Explore the vast range of titles available.

The prevalent DNA modification in higher organisms is the methylation of cytosine to 5-methylcytosine (5mC), which is partially converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) family of dioxygenases. Despite their importance in epigenetic regulation, it is unclear how these cytosine modifications are reversed. Here, we demonstrate that 5mC and 5hmC in DNA are oxidized to 5-carboxylcytosine (5caC) by Tet dioxygenases in vitro and in cultured cells. 5caC is specifically recognized and excised by thymine-DNA glycosylase (TDG). Depletion of TDG in mouse embyronic stem cells leads to accumulation of 5caC to a readily detectable level. These data suggest that oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of 5caC constitutes a pathway for active DNA demethylation.

Multidrug transport by ATP binding cassette (ABC) exporters entails a mechanism to modulate drug affinity across the transport cycle. Here, we combine cryo-EM and molecular dynamics (MD) simulations to illuminate a lipid-competition mechanism to drive substrate translocation by ABC exporters. We determine cryo-EM structures of the ABC transporter BmrCD in drug-loaded inward-facing (IF) and outward-facing (OF) conformations in lipid nanodiscs to reveal the structural basis of alternating access, details of drug-transporter interactions, and the scale of drug movement between the two conformations. Remarkably, the structures uncover lipid molecules bound in or near the transporter vestibule along with the drugs. MD trajectories from the IF structure show that these lipids stimulate drug disorder and translocation towards the innermost constricted region of the vestibule. Similarly, bound lipids enter the OF vestibule and weaken drug-transporter interactions facilitating drug release. Our results complete a near-atomic model of BmrCD’s conformational cycle and suggest the modulation of substrate-transporter interactions by lipids. Drug transport by ABC exporters has been associated with multidrug resistance in cancer and bacterial infections. Here, we describe structures of an ABC heterodimer that illuminate drug transporter interactions and the role of lipids in facilitating drug expulsion across membranes.

Gallbladder cancer (GBC) is a highly aggressive malignancy with a propensity for lymph node metastasis (LNM), which significantly worsens prognosis. This review explores the molecular mechanisms underlying LNM in GBC, focusing on the roles of vascular endothelial growth factors (VEGFs), chemokines, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), hypoxia-inducible factors (HIFs), and non-coding RNAs (ncRNAs) in shaping the tumor microenvironment (TME). Unique features of GBC, such as its bile-rich microenvironment and hypoxia-driven lymphangiogenesis, are highlighted. We discuss how these factors promote lymphangiogenesis, immune evasion, and extracellular matrix (ECM) remodeling, collectively facilitating LNM. Potential therapeutic targets, including VEGF-C/D pathways, matrix metalloproteinase (MMP) inhibitors, and immune-modulating therapies, are also reviewed. Future research integrating single-cell omics and patient-derived organoid models is essential for advancing precision medicine in GBC.

Here we used cryo-electron microscopy (cryo-EM), double electron-electron resonance spectroscopy (DEER), and molecular dynamics (MD) simulations, to capture and characterize ATP- and substrate-bound inward-facing (IF) and occluded (OC) conformational states of the heterodimeric ATP binding cassette (ABC) multidrug exporter BmrCD in lipid nanodiscs. Supported by DEER analysis, the structures reveal that ATP-powered isomerization entails changes in the relative symmetry of the BmrC and BmrD subunits that propagates from the transmembrane domain to the nucleotide binding domain. The structures uncover asymmetric substrate and Mg 2+ binding which we hypothesize are required for triggering ATP hydrolysis preferentially in one of the nucleotide-binding sites. MD simulations demonstrate that multiple lipid molecules differentially bind the IF versus the OC conformation thus establishing that lipid interactions modulate BmrCD energy landscape. Our findings are framed in a model that highlights the role of asymmetric conformations in the ATP-coupled transport with general implications to the mechanism of ABC transporters. Multidrug resistance through active extrusion of molecules by transporters is a pressing clinical problem. Here, authors dissect the mechanism by which an ABC transporter from B. Subtilis binds and removes drugs by consuming the energy of ATP hydrolysis.

Substrate efflux by ATP-binding cassette (ABC) transporters, which play a major role in multidrug resistance, entails the ATP-powered interconversion between transporter intermediates. Despite recent progress in structure elucidation, a number of intermediates have yet to be visualized and mechanistically interpreted. Here, we combine cryogenic-electron microscopy (cryo-EM), double electron–electron resonance spectroscopy and molecular dynamics simulations to profile a previously unobserved intermediate of BmrCD, a heterodimeric multidrug ABC exporter from Bacillus subtilis. In our cryo-EM structure, ATP-bound BmrCD adopts an inward-facing architecture featuring two molecules of the substrate Hoechst-33342 in a striking asymmetric head-to-tail arrangement. Deletion of the extracellular domain capping the substrate-binding chamber or mutation of Hoechst-coordinating residues abrogates cooperative stimulation of ATP hydrolysis. Together, our findings support a mechanistic role for symmetry mismatch between the nucleotide binding and the transmembrane domains in the conformational cycle of ABC transporters and is of notable importance for rational design of molecules for targeted ABC transporter inhibition.Cryo-EM analysis with DEER spectroscopy and molecular dynamics simulations of the ABC exporter BmrCD reveal dual-mode substrate binding in an ATP- and substrate-bound state.

Alkali-activated materials (AAMs) are considered to be alternative cementitious materials for civil infrastructures. Nowadays, efforts have been made in developing AAMs with self-compacting ability. The obtained self-compacting AAMs (SCAAMs) accomplish superior passing and filling properties as well as excellent mechanical and environmental advantages. This work critically revisits recent progresses in SCAAMs including mixture proportions, fresh properties, mechanical strength, microstructure, acid and sulfate resistance, high temperature behaviors, impact resistance and interface shear strength. To facilitate direct comparison and interpretation of data from different publications, mixture proportions were normalized in terms of the content of key reactive components from precursors and activators, and correlation with mechanical behaviors was made. Moreover, special attention was paid to current research challenges and perspectives to promote further investigation and field application of SCAAMs as advanced construction material.

Deep vaginal wall hematoma is a common vaginal delivery complication. Exploring effective treatments is key to improving clinical management and patient outcomes. A patient with deep vaginal wall hematoma (admitted in November 2024) underwent hematoma removal, followed by \"T\"-shaped drainage tube combined with vaginal packing gauze. The treatment achieved remarkable hemostasis; the patient recovered rapidly with well-healed perineal wounds, shorter hospital stays, and low pain scores. Early detection and timely treatment of vaginal wall hematoma, combined with \"T\"-shaped drainage tube drainage, avoid open abdominal hemostasis and related damage. This method is safe, effective, and worthy of clinical application.

Dear Editor, Males-absent-on-the-first （MOF, also called MYST1 or KAT8） is a histone acetyltransferase （HAT） belonging to the MOZ, Ybf2/Sas3, Sas2 and Tip60 （MYST） family. MOF has been shown to possess a specific HAT activity towards Lysl6 of histone H4 （H4K16） [1]. Homozygous knockout of MOF in mice results in loss of H4K16 acetylation and embryonic lethality,

During reproduction in flowering plants, the male gametophyte delivers an immotile male gamete to the female gametophyte in the pistil by formation of pollen tubes. In Arabidopsis thaliana , two synergid cells situated on either side of the egg cell produce cysteine-rich chemoattractant peptide LURE that guides the pollen tube to the female gametophyte for sexual reproduction. Recently, in Arabidopsis thaliana , Pollen Receptor Kinase 3 (PRK3), along with PRK1, PRK6, and PRK8, have been predicted to be the receptors responsible for sensing LURE. These receptors belong to the Leucine Rich Repeat Receptor Like Kinases (LRR-RLKs), the largest family of receptor kinases found in Arabidopsis thaliana . How PRKs regulate the growth and development of the pollen tube remains elusive. In order to better understand the PRK-mediated signaling mechanism in pollen tube growth and guidance, we have determined the crystal structure of the extracellular domain (ecd) of PRK3 at 2.5 Å, which resembles the SERK family of plant co-receptors. The structure of ecdPRK3 is composed of a conserved surface that coincides with the conserved receptor-binding surface of the SERK family of co-receptors. Our structural analyses of PRK3 have provided a template for future functional studies of the PRK family of LRR-RLK receptors in the regulation of pollen tube development.

Dewatering is critical to oily cold rolling mill (CRM) sludge treatment. Therefore, finding an efficient, energy-saving, and applicable dewatering technology for oily CRM sludge is still urgent. This study investigated the performance of quicklime as a conditioning agent for oily CRM sludge conditioning and dewatering. The interactive effects of quicklime dosage, temperature, and time on filter cake’s specific resistance to filtration (SRF) and the dewatering rate of oily CRM sludge were studied by response surface methodology (RSM). The optimal parameters for conditioning oily CRM sludge were quicklime dosage of 18.7%, temperature of 54 °C, and time of 43.3 min, which resulted in filter cake SRF of 0.50 × 10 10 m/kg and dewatering rate of 61.2%. The viscosity of oily CRM sludge could be reduced by 90% after conditioned with quicklime, which caused by the neutralization or hydrolysis of high viscosity organic matter in the oil phase with quicklime to produce low viscosity organic matter. The study indicated the excellent performance of quicklime as a conditioning agent for oily CRM sludge treatment and provided an effective route for the recycling of the oily CRM sludge for steel production.