ACS Publications最新文献

Colorectal cancer (CRC) is the second leading cause of death in the United States in the adult population. When detected at early stages, the survival rate is higher than 70% but when diagnosed at a metastatic stage, the 5-year survival rate significantly declines to 15%. In recent years, immunotherapy has shown promising results in a selective patient population with advanced or metastatic CRC with microsatellite instability (MSI) and mismatch repair (MMR). Hydrogels are a growing field of research to improve the delivery of monoclonal antibodies. In this work, a gellan gum-based (GG) hydrogel noncovalently cross-linked using trilysine (TLA) was characterized for its drug release and diffusion properties. A partial release of the checkpoint inhibitor anti-programmed death-1 (aPD-1) was observed with an almost 40% cumulative release within the first 24 h. FRAP analysis showed varying diffusion rates (μm²/s) for Atto 488-IgG (2.63 ± 0.32), 60-76 kDa FITC-Dextran (2.65 ± 0.31), and 150 kDa FITC-Dextran (2.80 ± 0.83), with a 70-90% recovery postbleaching. Additionally, intratumoral delivery of aPD-1 was evaluated in a CRC mouse (C57BL/6) tumor model inoculated with MC38 cells. Quantification of aPD-1 in the plasma and tumor showed an increase in concentration by 1.5- and 3-fold, respectively, when delivered using the intratumoral hydrogel route in comparison with either intraperitoneal (i.p.) or drug-free intratumoral administration. Overall, this noncytotoxic hydrogel provided an alternative delivery route for aPD-1, maximizing its presence both in circulating blood and in the treatment site, serving as a simple localized delivery system in CRC.

Although HPV vaccines currently in use with aluminum adjuvants demonstrate significant stimulation of humoral immunity, the weak cellular immune response that they elicit indicates a need for further improvement. On the other hand, not only the poor immune promotion effect inducted by a single adjuvant but also finding an efficient antigen and adjuvant codelivery carriers need to be addressed. Here, a double Toll like receptor agonist (R848, Poly(I:C)) and antigen of HPV16 L1 pentamer were codelivered by using calcium phosphate (CaP) mineralized PLGA microparticles. The results of in vivo experiments indicate that the secretion of specific antibodies and neutralizing antibodies was significantly increased, and T/B cells in lymph nodes were effectively activated. Of particular note is the formation of more germinal centers in vivo stimulated by the formulation. In addition, the cellar immunity is also promoted with a higher level of cytokines secretion as IFN-γ, TNF-α, and IL-12p70. Therefore, the as-prepared formulations are a potential platform for preventing the HPV virus infection.

The use of generative machine learning models, trained on the experimentally resolved structures deposited in the protein data bank, is an attractive approach to sampling conformational ensembles of proteins. However, the ensembles generated by these models lack time scale or causal information. We use the structural ensembles generated from AlphaFold2 at a range of MSA depths to parametrize the potential of mean force of an overdamped, memory-free, coarse-grained Langevin equation. This approach couples the AlphaFold2 ensembles to a causal model, allowing us to estimate the time scales spanned by the ensembles generated at each MSA depth. Performing this analysis on six variants of HIV-1 protease, we confirm an inverse relationship between MSA depth and the time scale of an ensemble's conformational fluctuations. The MSA depth essentially serves as a conformational restraint, and AlphaFold2 is generally able to probe time scales at or below those seen in microsecond-long, unbiased molecular dynamics simulations. We conclude by generalizing this approach to other generative structural ensemble-prediction methods as well as cofolding models, in this case, the biologically functional HIV-1 protease dimer.

The integration of excellent performance and facile closed-loop recycling of poly(butylene terephthalate) (PBT) copolyesters remains a significant challenge. Herein, a biobased rigid diol (denoted as HT) was prepared by an acid-catalyzed acetalization reaction from 5-hydroxymethylfurfural (HMF) and trimethylolpropane (TMP). HT was copolymerized with PBT to prepare a series of PBT_xTT_y copolyesters with high M_n up to 45.5 kDa. The insertion of HT led to excellent thermomechanical and UV shielding properties, such as the glass transition temperature (T_g of 47.3 °C) and strength (43 MPa) of PBT₈₀TT₂₀ outdistancing those of PBT. More importantly, the acetal-based HT enabled dual closed-loop recycling pathways for PBT_xTT_y copolyesters via selective cleavage of acetal or ester bonds, allowing the recovery of structures terminated with aldehyde/hydroxyl end groups or PBT. Both recycled products could be repolymerized. Overall, HT is an effective biobased precursor that can prepare PBT-based copolyesters with excellent physical properties and dual closed-loop recyclability.

Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP) is an ultrarare, autosomal recessive form of Hereditary Spastic Paraplegia (HSP), caused by mutations in the ALS2 gene, which encodes the protein ALSIN. In a previous study, we proposed a personalized therapeutic strategy for an Italian IAHSP patient (AO), aiming to correct the aberrant function of the R1611W mutant ALSIN using Menatetrenone (MK4). While our results supported compassionate-use approval for a patient-specific therapeutic regimen, further investigation was needed to highlight the treatment's benefits in the absence of tractable biophysical assays and in vivo models. In this respect, we first characterized MK4's interaction with the mutation site through Molecular Dynamics simulations. Next, we established and characterized a skin fibroblast cell line derived from patient AO. We analyzed the expression and stability of the mutant ALSIN protein in AO's fibroblasts and observed elevated oxidative stress levels. Using advanced microscopy and automated image analysis, we identified a characteristic mitochondrial phenotype associated with AO's IAHSP. One specific morphological parameter of mitochondria (Mean Branch Diameter) accurately reflected the IAHSP phenotype and was selected as a cell marker. Treatment of IAHSP fibroblasts with MK4 highlighted the rescue of Mean Branch Diameter and ALSIN levels, supporting cellular efficacy. Overall, this work presents an approach that integrates computational and cell-based methodologies to overcome the data scarcity challenges of drug discovery in rare diseases. Our study provides a framework for preclinical, alternative drug discovery programs in monogenic rare disorders such as IAHSP.

Molecular self-assembly creates complex structures through noncovalent interactions. Synthetic fuel-driven systems mimic biology, yet the effects of subtle design changes, particularly hydrophobic groups such as alkyl chains, are still not well understood. This study showed that the alkyl chain length critically influences the dynamic assembly of short peptides. Z-capped peptides C3 and C6, composed of l-phenylalanine and -glutamic acid, with L-aspartic acid as the reactive site and alkylamide groups of varying lengths at the C-terminus, have been observed to form metastable aggregates via intramolecular anhydride formation during a chemically fueled reaction cycle. We elucidated that the difference in alkyl chain length resulted in either highly dynamic assemblies or delayed structural dissolution. Our findings provide a comprehensive understanding of these observations, illustrating how rational peptide design enable precise control over nanostructure properties and catalytic lifetimes.

Carbon black (CB) and silica are the most widely used reinforcing fillers for rubber composites. However, their molecular-scale surface differences and quantitative effects on interfacial interactions remain unclear, hindering the rational design of high-performance materials. In this study, CB- and silica-filled composites with equivalent interfacial areas were prepared to experimentally compare their interfacial interaction strengths. Molecular dynamics simulations using trans-3-hexene as probe molecules subsequently quantified the interaction strengths of CB and silica, showing good agreement with the experiments. Further analyses of surface energy distribution and the dependence of binding energy on adsorption distance revealed that the molecular-scale surface characteristics differ in three key aspects: adsorption energy, energy heterogeneity, and binding energy-distance correlation, thereby accounting for the inferior performance of silica-NR interfaces despite the presence of covalent bonding. On the basis of the simulation results, experiments under equivalent interfacial adsorption energies confirmed that interfacial physical adsorption dominates the overall interfacial interactions and validated the critical role of specific strong binding sites. In this study, an efficient molecular simulation methodology was established to overcome experimental limitations, and by integrating simulations with experiments, the influence of filler surface characteristics on interfacial interactions was elucidated, providing guidance for rational composite design.

Coke deposition is a key obstructive problem to be solved in the production of ethylene via steam cracking; moreover, the removal of graphitic carbon in coke is particularly difficult. A strategy integrating Fe-Mn bimetallic synergy at the B-site with oxygen vacancy engineering in perovskites was proposed to accelerate the catalytic conversion of coke/graphitic carbon via steam. DFT simulations and experimental results revealed that Mn incorporation induces dynamic lattice reconstruction of SrFeO₃, generating abundant oxygen vacancies that enhance oxygen ion mobility and H₂O adsorption. The interaction between Fe and Mn atoms has been observed to narrow the band gap, strengthen the hybridization of the O-2p and Fe-3d orbitals, induce electron delocalization, regulate the transfer of electrons from surrounding atoms to the adsorbed oxygen species, and thus accelerate the desorption and activation of *OH and the transfer of *O^2-, which provides the possible reaction pathway for the transformation of graphitic carbon into CO or CO₂. At 900 °C, the conversion of graphitic carbon and coke with steam catalyzed by SrFe_0.1Mn_0.9O₃ reached 60.61% and 99.87%, respectively. This study provides an active material that facilitates the in situ online decoking strategy for catalytic coatings on steam cracking furnace tubes along with theoretical insights into the underlying reaction mechanism.

Elastin-like polypeptides (ELPs) are a family of recombinant biopolymers that offer precise sequence control. Six ELP sequences with systematically varied hydrophobicity and charge were designed to investigate how hydrophobicity and charge influence dilute solution phase behavior in 0-40 mol % ethanol and 0-200 mM sodium chloride. Both hydrophobic and hydrophilic ELPs in this study display four characteristic regimes in their phase diagrams: lower critical solution temperature (LCST)-like transitions at low ethanol concentrations, a one-phase region at low-to-moderate ethanol concentrations, upper critical solution temperature (UCST)-like transitions at intermediate ethanol concentrations, and full miscibility at high ethanol concentrations. Despite an identical overall composition with a previously studied ELP sequence, differences in sequence and molecular weight significantly impact phase behavior in ethanol/water mixtures. These results reveal both sequence dependence in the phase behavior of ELPs and universal cononsolvency behavior in uncharged hydrophobic and hydrophilic ELPs.