Shortening the Saturation Time of PBAT Sheet Foaming via the Pre-Introducing of Microporous Structures.

Poly (butylene adipate-co-terephthalate) (PBAT) foam sheets prepared by foaming supercritical fluids are characterized by high resilience, homogeneous cellular structure, and well-defined biodegradability. However, the inert chemical structure and the rigid hard segments restrict the diffusion of CO within the PBAT matrix, resulting in extremely long gas saturation times as long as 9 h at a thickness of 12 mm. In this study, microporous structures were pre-introduced into the PBAT matrix to provide a fast gas diffusion pathway during the saturation process.

Modular Photoswitchable Molecular Glues for Chemo-Optogenetic Control of Protein Function in Living Cells.

Optogenetic systems using photosensitive proteins and chemically induced dimerization/proximity (CID/CIP) approaches enabled by chemical dimerizers (also termed molecular glues), are powerful tools to elucidate the dynamics of biological systems and to dissect complex biological regulatory networks. Here, we report a versatile chemo-optogenetic system using modular, photoswitchable molecular glues (sMGs) that can undergo repeated cycles of optical control to switch protein function on and off. We use molecular dynamics (MD) simulations to rationally design the sMGs and further expand their scope by incorporating different photoswitches, resulting in sMGs with customizable properties.

Substrate and inhibitor specificity of Plasmodium nucleoside transporters ENT1 orthologs.

Malaria caused by Plasmodium infection poses a serious hazard to human health. Plasmodium falciparum equilibrative nucleoside transporter 1 (PfENT1), which mediates nucleoside uptake, is essential for the growth and proliferation of Plasmodium parasites, suggesting that PfENT1 is a potential antimalarial target. The promising compound GSK4 effectively inhibits the transport activity of PfENT1, thereby restraining the growth of Plasmodium parasites.

Structural insights into the inhibition mechanism of fungal GWT1 by manogepix.

Glycosylphosphatidylinositol (GPI) acyltransferase is crucial for the synthesis of GPI-anchored proteins. Targeting the fungal glycosylphosphatidylinositol acyltransferase GWT1 by manogepix is a promising antifungal strategy. However, the inhibitory mechanism of manogepix remains unclear.

Structure-Based Design of CBP/EP300 Degraders: When Cooperativity Overcomes Affinity.

We present the development of , a structurally novel PROTAC targeting the CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. The design of was based on the crystal structure of an in-house bromodomain (BRD) inhibitor featuring a 3-methyl-cinnoline acetyl-lysine mimic acetyl-lysine mimic discovered by high-throughput fragment docking. Our study shows that, despite its modest binding affinity to CBP/EP300-BRD, 's remarkable protein degradation activity stems from its good cooperativity, which we demonstrate by the characterization of its ternary complex formation both and .

Comparative Study of the Foaming Behavior of Ethylene-Vinyl Acetate Copolymer Foams Fabricated Using Chemical and Physical Foaming Processes.

Ethylene-vinyl acetate copolymer (EVA), a crucial elastomeric resin, finds extensive application in the footwear industry. Conventional chemical foaming agents, including azodicarbonamide and 4,4'-oxybis(benzenesulfonyl hydrazide), have been identified as environmentally problematic. Hence, this study explores the potential of physical foaming of EVA using supercritical nitrogen as a sustainable alternative, garnering considerable interest in both academia and industry.

Structure-Based Design of a Potent and Selective YTHDC1 Ligand.

N-Adenosine methylation (mA) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the cell nucleus. Here, we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor , which shows an equilibrium dissociation constant () of 49 nM. The crystal structure of the complex (1.

The catalytic mechanism of the RNA methyltransferase METTL3.

The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N-methyladenosine (mA) modifications on messenger RNA (mRNA) in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor -adenosylmethionine (SAM).

The catalytic mechanism of the RNA methyltransferase METTL3.

The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N6-methyladenosine (m6A) modifications on mRNA in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor S-adenosylmethionine (SAM).

Structure-Based Design of Inhibitors of the mA-RNA Writer Enzyme METTL3.

Methyltransferase-like 3 (METTL3) and METTL14 form a heterodimeric complex that catalyzes the most abundant internal mRNA modification, -methyladenosine (mA). METTL3 is the catalytic subunit that binds the co-substrate -adenosyl methionine (SAM), while METTL14 is involved in mRNA binding. The mA modification provides post-transcriptional level control over gene expression as it affects almost all stages of the mRNA life cycle, including splicing, nuclear export, translation, and decay.

Fabrication of Poly(ε-caprolactone)-embedded Lignin-Chitosan Nanocomposite Porous Scaffolds from Pickering Emulsions.

Poly(ε-caprolactone) (PCL)-incorporated lignin-chitosan biomass-based nanocomposite porous scaffolds have been effectively prepared by templating oil-in-water Pickering high internal phase emulsions (HIPEs). PCL is dissolved in oil and chitosan and lignin nanoparticles originate in water. The continuous phase of the emulsions is gelled by cross-linking of chitosan with genipin and then freeze-dried to obtain porous scaffolds.

Bioinspired Self-Standing, Self-Floating 3D Solar Evaporators Breaking the Trade-Off between Salt Cycle and Heat Localization for Continuous Seawater Desalination.

Facing the global water shortage challenge, solar-driven desalination is considered a sustainable technology to obtain freshwater from seawater. However, the trade-off between the salt cycle and heat localization of existing solar evaporators (SE) hinders its further practical applications. Here, inspired by water hyacinth, a self-standing and self-floating 3D SE with adiabatic foam particles and aligned water channels is built through a continuous directional freeze-casting technique.

Supercritical Fluid Microcellular Foaming of High-Hardness TPU via a Pressure-Quenching Process: Restricted Foam Expansion Controlled by Matrix Modulus and Thermal Degradation.

High-hardness thermoplastic polyurethane (HD-TPU) presents a high matrix modulus, low-temperature durability, and remarkable abrasion resistance, and has been used in many advanced applications. However, the fabrication of microcellular HD-TPU foam is rarely reported in the literature. In this study, the foaming behavior of HD-TPU with a hardness of 75D was investigated via a pressure-quenching foaming process using CO as a blowing agent.

Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay.

Targeting the interaction between the spike protein receptor binding domain (S-RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and angiotensin-converting enzyme 2 (ACE2) is a potential therapeutic strategy for treating coronavirus disease 2019 (COVID-19). However, we still lack small-molecule drug candidates for this target due to the missing knowledge in the hot spots for the protein-protein interaction. Here, we used NanoBiT technology to identify three Ginkgolic acids from an in-house traditional Chinese medicine (TCM) library, and they interfere with the S-RBD/ACE2 interplay.

Fragment Ligands of the mA-RNA Reader YTHDF2.

We report 17 small-molecule ligands that compete with -methyladenosine (mA) for binding to the mA-reader domain of YTHDF2 (YT521-B homology domain family 2). We determined their binding mode at high resolution by X-ray crystallography and quantified their affinity by a fluorescence-based binding assay. 6-Cyclopropyluracil and a pyrazolopyrimidine derivative have favorable ligand efficiencies of 0.

Formation of cinnamon essential oil/xanthan gum/chitosan composite microcapsules basing on Pickering emulsions.

Cinnamon essential oil (CNO) is a natural and renewable antibacterial agent. However, CNO is highly volatile and unstable, which limits its practical application as a long-term and wide antibacterial agent. In order to improve the CNO stability, we have microencapsulated CNO into composite microcapsules basing on Pickering emulsion stabilized by silica (SiO) nanoparticles.

METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes.

The methylase METTL3 is the writer enzyme of the N -methyladenosine (m A) modification of RNA. Using a structure-based drug discovery approach, we identified a METTL3 inhibitor with potency in a biochemical assay of 280 nM, while its enantiomer is 100 times less active. We observed a dose-dependent reduction in the m A methylation level of mRNA in several cell lines treated with the inhibitor already after 16 h of treatment, which lasted for at least 6 days.

Atomistic and Thermodynamic Analysis of N6-Methyladenosine (mA) Recognition by the Reader Domain of YTHDC1.

N6-Methyladenosine (mA) is the most frequent modification in eukaryotic messenger RNA (mRNA) and its cellular processing and functions are regulated by the reader proteins YTHDCs and YTHDFs. However, the mechanism of mA recognition by the reader proteins is still elusive. Here, we investigate this recognition process by combining atomistic simulations, site-directed mutagenesis, and biophysical experiments using YTHDC1 as a model.

Effect of HIF1α on the TRPC6 channel of glomerular podocytes under chronic hypoxia.

Background: Chronic hypoxia plays an important role in the initiation and progression of chronic renal disease. The pathogenic role of chronic hypoxia in tubulointerstitial injury has been investigated widely, but little is known about acute hypoxia implications in glomerular damage. In this study, we investigated the effect of chronic hypoxia on transient receptor potential cation channel 6 (TRPC6) and the underlying mechanism in cultured human podocytes.

Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ.

Biological processes are regulated by intermolecular interactions and chemical modifications that do not affect protein levels, thus escaping detection in classical proteomic screens. We demonstrate here that a global protein structural readout based on limited proteolysis-mass spectrometry (LiP-MS) detects many such functional alterations, simultaneously and in situ, in bacteria undergoing nutrient adaptation and in yeast responding to acute stress. The structural readout, visualized as structural barcodes, captured enzyme activity changes, phosphorylation, protein aggregation, and complex formation, with the resolution of individual regulated functional sites such as binding and active sites.

Structural and Dynamic Insights into Redundant Function of YTHDF Proteins.

Three YTH-domain family proteins (YTHDF1, YTHDF2, and YTHDF3) recognize the N-methyladenosine (mA) modification of mRNA in cells. However, the redundancy of their cellular functions has been disputed. We investigate their interactions with mA-containing RNA using X-ray crystallography and molecular dynamics (MD).

Repulsive Soft-Core Potentials for Efficient Alchemical Free Energy Calculations.

In alchemical free energy (FE) simulations, annihilation and creation of atoms are generally achieved with the soft-core potential that shifts the interparticle separations. While this soft-core potential eliminates the numerical instability occurring near the two end states of the transformation, it makes the hybrid Hamiltonian vary nonlinearly with respect to the parameter λ, which interpolates between the Hamiltonians representing the two end states. This complicates FE estimation by Bennett acceptance ratio (BAR), free energy perturbation (FEP), and thermodynamic integration (TI) methods, thus reducing their calculation efficiency.

Selectively Disrupting mA-Dependent Protein-RNA Interactions with Fragments.

We report a crystallographic analysis of small-molecule ligands of the human YTHDC1 domain that recognizes N6-methylated adenine (mA) in RNA. The 30 binders are fragments (molecular weight < 300 g mol) that represent 10 different chemotypes identified by virtual screening. Despite the structural disorder of the binding site loop (residues 429-439), most of the 30 fragments emulate the two main interactions of the -NHCH group of mA.

Flexible Binding of mA Reader Protein YTHDC1 to Its Preferred RNA Motif.

-Methyladenosine (mA) is the most prevalent chemical modification in human mRNAs. Its recognition by reader proteins enables many cellular functions, including splicing and translation of mRNAs. However, the binding mechanisms of mA-containing RNAs to their readers are still elusive due to the unclear roles of mA-flanking ribonucleotides.