Explore the vast range of titles available.

1,2-Bis-silyl alkenes have exciting synthetic potential for programmable sequential synthesis via manipulation of the two vicinal silyl groups. Transition metal-catalyzed bis-silylation of alkynes with disilanes is the most straightforward strategy to access such useful building blocks. However, this process has some limitations: (1) symmetric disilanes are frequently employed in most of the reactions to assemble two identical silyl groups, which makes chemoselective differentiation for stepwise downstream transformations difficult; (2) the main catalysts are low-valent platinum group transition metal complexes, which are expensive; and (3) internal alkynes remain challenging substrates with low inherent reactivity. Thus, the development of abundant metal-catalyzed bis-silylation of internal alkynes with unsymmetrical disilanes is of significance. Herein, we solve most of the aforementioned limitations in bis-silylation of unsaturated bonds by developing a strongly coordinating disilane reagent and a Ni(0) catalytic system. Importantly, we sufficiently realize the stepwise recognition of the two silyl groups, making this synthetic protocol of wide potential utility. Bis-silylated alkenes offer the advantage of two functional handles with distinguished reactivity for downstream functionalization. Here, the authors report a nickel-catalyzed bis-silylation of internal alkynes to versatile silylated alkene intermediates which can be chemoselectively manipulated.

In organic electronics, an aromatic fused ring is a basic unit that provides π-electrons to construct semiconductors and governs the device performance. The main challenge in developing new π-skeletons for tuning the material properties is the limitation of the available chemical approach. Herein, we successfully synthesize two pentacyclic siloxy-bridged π-conjugated isomers to investigate the synergistic effects of Si and O atoms on the geometric and electronic influence of π-units in organic electronics. Notably, the synthesis routes for both isomers possess several advantages over the previous approaches for delivering conventional aromatic fused-rings, such as environmentally benign tin-free synthesis and few synthetic steps. To explore their potential application as photovoltaic materials, two isomeric acceptor–donor–acceptor type acceptors based on these two isomers were developed, showing a decent device efficiency of 10%, which indicates the great potential of this SiO-bridged ladder-type unit for the development of new high-performance semiconductor materials. Developing a new π-skeletal aromatic fused-ring for tuning material properties in organic electronics is still a challenge due to limited chemical approach. Here, the authors enrich the chemistry by synthesizing SiO-bridged ladder-type π-skeletons with enhanced planarity and deeper energy levels than CO-bridged counterpart.

Transition metal-catalyzed reactions of silacyclobutanes with a variety of π units have attracted much attention and become one of the most straightforward and efficient approaches to rapidly access structurally diverse organosilicon compounds. However, the reaction of silacyclobutanes with alkynes still suffers from some limitations: (1) internal alkynes remain challenging substrates; (2) expensive Pd- or Rh-based catalysts have been employed in all existing systems; (3) controlling chemodivergence has not yet been realized. Herein we realize Ni-catalyzed chemodivergent reactions of silacyclobutanes with alkynes. In comparison with the previous Pd or Rh catalytic systems, our Ni-catalytic system features: 1) complementary substrate scope; 2) ligand-controlled chemodivergence; 3) low cost. The ligand precisely dictates the pathway selectivity, leading to the divergent formation of (benzo)silacyclohexenes and allyl vinylsilanes. Moreover, we demonstrate that employment of a chiral phosphine ligand is capable of forming silicon-stereogenic allyl vinylsilanes in high yields and enantioselectivities. In addition, DFT calculation is performed to elucidate the origin of the switchable selectivities, which is mainly attributed to different ligand steric effects. Transition metal-catalyzed reactions of silacyclobutanes to access structurally diverse organosilicon compounds have attracted attention in recent years. Here, the authors show nickel-catalysed, ligand-controlled chemodivergent reactions of these compounds with alkynes to (benzo)silacyclohexenes and allyl vinylsilane.

The development of innovative strategies for the synthesis of N-heterocyclic compounds is an important topic in organic synthesis. Ring expansion methods to form large N-heterocycles often involve the cycloaddition of strained aza rings with π bonds. However, in some cases such strategies suffer from some limitations owing to the difficulties in controlling the regioselectivity and the accessibility of specific π-bond synthons. Here, we report the development of a general ring expansion strategy that involves a formal cross-dimerization between three-membered aza heterocycles and three- and four-membered-ring ketones through synergistic bimetallic catalysis. These formal cross-dimerizations of two different strained rings are efficient and scalable, and provide a straightforward and broadly applicable means of assembling diverse N-heterocycles, such as 3-benzazepinones, dihydropyridinones and uracils, which are versatile units in numerous drugs and biologically active compounds. Preliminary mechanistic studies revealed that the C–C bond of strained ring ketones is first cleaved by the Pd0 species during the reaction.Using synergistic bimetallic catalysis, a general ring expansion strategy has been developed for cross-dimerization between three-membered aza heterocycles and three- and four-membered-ring ketones. This method provides a straightforward and broadly applicable route for the assembly of 3-benzazepinones, dihydropyridinones and uracils, which are versatile units in numerous drugs and biologically active compounds.

Functional characterization of pseudouridine (Ψ) in mammalian mRNA has been hampered by the lack of a quantitative method that maps Ψ in the whole transcriptome. We report bisulfite-induced deletion sequencing (BID-seq), which uses a bisulfite-mediated reaction to convert pseudouridine stoichiometrically into deletion upon reverse transcription without cytosine deamination. BID-seq enables detection of abundant Ψ sites with stoichiometry information in several human cell lines and 12 different mouse tissues using 10–20 ng input RNA. We uncover consensus sequences for Ψ in mammalian mRNA and assign different ‘writer’ proteins to individual Ψ deposition. Our results reveal a transcript stabilization role of Ψ sites installed by TRUB1 in human cancer cells. We also detect the presence of Ψ within stop codons of mammalian mRNA and confirm the role of Ψ in promoting stop codon readthrough in vivo. BID-seq will enable future investigations of the roles of Ψ in diverse biological processes. Pseudouridine sites in mRNA are detected at base resolution and functionally investigated.

Poor clinical responses to immune checkpoint blockade (ICB) observed in ovarian cancer (OC) highlight an unmet need to understand the mechanisms driving immune evasion in this disease. To address this, an integrative analysis is conducted by combining in vitro genome‐wide immune screens, in vivo ICB screens, and clinical data mining, and METTL5 is identified as a crucial OC‐intrinsic factor that promotes immune resistance. Immunologically “cold” OC tumors and poor responders to ICB exhibit elevated METTL5 expression. Mechanistically, knocking out (KO) METTL5 in OC disrupts ATF4 translation by altering 18S rRNA m6A levels, leading to the downregulation of SLC7A11 and SLC3A2, whose function is to suppress ferroptosis activity. Consequently, METTL5 KO enhances tumor sensitivity to T cell‐mediated antitumor immunity. Notably, the immune‐sensitive phenotypes seen in METTL5‐KO tumors can be reversed by either ATF4 overexpression or ferroptosis inhibition. These findings underscore the central role of the METTL5/ATF4/ferroptosis axis in controlling OC responses to immunotherapy. An integrative analysis combining in vitro genome‐wide immune screens, in vivo ICB screens, and clinical data mining identifies METTL5 as a key tumor‐intrinsic immune factor. Mechanistic studies further reveal the importance of the METTL5‐ATF4‐SLC7A11/SLC3A2‐ferroptosis axis in modulating antitumor immune responses. These findings highlight METTL5 as a prognostic biomarker and therapeutic target in ovarian cancer.

Pseudouridine (Ψ) is a widespread RNA modification in various RNA species, including rRNA, tRNA, snRNA and mRNA. Ψ plays a crucial role in RNA metabolism, where it regulates pre-mRNA splicing and affects protein translation. Whether and how Ψ may regulate transcription have not been adequately studied. Here, we report that pseudouridine synthase 7 (PUS7) can mediate pseudouridylation of 7SK small nuclear RNA (snRNA), a regulator of RNA polymerase II (Pol II) promoter-proximal pausing. PUS7 loss leads to hypo-pseudouridylation of 7SK, which promotes dissociation of the positive transcription elongation factor b (P-TEFb) complex from 7SK. The release of P-TEFb from 7SK increases serine 2 phosphorylation (Ser2P) in the RNA Pol II C-terminal domain and enhances transcription elongation. In colorectal cancer (CRC) cells, the Ψ level of 7SK can be modulated by PUS7, or by site-specifically targeted pseudouridylation through dCas13b-guided system. Hypo-pseudouridylation on 7SK upon PUS7 depletion promotes KLF6/DDIT3-mediated cell apoptosis and sensitizes CRC cells to 5-FU. Pseudouridine is prevalent modification in cellular RNA. Here, the authors show that the PUS7-mediated pseudouridylation of 7SK RNA regulates Pol II elongation and affects colorectal cancer cell survival and response to 5-FU treatment.

Dihydrouridine (D) is an abundant RNA modification, yet its roles in mammals remain poorly understood due to limited detection methods. We even do not have a comprehensive profile of D site location and modification stoichiometry in tRNA. Here, we introduce C hemical R eduction A ssisted C ytosine I ncorporation sequencing (CRACI), a highly sensitive, quantitative approach for mapping D at single-base resolution. Using CRACI, we generate the transcriptome-wide maps of D in both cytoplasmic and mitochondrial tRNAs from mammals and plants. We uncover D sites in mitochondrial tRNAs and identify DUS2L as the ‘writer’ protein responsible for human mitochondrial tRNAs. Furthermore, we demonstrate that most D modifications have a limited impact on tRNA stability, except for D20a, which also exhibits cis-regulation of adjacent D20 sites. Application of CRACI to human mRNA reveals that D modifications are present but rare and occur at very low stoichiometry. CRACI thus provides a powerful platform for investigating D biology across species. Dihydrouridine (D) is an abundant RNA modification but its functions are currently unclear. Here, authors develop CRACI, a sensitive method for transcriptome-wide, single-base D mapping, identifying sites across mammalian and plant transcriptomes and identifying DUS2L as a mitochondrial D writer.

Suxiao Jiuxin pill (SJP) is a traditional Chinese medicine for the treatment of acute coronary syndrome in China, which contains two principal components, tetramethylpyrazine (TMP) and borneol (BOR). Thus far, however, the molecular mechanisms underlying the beneficial effects of SJP on the cardiac microenvironment are unknown. Cardiac mesenchymal stem cells (C-MSCs) communicate with cardiomyocytes (CMs) through the release of microvesicles (exosomes) to restore cardiac homeostasis and elicit repair, in part through epigenetic regulatory mechanisms. In this study, we examined whether SJP treatment altered C-MSC-derived exosomes (SJP-Exos) to cause epigenetic chromatic remodeling in recipient CMs. C-MSC isolated from mouse hearts were pretreated with SJP (SJP-Exos), TMP (TMP-Exos) or BOR (BOR-Exos). Then, HL-1 cells, a mouse cardiomyocyte line, were treated with exosomes from control C-MSCs (Ctrl-Exos), SJP-Exos, TMP-Exos or BOR-Exos. Treatment with SJP-Exos significantly increased the protein levels of histone 3 lysine 27 trimethylation (H3K27me3), a key epigenetic chromatin marker for cardiac transcriptional suppression, in the HL-1 cells. To further explore the mechanisms of SJP-Exo-mediated H3K27me3 upregulation, we assessed the mRNA expression levels of key histone methylases (EZH1, EZH2 and EED) and demethylases (JMJD3 and UTX) in the exosome-treated HL-1 cells. Treatment with SJP-Exo selectively suppressed UTX expression in the recipient HL-1 cells. Furthermore, PCNA, an endogenous marker of cell replication, was significantly higher in SJP-Exo-treated HL-1 cells than in Ctrl-Exo-treated HL-1 cells. These results show that SJP-Exos increase cardiomyocyte proliferation and demonstrate that SJP can modulate C-MSC-derived exosomes to cause epigenetic chromatin remodeling in recipient cardiomyocytes; consequently, SJP-Exos might be used to promote cardiomyocyte proliferation.

There are some controversies on the utilization and benefits of thrombus aspiration in patients with ST-segment elevation myocardial infarction (STEMI). However, a few studies investigated this issue and the age-associated effects among the large population in China. Hence, we aimed to figure out the age-associated utilization and in-hospital outcomes of thrombus aspiration to improve therapeutic decisions in clinical routine. We retrospectively recruited 13,655 eligible STEMI patients from the database of the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. These subjects were allocated into primary percutaneous coronary intervention (PPCI)-only group and thrombus aspiration group after being subdivided into three age groups (G , G , and G ). After 1:1 propensity score matching for PPCI-only and thrombus aspiration groups, a total of 8,815 matched patients were enrolled for the subsequent analysis. The primary outcome was in-hospital cardiovascular death, and the key safety outcome was in-hospital stroke. We observed that the ratio of STEMI patients undergoing thrombus aspiration to PPCI-only reduced with aging. For patients ≤ 75 years, the culprit lesion suffered from thrombus aspiration was mainly located in the left anterior descending branch, and left-ventricular ejection fraction (LVEF) was lower (G : 54.9 ± 8.9 vs. 56.0 ± 8.7%, = 0.01; G : 53.9 ± 9.6 vs. 54.8 ± 9.0%, = 0.001) and the rate of regional wall motion abnormality was higher (G : 75.7 vs. 66.5%, < 0.001; G : 75.4 vs. 69.1%, < 0.001) in the thrombus aspiration group. By contrast, for patients > 75 years, the right coronary artery was the predominant culprit lesion undergoing thrombus aspiration, LVEF (63.1 ± 10.5 vs. 53.1 ± 9.5%, = 0.985) and the regional wall motion abnormality (79.2 vs. 74.2%, = 0.089) were comparable between the two treatment groups. Thrombus aspiration neither reduced the in-hospital risk of cardiovascular death, all-cause death, recurrent myocardial infarction, acute stent thrombosis, heart failure, cardiogenic shock, and sudden cardiac arrest nor increased stroke risk compared with the PPCI-only group. However, after adjustment for age, thrombus aspiration presented the tendency to reduce the incidence of sudden cardiac arrest (4.9 vs. 2.5%, = 0.06) and in-hospital cardiovascular death at 3 days (hazard ratio 0.46; 95% CI, 0.20-1.06; log-rank = 0.08) in G group and tended to increase the incidence of heart failure in G (5.7 vs. 6.9%, = 0.07). The thrombus aspiration neither significantly reduced the in-hospital incidence of major adverse cardiac events nor increased stroke risk. However, it might play a protective role in reducing in-hospital sudden cardiac arrest and increasing survival from cardiovascular death at 3 days for the elderly.