Advanced Science最新文献

Fano resonances in photonics arise from the coupling and interference between two resonant modes in structures with broken symmetry. They feature an uneven and narrow and tunable lineshape and are ideally suited for optical spectroscopy. Many Fano resonance structures have been suggested in nanophotonics over the last ten years, but reconfigurability and tailored design remain challenging. Herein, an all-optical "pick-and-place" approach aimed at assembling Fano metamolecules of various geometries and compositions in a reconfigurable manner is proposed. Their coupling behavior by in situ dark-field scattering spectroscopy is studied. Driven by a light-directed opto-thermoelectric field, silicon nanoparticles with high-quality-factor Mie resonances (discrete states) and low-loss BaTiO₃ nanoparticles (continuum states) are assembled into all-dielectric heterodimers, where distinct Fano resonances are observed. The Fano parameter can be adjusted by changing the resonant frequency of the discrete states or the light polarization. Tunable coupling strength and multiple Fano resonances by altering the number of continuum states and discrete states in dielectric heterooligomers are also shown. This work offers a general design rule for Fano resonance and an all-optical platform for controlling Fano coupling on demand.

Recent advancements in microRNAs (miRNAs) research have revealed their key roles in both normal physiological processes and pathological conditions, leading to potential applications in diagnostics and therapeutics. However, the path forward is fraught with several scientific and technical challenges. This review article briefly explores the milestones of the discovery, biogenesis, functions, and application for clinical diagnostic and therapeutic strategies of miRNAs. The potential challenges and future directions are also discussed to fully harness their capabilities.

ℤ-classified higher-order topological insulators (HOTIs) with chiral-symmetric higher-order topological phases protected by multipole chiral numbers (MCNs) have attracted extensive interest recently. However, how to design artificial ℤ-classified HOTIs with multiple topological phases remains an unresolved issue. Here, multiorbital degrees of freedom are introduced to acoustic crystals and the various methods of topological phase transitions are achieved for the orbital ℤ-classified HOTIs. Experimental results demonstrate the realization the coexistence of corner modes with distinct mechanisms within one single model. This provides a pathway for finding ℤ-classified with large MCNs independent of long-range coupling. Additionally, a universal approach is introduced here to fabricate topological bound states in the continuum derived from the discrepant onsite energy of degenerate p-orbitals. These findings provide new insights into the study of topological wave physics using orbital degrees of freedom and may pave the way for designing innovative orbital topological devices for sensing and computing.

The initiation of calcium oxalate (CaOx) kidney stone formation is highly likely to stem from injury to the renal tubular epithelial cells (RTECs) induced by stimulation from an aberrant urinary environment. CHAC1 plays a critical role in stress response mechanisms by regulating glutathione metabolism. Endoplasmic reticulum (ER) stress and ferroptosis are demonstrated to be involved in stone formation. This study attempted to elucidate the mechanism of ER stress-dependent ferroptosis and the role of CHAC1 in CaOx kidney stones. Here, regulating ER stress and CHAC1 expression are performed in in vivo and in vitro stone models. These findings indicated that 4-Phenylbutyric acid (4-PBA)treatment and CHAC1 deficiency alleviated the ferroptotic status, including restoring GSH content, suppressing Fe²⁺ and lipid peroxidation accumulation, as well as regulating ferroptosis-related proteins. Notably, 4-PBA treatment and CHAC1 deficiency both attenuated oxidative damage, improved renal function, importantly, decreased crystal deposition. Additionally, ChIP-seq and ChIP-qPCR analyses demonstrated that CHAC1 is the vital downstream target gene of ATF4. The results indicated that ATF4 depletion inhibited the upregulation of CHAC1 and pro-ferroptotic response induced by Ox stimulation. Overall, ATF4/CHAC1 axis mediating ER stress-dependent ferroptosis may be a promising research direction for identifying potential strategy to prevent and treat CaOx kidney stones.

Triple-negative breast cancer (TNBC) is a difficulty and bottleneck in the clinical treatment of breast cancer due to a lack of effective therapeutic targets. Herein, we first report that secernin 2 (SCRN2), an uncharacterized gene in human cancer, acts as a novel tumor suppressor in TNBC to inhibit cancer progression and enhance therapeutic sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. SCRN2 is downregulated in TNBC through chaperone-mediated autophagic degradation, and its downregulation is associated with poor patient prognosis. Moreover, SCRN2 impedes the proteasomal degradation of histone-lysine N-methyltransferase 2C (KMT2C) by recruiting Bcl2-associated athanogene 2 to block the interaction of KMT2C with E3 ubiquitin-protein ligase CHIP. Consistently, SCRN2 transcriptionally activates Bcl2-modifying factor by amplifying histone H3 monomethylation at lysine 4 at its enhancer, thereby inducing intrinsic apoptosis. Notably, KMT2C knockdown restores the impaired TNBC progression caused by SCRN2 overexpression both in vitro and in vivo. Furthermore, SCRN2 decreases the expression of key DNA repair-related genes and induces endogenous DNA damage, thus conferring therapeutic sensitivity of TNBC cells to PARP inhibition.   Collectively, these findings identify SCRN2 as a novel suppressor of TNBC, reveal its mechanism of action, and highlight its potential role in TNBC therapy.

Current treatments for ulcerative colitis (UC) remain limited, highlighting the need for novel therapeutic strategies. Trilobatin (TLB), a naturally derived food additive, exhibits potential anti-inflammatory properties. In this study, a dextran sulfate sodium (DSS)-induced animal model is used to investigate the effects of TLB on UC. It is found TLB significantly alleviates DSS-induced UC in mice, as evidenced by a reduction in the disease activity index, an increase in colon length, improvement in histopathological lesions. Furthermore, TLB treatment results in a decrease in proinflammatory cytokines and an increase in anti-inflammatory cytokines. TLB mitigates UC by modulating the intestinal microbiota, particularly Akkermansia, which enhances tryptophan metabolism and upregulates the production of xanthurenic acid (XANA). To confirm the role of TLB-induced microbiota changes, experiments are performed with pseudogerm-free mice and fecal transplantation. It is also identified XANA as a key metabolite that mediates TLB's protective effects. Both TLB and XANA markedly activate the aromatic hydrocarbon receptor (AhR). Administration of an AhR antagonist abrogates their protective effects, thereby confirming the involvement of AhR in the underlying mechanism. In conclusion, the study reveals a novel mechanism through which TLB alleviates UC by correcting microbiota imbalances, regulating tryptophan metabolism, enhancing XANA production, and activating AhR.

Intrahepatic cholangiocarcinoma (ICC), a formidable challenge in oncology, demands innovative biomarkers and therapeutic targets. This research highlights the importance of the circular RNA (circRNA) circPCSK6 and its peptide derivative circPCSK6-167aa in ICC. CircPCSK6 is significantly downregulated in both ICC patients and mouse primary ICC models, and its lower expression is linked to adverse prognosis, highlighting its pivotal role in ICC pathogenesis. Functionally, this study elucidates the regulatory effect of circPCSK6-167aa on IκBα ubiquitination within the NF-κB pathway, which is mediated by its competitive binding to the E3 ligase RBBP6. This complex interaction leads to reduced activation of the NF-κB pathway, thereby curbing tumor cell proliferation, migration, invasion, stemness, and hepatic-lung metastasis in vivo. This groundbreaking discovery expands the understanding of circRNA-driven tumorigenesis through atypical signaling pathways. Additionally, this investigation identified EIF4A3 as a detrimental regulator of circPCSK6, exacerbating ICC malignancy. Importantly, by leveraging patient-derived xenograft (PDX), organoids, and organoid-derived PDX models, higher levels of circPCSK6-167aa enhance sensitivity to gemcitabine, indicating its potential to improve the effectiveness of chemotherapy. These insights emphasize the therapeutic promise of targeting circPCSK6-167aa, offering vital biological insights and clinical directions for developing cutting-edge therapeutic approaches, thus revealing innovative strategies and targets for future treatments.

Although a fraction of functional peptides concealed within long non-coding RNAs (lncRNAs) is identified, it remains unclear whether lncRNA-encoded peptides are involved in the malignancy of cervical cancer (CC). Here, a 92-amino acid peptide is discovered, which is named TUBORF, encoded by lncRNA TUBA3FP and highly expressed in CC tissues. TUBORF inhibits ferroptosis to promote the malignant proliferation of CC cells. Mechanistically, human papillomavirus (HPV) oncogenes E6 and E7 upregulate TUBORF through CREB-binding protein (CBP)/E1A-binding protein p300 (p300)-mediated histone H3 lysine 27 acetylation (H3K27ac) of lncTUBA3FP enhancer. Furthermore, E6 and E7 elevate and recruit acetyltransferase establishment of sister chromatid cohesion N-acetyltransferase 1 (ESCO1) to bind to and acetylate TUBORF, which facilitates the degradation of immunity-related GTPase Q (IRGQ) via a ubiquitin-proteasome pathway, resulting in the inhibition of ferroptosis and promotion of the malignant proliferation of CC cells. Importantly, silencing ESCO1 or TURORF amplifies anticancer effects by paclitaxel both in CC cells and in vivo. These novel findings reveal oncopeptide TUBORF and its acetyltransferase ESCO1 as important regulators of ferroptosis and tumorigenesis during cervical cancer pathogenesis and establish the scientific basis for targeting these molecules for treating CC.

Magnetic resonance imaging (MRI) is a cornerstone technology in clinical diagnostics and in vivo research, offering unparalleled visualization capabilities. Despite significant advancements in the past century, traditional ¹H MRI still faces sensitivity limitations that hinder its further development. To overcome this challenge, hyperpolarization methods have been introduced, disrupting the thermal equilibrium of nuclear spins and leading to an increased proportion of hyperpolarized spins, thereby enhancing sensitivity by hundreds to tens of thousands of times. Among these methods, hyperpolarized (HP) ¹²⁹Xe MRI, also known as ultrasensitive ¹²⁹Xe MRI, stands out for achieving the highest polarization enhancement and has recently received clinical approval. It effectively tackles the challenge of weak MRI signals from low proton density in the lungs. HP ¹²⁹Xe MRI is valuable for assessing structural and functional changes in lung physiology during pulmonary disease progression, tracking cells, and detecting target molecules at pico-molar concentrations. This review summarizes recent developments in HP ¹²⁹Xe MRI, including its physical principles, manufacturing methods, in vivo characteristics, and diverse applications in biomedical, chemical, and material sciences. In addition, it carefully discusses potential technical improvements and future prospects for enhancing its utility in these fields, further establishing HP ¹²⁹Xe MRI's importance in advancing medical imaging and research.

Metabolic disorders have been identified as one of the causes of drug-induced liver injury; however, the direct regulatory mechanism regarding this disorder has not yet been clarified. In this study, a single regulatory mechanism of small molecule kinase inhibitors, with crizotinib as the representative drug is elucidated. First, it is discovered that crizotinib induced aberrant lipid metabolism and apoptosis in the liver. A mechanistic study revealed that crizotinib treatment promoted the accumulation of squalene epoxidase (SQLE) by inhibiting autophagosome-lysosome fusion which blocked the autophagic degradation of SQLE. A maladaptive increase in SQLE led to disturbances in cholesterol and sphingolipid metabolism via an enzymatic activity-dependent manner. Abnormal cholesterol results in both steatosis and inflammatory infiltration, and disturbances in sphingolipid metabolism promote cell apoptosis by inducing lysosomal membrane permeabilization. The restoration of the level or activity of SQLE ameliorated steatosis and hepatocyte injury. The autophagy activator known as metformin or the SQLE enzymatic inhibitor known as terbinafine has potential clinical use for alleviating crizotinib hepatotoxicity.