化学•材料最新文献

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

The FDA's directive to deal with delayed confirmatory trials: lessons from pralatrexate and belinostat for T-cell lymphoma.

Despite extensive research on the sequence-determined self-assembly of both pathogenic and nonpathogenic proteins, the question of how the sequence identity would influence the coassembly or cross-seeding of diverse proteins without distinct sequence similarity remains largely unanswered. Here, we demonstrate that the rapid coaggregation of proteins with negligible sequence similarity is fundamentally governed by preferred heteromeric interactions between their partially unfolded states via the gain of additional charge complementarity and hydrophobic interactions. The partial loss of intramolecular interactions and concurrent gain of non-native intrinsically disordered regions with sticky groups become crucial for both aggressive heteromeric primary nucleation and secondary nucleation events. The results signify the direct relevance of sequence-independent conformational cross-talk between diverse proteins to the foundational events required for the growth of biological multiprotein amyloid deposits.

Within the framework of liquid-liquid phase separation (LLPS), biomolecular condensation orchestrates vital cellular processes, and its dysregulation is implicated in severe pathological conditions. Recent studies highlight the role of intrinsically disordered proteins (IDPs) in LLPS, yet the influence of microenvironmental factors has remained a puzzling factor. Here, via computational simulation of the impact of solution conditions on LLPS behavior of neurologically pathogenic IDP Aβ40, we chanced upon a salt-driven reentrant condensation phenomenon, wherein Aβ40 aggregation increases with low salt concentrations (25-50 mM), followed by a decline with further salt increments. An exploration of the thermodynamic and kinetic signatures of reentrant condensation unveils a nuanced interplay between protein electrostatics and ionic strength as potential drivers. Notably, the charged residues of the N-terminus exhibit a nonmonotonic response to salt screening, intricately linked to the recurrence of reentrant behavior in hydrophobic core-induced condensation. Intriguingly, our findings also unveil the reappearance of similar reentrant condensation phenomena under varying temperature conditions. Collectively, our study illuminates the profoundly context-dependent nature of Aβ40s liquid-liquid phase separation behavior, extending beyond its intrinsic molecular framework, where microenvironmental cues wield significant influence over its aberrant functionality.

Tire wear particles (TWPs), generated from tire abrasion, contribute significantly to environmental contamination. The toxicity of TWPs to organisms has raised significant concerns, yet their effects on terrestrial plants remain unclear. Here, we investigated the long-term impact of pristine and naturally aged TWPs on water spinach (Ipomoea aquatica) and its rhizospheric soil. The results indicated that natural aging reduced the toxicity of TWPs, as evidenced by decreased levels of polycyclic aromatic hydrocarbons (PAHs) in soil and TWPs themselves. Consequently, aged TWPs were found to enhance the plant growth and chlorophyll content, whereas pristine TWPs increased the plant stress. Furthermore, aged TWPs improved soil organic matter (SOM) and total organic carbon (TOC), thereby boosting the microbial enzymes involved in nitrogen cycling. Metabolomic analysis revealed that aged TWPs upregulated key pathways related to carbon and nitrogen metabolism, enhancing plant growth and stress responses. Additionally, rhizosphere bacterial diversity was higher under aged TWPs, favoring nutrient-cycling taxa such as Acidobacteriota and Nitrospirota. Pristine TWPs may lead to overproliferation of certain dominant species, thereby reducing microbial diversity in soil, which could ultimately compromise the soil health. These findings contribute to a deeper understanding of the mechanisms underlying TWP toxicity in plants and highlight the necessity for further research on the impact of aged TWPs across various plant species over different exposure durations for comprehensive risk assessment.

The research presented in this paper focuses on the EWS-FLI1 oncoprotein, a critical factor in Ewing sarcoma, a rare and lethal cancer primarily affecting children and young adults. Through molecular dynamics and quantum mechanics analyses, the study explores the reactivity properties of six snapshots of the EWS-FLI1 oncoprotein, aiming to contribute to the development of targeted therapies. The investigation emphasizes the significance of understanding the molecular behavior of EWS-FLI1 for effective treatment development, utilizing computational methods such as density functional theory. The findings suggest that EWS-FLI1 is a compact, electrophilic protein with localized reactive sites, providing valuable insights for potential drug development and enhancing our knowledge of Ewing sarcoma for targeted treatments.

Methanogenic archaea are known to play a crucial role in the biogeochemical cycling of arsenic (As); however, the molecular basis of As transformation mediated by methanogenic archaea remains poorly understood. Herein, the characterization of the redox transformation and methylation of As by Methanosarcina acetivorans, a model methanogenic archaeon, is reported. M. acetivorans was demonstrated to mediate As(V) reduction via a cytoplasmic As reductase (ArsC) in the exponential phase of methanogenic growth and to methylate As(III) via a cytoplasmic As(III) methyltransferase (ArsM) in the stationary phase. Characterization of the ArsC-catalyzed As(V) reduction and the ArsM-catalyzed As(III) methylation showed that a thioredoxin (Trx) encoded by MA4683 was preferentially utilized as a physiological electron donor for ArsC and ArsM, providing a redox link between methanogenesis and As transformation. The structures of ArsC and ArsM complexed with Trx were modeled using AlphaFold-Multimer. Site-directed mutagenesis of key cysteine residues at the interaction sites of the complexes indicated that the archaeal ArsC and ArsM employ evolutionarily distinct disulfide bonds for interacting with Trx compared to those used by bacterial ArsC or eukaryotic ArsM. The findings of this study present a major advance in our current understanding of the physiological roles and underlying mechanism of As transformation in methanogenic archaea.

¹⁹F NMR spectroscopy has recently witnessed a resurgence as an attractive analytical tool for the study of the structure and dynamics of biomolecules in vitro and in cells, despite reports of its applications in biomolecular NMR since the 1970s. The high gyromagnetic ratio, large chemical shift dispersion, and complete absence of the spin 1/2 ¹⁹F nucleus from biomolecules results in background-free, high-resolution ¹⁹F NMR spectra. The introduction of ¹⁹F probes in a few selected locations in biomolecules reduces spectral crowding despite its increased line width in comparison to typical ¹H NMR line widths and allows rapid site-specific measurements from simple 1D spectra alone. The design and synthesis of novel ¹⁹F probes with reduced line widths and increased chemical shift sensitivity to the surrounding environment, together with advances in labeling techniques, NMR methodology, and hardware, have overcome several drawbacks of ¹⁹F NMR spectroscopy. The increased interest and widespread use of ¹⁹F NMR spectroscopy of biomolecules is gradually establishing it as a sensitive and high-resolution probe of biomolecular structure and dynamics, supplementing traditional ¹³C/¹⁵N-based methods. This Review focuses on the advances in ¹⁹F solution NMR spectroscopy of proteins in the past 5 years, with an emphasis on novel ¹⁹F tags and labeling techniques, NMR experiments to probe protein structure and conformational dynamics in vitro, and in-cell NMR applications.

Influenza B viruses have cocirculated during most seasonal flu epidemics and can cause significant human morbidity and mortality due to their rapid mutation, emerging drug resistance, and severe impact on vulnerable populations. The influenza B M2 proton channel (BM2) plays an essential role in viral replication, but the mechanisms behind its symmetric proton conductance and the involvement of a second histidine (His27) cluster remain unclear. Here we performed membrane-enabled continuous constant-pH molecular dynamics simulations on wildtype BM2 and a key H27A mutant channel to explore its pH-dependent conformational switch. Simulations captured the activation as the first histidine (His19) protonates and revealed the transition at lower pH values compared to AM2 is a result of electrostatic repulsions between His19 and preprotonated His27. Crucially, we provided an atomic-level understanding of the symmetric proton conduction by identifying preactivating channel hydration in the C-terminal portion. This research advances our understanding of the function of BM2 function and lays the groundwork for further chemically reactive modeling of the explicit proton transport process as well as possible antiflu drug design efforts.