National Science Review最新文献

Although adeno-to-squamous transition (AST) has been observed in association with resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in clinic, its causality, molecular mechanism and overcoming strategies remain largely unclear. We here demonstrate that squamous transition occurs concomitantly with TKI resistance in PC9-derived xenograft tumors. Perturbation of squamous transition via DNp63 overexpression or knockdown leads to significant changes in TKI responses, indicative of a direct causal link between squamous transition and TKI resistance. Integrative RNA-seq, ATAC-seq analyses and functional studies reveal that FOXA1 plays an important role in maintaining adenomatous lineage and contributes to TKI sensitivity. FOXM1 overexpression together with FOXA1 knockout fully recapitulates squamous transition and TKI resistance in both PC9 xenografts and patient-derived xenograft (PDX) models. Importantly, pharmacological inhibition of RAPGEF3 combined with EGFR TKI efficiently overcomes TKI resistance, especially in RAPGEF3^high PDXs. Our findings provide novel mechanistic insights into squamous transition and therapeutic strategy to overcome EGFR TKI resistance in lung cancer.

Lipid droplets (LDs) are the major sites of lipid and energy homeostasis. However, few LD biogenesis proteins have been identified. Using model microalga Chlamydomonas, we show that ABHD1, an α/β-hydrolase domain-containing protein, is localized to the LD surface and stimulates LD formation through two actions: one enzymatic and one structural. The knockout mutants contained similar amounts of triacylglycerols (TAG) but their LDs showed a higher content of lyso-derivatives of betaine lipid diacylglyceryl-N,N,N-trimethylhomoserine (DGTS). Over-expression of ABHD1 increased LD abundance and boosted TAG content. Purified recombinant ABHD1 hydrolyzed lyso-DGTS, producing a free fatty acid and a glyceryltrimethylhomoserine. In vitro droplet-embedded vesicles showed that ABHD1 promoted LD emergence. Taken together, these results identify ABHD1 as a new player in LD formation by its lipase activity on lyso-DGTS and by its distinct biophysical property. This study further suggests that lipases targeted to LDs and able to act on their polar lipid coat may be interesting tools to promote LD assembly in eukaryotic cells.

Constructing 3D functional covalent organic frameworks (COFs) with both robust linkage and planar macrocycle building blocks still remains a challenge due to the difficulty in adjusting both the crystallinity and the dominant 2D structures. In addition, it is also challenging to selectively convert inert C(sp³)-H bonds into value-added chemicals. Herein, robust 3D COFs, USTB-28-M (M=Co, Ni, Cu), have been polymerized from the nucleophilic aromatic substitution reaction of D _3h-symmetric 2,3,6,7,14,15-hexahydroxyltriptycene with D _4h-symmetric hexadecafluorophthalocyanine (MPcF₁₆) under solvothermal conditions. These chemically stable dioxin-linked COFs show isostructural tbo topology made up of three kinds of polyhedron subunits, exhibiting high Brunauer-Emmett-Teller surface areas of ≤1477 m² g^-1. In particular, the multiple polyhedron subunits in USTB-28-M could trap N-hydroxyphthalimide at their corners for easily forming stable phthalimide-N-oxyl radicals under visible-light irradiation. The generated radicals efficiently promote the aerobic oxidation of alkyl benzenes with an inert C(sp³)-H bond into various ketones. Among the three investigated COFs, the USTB-28-Co radical initiator exhibits the best photocatalytic oxidation activity, converting ethylbenzene into acetophenone with a turnover frequency of 63 h^-1, which is much higher than those of the monomer CoPcF₁₆ (8 h^-1) and 2D dioxin-linked counterparts (13 h^-1). This is due to the much prolonged lifetime of the excited state for USTB-28-Co based on the femtosecond transient absorption result. The present work not only presents 3D functional COFs with robust connection and permanent porosity, but also illustrates the uniqueness of porous structures of 3D COFs for high-performance photocatalysis.

Solid additive engineering has been intensively explored on morphology tuning for highly efficient all-polymer solar cells (all-PSCs), a promising photovoltaic technology towards multi-scenario application. Although the nano-fibrillar network of the active layer induced by additive treatment is confirmed as the key factor for power conversion efficiency (PCE) of all-PSCs, its formation mechanism is not clearly revealed, for lack of precise and convincing real-time observation of crystallization and phase separation during the liquid-to-solid transition process of spin-coating. Herein we report an in-situ grazing incidence wide-angle/small-angle X-ray scattering (GIWAXS/GISAXS) screening that reveals the fact that naphthalene derived solid additives can suppress the aggregation of the polymer acceptor (PY-IT) at the beginning stage of spin coating, which provides sufficient time and space for the polymer donor (PM6) to form the fibril structure. Moreover, guided by this knowledge, a ternary all-polymer system is proposed, which achieves cutting-edge level PCEs for both small-area (0.04 cm²) (also decent operational stability) and large-area (1 cm²) devices.

The Mpox virus (MPXV) has emerged as a formidable orthopoxvirus, posing an immense challenge to global public health. An understanding of the regulatory mechanisms of MPXV infection, replication and immune evasion will benefit the development of novel antiviral strategies. Despite the involvement of G-quadruplexes (G4s) in modulating the infection and replication processes of multiple viruses, their roles in the MPXV life cycle remain largely unknown. Here, we found a highly conservative and stable G4 in MPXV that acts as a positive regulatory element for viral immunodominant protein expression. Furthermore, by screening 42 optically pure chiral metal complexes, we identified the Λ enantiomer of a pair of chiral helical compounds that can selectively target mRNA G4 and enhance expression of the 39-kDa core protein encoded by the MPXV A5L gene. Mechanistically, RNA G4-specific helicase DHX36 inhibits A5L protein expression by unwinding G4s. In contrast, MH3 Λ enhanced mRNA stability by specifically targeting G4 structures and subsequently increased protein expression. Furthermore, given the pivotal role of the 39-kDa core protein in activating immune responses and facilitating virion maturation, modulation of MPXV G4 folding by MH3 Λ exhibited inhibitory effects on MPXV replication through enhancing the immune response. Our findings underscore the critical involvement of G4 in the MPXV life cycle and offer potential avenues for developing antiviral drugs that target G4.

The incorporation of polymeric insulators has led to notable achievements in the field of organic semiconductors. By altering the blending concentration, polymeric insulators exhibit extensive capabilities in regulating molecular configuration, film crystallinity, and mitigation of defect states. However, current research suggests that the improvement in such physical properties is primarily attributed to the enhancement of thin film morphology, an outcome that seems to be an inevitable consequence of incorporating insulators. Herein, we report a general and completely new effect of polymeric insulators in organic semiconductors: the insulator-donor electron wavefunction coupling effect. Such insulators can couple with donor polymers to reduce the energy barrier level and facilitate intramolecular electron transport. Besides the morphological effects, we observed that this coupling effect is another mechanism that can significantly enhance electron mobility (up to 100 times) through the incorporation of polymeric insulators in a series of donor systems. With this effect, we proposed a polymeric insulator blending approach to fabricate state-of-the-art pseudo-bilayer organic solar cells, and the PM6/L8-BO device exhibits a high efficiency of 19.50% (certificated 19.18%) with an improved interfacial electron transport property. This work not only offers a novel perspective on the quantum effect of polymeric insulators in organic semiconductors, but also presents a simple yet effective method for enhancing the performance of organic solar cells.