mediated changes in m6A modifications may be a potential mechanism for the pathogenesis of depression and the efficacy of antidepressants, and that the neurotrophin signaling pathway plays a key role in this process.

DNA replication in eukaryotes is strictly regulated by several mechanisms. A central step in this replication is the assembly of the heterohexameric minichromosome maintenance (MCM2–7) helicase complex at replication origins during G1 phase as an inactive double hexamer. Here, using cryo-electron microscopy, we report a near-atomic structure of the MCM2–7 double hexamer purified from yeast G1 chromatin. Our structure shows that two single hexamers, arranged in a tilted and twisted fashion through interdigitated amino-terminal domain interactions, form a kinked central channel. Four constricted rings consisting of conserved interior β-hairpins from the two single hexamers create a narrow passageway that tightly fits duplex DNA. This narrow passageway, reinforced by the offset of the two single hexamers at the double hexamer interface, is flanked by two pairs of gate-forming subunits, MCM2 and MCM5. These unusual features of the twisted and tilted single hexamers suggest a concerted mechanism for the melting of origin DNA that requires structural deformation of the intervening DNA. Cryo-electron microscopy is used to visualize the double hexamer of the eukaryotic minichromosome maintenance complex (MCM), which is assembled during the G1 phase of DNA replication; two interdigitated hexamers have a central channel that tightly fits a DNA duplex, and the orientation of the tilted single hexamers sheds light on many functional aspects, particularly in the initial origin DNA melting. Replication-ready MCM complex In eukaryotes, DNA replication begins with the binding of a hexameric ring of minichromosome maintenance (MCM) proteins at regions known as replication origins during the G1 phase of the cell cycle. The resulting complex is dormant until the cell enters S phase, when replication occurs. This entails conversion of an MCM double hexamer into an active species, but the structure of this complex was unknown. Ning Gao and colleagues have used cryo-electron microscopy to visualize the double hexamer complex. They observe two interdigitated hexamers that have a central channel that tightly fits a DNA duplex. The orientation of the single rings suggests models in which relative movements between the two hexamers would deform the origin DNA so that other replication proteins can bind to the melted DNA double helix.

This study addresses critical bottlenecks in photocatalytic water treatment technologies, including difficulties in recovering traditional powdered catalysts, low mass transfer efficiency in immobilized reactors, and limited structural diversity. By integrating topology optimization with 3D printing technology, we designed and fabricated five types of triply periodic minimal surface photocatalytic reactors (TPMS-PCRs) with hierarchical porous structures—Fischer-Radin-Dunn (FRD), Neovius (N), Diamond (D), I-graph Wrapped Package (IWP) and Gyroid (G). Using fused deposition modeling (FDM), these TPMS configurations were manufactured from polylactic acid (PLA), 1.5 wt% TiO2/PLA, and 2.5 wt% TiO2/PLA. The catalytic degradation performance of these structurally distinct reactors for organic pollutants varied significantly. Notably, the FRD-type TPMS-PCR loaded with 2.5 wt% TiO2 achieved a methylene blue (MB) degradation rate of 93.4% within 2.5 h under rotational flow conditions, compared to 87.5% under horizontal flow conditions.

Now the occurrence of delirium is more concerning to clinicians and psychiatrists. It has been reported that vitamin D deficiency may be a relevant factor in the development of delirium in hospitalized patients. To investigate the association between vitamin D concentration and delirium in hospitalized patients. Meta-analysis. A systematic literature search was conducted using PubMed, EMBASE, and the Cochrane Library. The primary outcome was the occurrence of delirium in the inpatient setting. Odds ratios (OR) were calculated with random or fixed effects models. In this article, we define the normal range of vitamin D concentrations as greater than 75 nmol / L, 50-75 nmol / L as vitamin D insufficiency, 25-50 nmol / L as vitamin D deficiency, and less than 25 nmol / L as vitamin D severe deficiency. The Results showed that severe vitamin D deficiency (OR: 1.98 [1.41-2.79], P<0.001) and vitamin D deficiency (OR: 1.50 [1.12-2.00], P = 0.006) were more likely to develop delirium than normal vitamin D levels. Subgroup analysis also revealed that low vitamin D concentrations were associated with a higher incidence of delirium, whether the cutoff point was 25 nmol/L (OR: 1.52 [1.40-1.64], P<0.001), 50 nmol/L (OR: 1.47 [1.19-1.82], P<0.001), or 75 nmol/L (OR: 1.54 [1.21-1.96], P<0.001). The included studies scored medium and high on the Newcastle-Ottawa quality assessment scale. Compared with normal vitamin D levels, severe vitamin D deficiency and vitamin D deficiency, but not vitamin D insufficiency, are associated with a higher incidence of delirium in hospitalized patients. This review was registered in the PROSPERO database under identifier CRD42021271347. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021271347.

Sugar beet is one of the important sugar crops in China, and drought has become the main constraint on the high-quality development of the sugar beet industry due to the regional factors such as lower precipitation, uneven seasonal distribution and limited water resources and so on. Heat shock protein 70 (HSP70) plays an important role in plant growth, development and abiotic stress response. However, there is still very limited information about the identification of HSP70s and drought resistance in sugar beet. In this study, bioinformatics was used to explore the HSP70s in sugar beet, and their gene structure, phylogenetic relationship, chromosome mapping, cis element distribution and expression under drought stress were analyzed. The results showed that a total of 28 BvHSP70 genes were identified, with sequence length ranges from 1551 bp to 3240 bp, which were distributed on 9 chromosomes of sugar beet. The number of amino acids encoding proteins are 516 ~ 1079, and the theoretical isoelectric point is between 4.98 and 9.33, most of which are acidic hydrophobic proteins, which are mainly located in the endoplasmic reticulum and cytoplasm. Collinearity analysis showed higher homology with rice and maize, and analysis of gene structure and protein conserved motif showed that it had different degrees of differentiation during the evolution of sugar beet. Analysis of cis-elements in the promoters revealed their association with growth and development, hormone response, and abiotic stress. RNA-seq and proteomics analysis showed that 20 genes of BvHSP70s responded to drought stress, and qRT-PCR validation confirmed that 10 of these genes were upregulated, and they were specifically expressed in roots, petioles and leaves of sugar beet, and more genes were expressed in roots. The results of this study lay a foundation for the subsequent in-depth analysis of the gene function of the BvHSP70 family in sugar beet, and also provided a theoretical basis for further exploring the response mechanism of beet under drought stress.

Salens are a class of important ligands and have been widely applied in asymmetric catalytic organic reactions. Enlarged salen-like ligands containing flexible chains were synthesized from L-phenylalanine, ethane/propanediamines, and salicylaldehydes, and successfully utilized in the scandium-catalyzed enantioselective Michael addition of indoles and enones (2-cinnamoylpyridine 1-oxides). The catalytic system demonstrates excellent reactivity and stereoselective control over electron-rich indole substrates with up to 99% yield and 99% enantiomeric excess. The enlarged Salen ligands with flexible and rigid combined linkers fit their coordination with large rare earth elements. Their coordination abilities were tuned by the electronic effect of substituents on their salicylaldehyde moiety, facilitating the construction of excellent chiral environments in the scandium(III)-catalyzed asymmetric Michael addition of indoles to 2-cinnamoylpyridine 1-oxides.

Background Selective serotonin reuptaker inhibitors, including fluoxetine, are widely studied and prescribed antidepressants, while their exact molecular and cellular mechanism are yet to be defined. We investigated the involvement of HDAC1 and eEF2 in the antidepressant mechanisms of fluoxetine using a lipopolysaccharide (LPS)-induced depression-like behavior model. Methods For in vivo analysis, mice were treated with LPS (2 mg/kg BW), fluoxetine (20 mg/kg BW), HDAC1 activator (Exifone: 54 mg/kg BW) and NH125 (1 mg/kg BW). Depressive-like behaviors were confirmed via behavior tests including OFT, FST, SPT, and TST. Cytokines were measured by ELISA while Iba-1 and GFAP expression were determined by immunofluorescence. Further, the desired gene expression was measured by immunoblotting. For in vitro analysis, BV2 cell lines were cultured; treated with LPS, exifone, and fluoxetine; collected; and analyzed. Results Mice treated with LPS displayed depression-like behaviors, pronounced neuroinflammation, increased HDAC1 expression, and reduced eEF2 activity, as accompanied by altered synaptogenic factors including BDNF, SNAP25, and PSD95. Fluoxetine treatment exhibited antidepressant effects and ameliorated the molecular changes induced by LPS. Exifone, a selective HDAC1 activator, reversed the antidepressant and anti-inflammatory effects of fluoxetine both in vivo and in vitro, supporting a causing role of HDAC1 in neuroinflammation allied depression. Further molecular mechanisms underlying HDAC1 were explored with NH125, an eEF2K inhibitor, whose treatment reduced immobility time, altered pro-inflammatory cytokines, and NLRP3 expression. Moreover, NH125 treatment enhanced eEF2 and GSK3β activities, BDNF, SNAP25, and PSD95 expression, but had no effects on HDAC1. Conclusions Our results showed that the antidepressant effects of fluoxetine may involve HDAC1-eEF2 related neuroinflammation and synaptogenesis.